NEw developments IN gynecological Oncology

NEw developments IN gynecological Oncology
highlights from the american society of clinical oncology (ascO) congress 2019 in chicago

ASCO 2019 Highlights from chicago
Author overview (listed alphabetically) Ovarian Cancer Highlights PD Dr. med. Nikolaus de Gregorio | Ulm PD Dr. med. Dominique Finas | Magdeburg PD Dr. med. Gülten Oskay-Özelik | Berlin Prof. Dr. med. Edgar Petru | Graz (Ö) Dr. med. Klaus Pietzner | Berlin Dr. med. Stephanie Schneider | Essen Prof. Dr. Alain G. Zeimet | Innsbruck (Ö) Endometrial, Cervical & Rare Gynaecological Cancer Highlights PD Dr. med. Holger Bronger | München Dr. med. Tom Degenhardt | München Dr. med. Martin Hellriegel | Göttingen Prof. Dr. med. Linn Wölber | Hamburg

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This slide-kit is intended for healthcare professionals only The authors of this report were supported by TESARO Bio Germany GmbH, their participation at the ASCO 2019 was in agreement with legal and ethical guidelines The content presented here corresponds to opinions and impressions of the authors and does not necessarily reflect the views of TESARO Bio Germany GmbH TESARO BIO Germany GmbH is not responsible for the content of this report Herausgeberin: TESARO Bio Germany GmbH Leopoldstraße 37 A 80802 München

News & Highlights for Ovarian cancer
Endometrial, cervical & rare tumors

ovarian CAncer (OC) OVERVIEW OF ASCO 2019 ORAL PRESENTATIONS
Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study—NSGO-AVANOVA2/ENGOT-OV24 (Mirza MR et al. ASCO 2019, oral abstract 5505) Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial (Penson RT et al. ASCO 2019, oral abstract 5506) Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer (Vanderstichele A et al. ASCO 2019, oral abstract 5507) EWOC-1: A randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-ENGOT-GINECO study (Falandry C et al. ASCO 2019, oral abstract 5508) Results of a phase 2 trial of ribociclib and letrozole in patients with either relapsed estrogen receptor (ER)-positive ovarian cancers or relapsed ER-positive endometrial cancers (Colon-Otero G et al. ASCO 2019, oral abstract 5510) Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study (Moore KN et al. ASCO 2019, poster discussion abstract 5513) Pembrolizumab with low dose carboplatin for recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer- interim results (Liao JB et al. ASCO 2019, poster discussion abstract 5519)

Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study- NSGO-AVANOVA2/ENGOT-OV24 (oral abstract 5505) Mansoor Raza Mirza, Elisabeth Avall-Lundqvist, Michael J. Birrer, Rene dePont Christensen, Gitte-Bettina Nyvang, Susanne Malander, Maarit Anttila, Theresa Louise Werner, Bente Lund, Gabriel Lindahl, Sakari Hietanen, Ulla Peen, Maria Dimoula, Henrik Roed, Anja Ør Knudsen, Louisa Boufercha, Synnove Staff, Anders Krog Vistisen, Line Bjørge, Johanna Unelma Maenpaa Abstract 5505: Background: Standard treatment of platinum-sensitive recurrent ovarian cancer (PSROC) is platinum based combination chemotherapy ± bevacizumab. However, this treatment modality is hardly curative, and is associated with significant toxicity. Both bevacizumab (BEV) and PARP inhibitors (PARPi) have demonstrated efficacy in PSROC. There is preclinical evidence of enhanced activity of the combination. This is the proof-of-concept randomized trial of PARPi-BEV combination against PARPi monotherapy as treatment in PSROC, regardless of number of previous lines of therapies. Methods: In this randomized, open-label, phase 2 study, women with measurable/evaluable, high-grade serous or endometrioid PSROC were randomized to niraparib 300mg once daily or the combination of niraparib 300mg once daily and BEV 15mg/kg IV every 3 weeks until disease progression (1:1 randomization). The primary endpoint was progression-free survival (PFS). Stratification was according to homologous recombination-deficiency(HRD) status (MyChoice HRD) and chemotherapy-free-interval (CFI)(6-12months (mo) vs. >12mo). First-line maintenance bevacizumab was permitted. Results: Of 97 enrolled patients, 48 were randomized to niraparib monotherapy and 49 to the chemotherapy-free combination. The combined treatment significantly improved PFS compared to niraparib alone: median 11.9 vs. 5.5 mo; hazard ratio (HR) adjusted for stratification factors 0.35; 95% confidence interval (CI),[0.21 to 0.57]; P< Pre-planned exploratory subgroup analyses: patients with HRD-positive tumors (n=54) HR 0.36 (CI, ); HRD-negative disease (n=43) HR, 0.47 (CI, ); gBRCAmut patients (n=34) HR 0.53 (CI, ); non-gBRCAmut patients (n=63) HR 0.33; CI, ); CFI of 6 to 12 mo (n=38) HR, 0.29 (CI, 0.14 to 0.62); CFI of ≥12 mo (n=59) HR, 0.42; (CI, 0.22 to 0.80). There was no difference in treatment-emergent grade 3-4 adverse events except for the rate of hypertension (26.5% vs. 0%) and neutropenia (12.2% vs. 2.1%). Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms. Conclusions: Both niraparib alone and the combination had meaningful activity in PSROC. Compared to niraparib alone, the chemotherapy-free regimen of niraparib and BEV significantly improved PFS in women with PSROC,regardless of HRD status and duration of CFI. Clinical trial information: NCT

Study background & methods
Standard treatment of PSROC is platinum based combination chemotherapy ± BEV However, this treatment modality is hardly curative and associated with significant toxicity Both BEV and PARP inhibitors (PARPi) have demonstrated efficacy in PSROC and there is preclinical evidence of enhanced activity of the combination This is the proof-of-concept randomized trial of PARPi-BEV combination against PARPi monotherapy as treatment in PSROC, regardless of number of previous lines of therapies PSROC, platinum-sensitive recurrent ovarian cancer BEV, bevacizumab PARPi, PARP inhibitor A randomized, open-label, phase 2 study Women with high-grade serous or endometrioid PSROC were randomized to niraparib mg once daily or the combination of niraparib 300 mg once daily and BEV 15 mg/kg IV every 3 weeks until disease progression (1:1 randomization) The primary endpoint was progression-free survival (PFS) Stratification was according to HRD status and chemotherapy-free-interval (6-12 months vs. >12 months). First-line maintenance bevacizumab was permitted HRD, homologous recombination deficiency Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study - NSGO-AVANOVA2/ENGOT-OV24 Mirza MR et al., ASCO 2019, abstract 5505 (oral presentation)

ENGOT-OV24 / Nsgo-avanova 2 trial design
High-grade serous / endometrioid PSROC Any number of previous lines of therapies Measurable / evaluable disease Prior bevacizumab permitted Niraparib 300 mg QD d1-21 Until disease progression or toxicity Randomize 1:1 Niraparib 300 mg QD d Bevacizumab 15 mg/kg q3w Stratification factors HRD status (positive vs negative) Chemotherapy-free interval (6-12 vs >12 months) ITT; Intention-To-Treat; QD, once daily; HRD, homologous recombination deficiency; PSROC, platinum-sensitive recurrent ovarian cancer Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study − NSGO-AVANOVA2/ENGOT-OV24 Mirza MR et al., ASCO 2019, abstract 5505 (oral presentation)

Baseline patient characteristics
ITT population Characteristic, n (%) Niraparib + Bevacizumab (n=48) Single-agent niraparib (n=49) HRD, homologous recombination deficiency Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study − NSGO-AVANOVA2/ENGOT-OV24 Mirza MR et al., ASCO 2019, abstract 5505 (oral presentation)

Time since randomization (months)
Primary Endpoint Progression-free survival (PFS) in the ITT population PFS (%) Time since randomization (months) 100 75 50 25 15 20 5 10 Adjusted HR=0.35 (95% CI ) P<0.0001 5.5 11.9 Number at risk Niraparib + bevacizumab 48 37 27 14 5 Niraparib 49 25 12 1 ITT, Intention-To-Treat; CI, Confidence Interval; HR, Hazard Ratio Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study - NSGO-AVANOVA2/ENGOT-OV24 Mirza MR et al., ASCO 2019, abstract 5505 (oral presentation)

Time since randomization (months) Time since randomization (months)
PFS by BRCA Status BRCA mutated BRCA wildtype PFS (%) Time since randomization (months) 100 75 50 25 15 20 5 10 HR=0.49 (95% CI ) p=0.0947 PFS (%) Time since randomization (months) 100 75 50 25 15 20 5 10 HR=0.32 (95% CI ) p=0.0001 9.0 14.4 4.2 11.3 Number at risk Niraparib + bevacizumab 15 13 10 4 3 Niraparib 18 8 1 Number at risk Niraparib + bevacizumab 33 24 17 10 2 Niraparib 31 12 4 CI, Confidence Interval; HR, Hazard Ratio Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study - NSGO-AVANOVA2/ENGOT-OV24 Mirza MR et al., ASCO 2019, abstract 5505 (oral presentation)

PFS by stratification factors: HRD status
HRD positive HRD negative 100 HR=0.38 (95% CI ) p=0.0019 100 HR=0.40 (95% CI ) p=0.0129 75 75 50 50 PFS (%) PFS (%) 25 25 6.1 11.9 4.2 11.3 5 10 15 20 5 10 15 20 Time since randomization (months) Time since randomization (months) Number at risk Niraparib + bevacizumab 28 23 18 10 5 Niraparib 30 17 8 3 1 Number at risk Niraparib + bevacizumab 20 14 9 4 Niraparib 19 8 2 CI, Confidence Interval; HR, Hazard Ratio Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study - NSGO-AVANOVA2/ENGOT-OV24 Mirza MR et al., ASCO 2019, abstract 5505 (oral presentation)

PFS by stratification factors: CT-free interval
CT-free interval: 6-12 months CT-free interval: >12 months PFS (%) Time since randomization (months) 100 75 50 25 15 20 5 10 HR=0.29 (95% CI ) p=0.0006 PFS (%) Time since randomization (months) 100 75 50 25 15 20 5 10 6.1 13.1 HR=0.42 (95% CI ) p=0.0062 11.3 2.2 Number at risk Niraparib + bevacizumab 20 14 10 5 1 Niraparib 17 2 Number at risk Niraparib + bevacizumab 28 23 17 9 4 Niraparib 32 20 10 1 CT, Chemotherapy; HR, Hazard Ratio; PFS, Progression-Free Survival Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study - NSGO-AVANOVA2/ENGOT-OV24 Mirza MR et al., ASCO 2019, abstract 5505 (oral presentation)

Dose reductions & treatment discontinuations
Number of niraparib dose reductions Niraparib + bevacizumab (n=48) Single-agent niraparib (n=49) None 23 (48%) 21 (43%) One (300 → 200 mg) 24 (50%) 27 (55%) Two (300 → 200 → 100 mg) 1 (2%) Treatment discontinuations for adverse events Niraparib + bevacizumab (n=48) Single-agent niraparib (n=49) Treatment discontinuations 6 (13%) 5 (10%) Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study - NSGO-AVANOVA2/ENGOT-OV24 Mirza MR et al., ASCO 2019, abstract 5505 (oral presentation)

SUMMARY & CONCLUSIONS ENGOT-OV24 / NSGO-AVANOVA 2 is the first randomized trial to evaluate a chemotherapy-free combination of two established agents approved for use in recurrent ovarian cancer (niraparib and bevacizumab) Compared with niraparib alone, the combination of niraparib + bevacizumab as definitive treatment for ovarian cancer significantly improved PFS, regardless of HRD status or chemotherapy-free interval Niraparib + bevacizumab combination therapy was well tolerated; most patients remained on treatment until disease progression No detrimental effect on quality of life was observed with the combination therapy A randomized phase 3 trial (NSGO-AVATAR) is planned to compare this regimen vs standard-of-care therapy in patients with platinum-sensitive recurrent ovarian cancer Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study - NSGO-AVANOVA2/ENGOT-OV24 Mirza MR et al., ASCO 2019, abstract 5505 (oral presentation)

Olaparib monotherapy versus chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients: Phase III SOLO3 trial (oral abstract 5506) Richard T. Penson, Ricardo Villalobos Valencia, David Cibula, Nicoletta Colombo, Charles A. Leath, Mariusz Bidziński, Jae-Weon Kim, Joo-Hyun Nam, Radoslaw Madry, Carlos Hernández , Paulo Alexandre Ribeiro Mora, Sang Young Ryu, Tsveta Milenkova, Elizabeth S. Lowe, Laura Barker, Giovanni Scambia Abstract 5506: Background: Data from a randomized Phase II trial (NCT ) of olaparib (capsules, 200 or 400 mg bid, n=32 per arm) vs pegylated liposomal doxorubicin (PLD, n=33) in gBRCAm OC pts with recurrence ≤12 months after prior platinum therapy indicated efficacy for olaparib (Kaye et al. JCO 2012). However, the efficacy of PLD was higher than previously reported in this setting. We led a confirmatory Phase III, open-label study of olaparib vs non-platinum chemotherapy in gBRCAm PSR OC pts (NCT ). Methods: Pts were randomized (2:1) to olaparib tablets (300 mg bid) or chemotherapy treatment of physician’s choice (TPC) (paclitaxel [P; 80 mg/m2 on day 1 (D1), D8, D15, D22 every 4 weeks (q4w)], topotecan [T; 4 mg/m2 D1, D8, D15 q4w], gemcitabine [G; 1000 mg/m2 D1, D8, D15 q4w] or PLD [50 mg/m2 D1 q4w]) until progression, stratified by: TPC, prior lines of chemotherapy (2–3 vs ≥4) and platinum-free interval (6–12 vs >12 months). Primary endpoint: ORR (blinded independent central review [BICR]). Secondary endpoints included PFS and safety. Results: 266 gBRCAm PSR OC pts were randomized (olaparib, n=178; TPC, n=88 [PLD, n=47; P, n=20; G, n=13; T, n=8]); 12 in the TPC arm withdrew before receiving study treatment. 223 pts (84%) had baseline BICR measurable disease (olaparib, n=151; TPC, n=72). ORR was 72% with olaparib vs 51% with TPC (OR 2.53, 95% CI 1.40–4.58; P=0.002). HR for PFS by BICR was 0.62 (95% CI 0.43–0.91; P=0.013; median 13.4 vs 9.2 months [olaparib vs TPC]) and by investigator assessment was 0.49 (95% CI 0.35–0.70; P<0.001; median 13.2 vs 8.5 months, respectively). Most common adverse events (AEs) with olaparib were nausea (65% vs 34% [TPC]) and anemia (50% vs 25%) and with TPC were palmar-plantar erythrodysesthesia (PPE; 36% vs 1% [olaparib]) and nausea. Most common grade ≥3 AEs in either arm were anemia (21% [olaparib] vs 0 [TPC]), PPE (0 vs 12%) and neutropenia (6% vs 11%). For olaparib vs TPC, serious AEs were reported by 24% vs 18% and AEs led to treatment discontinuation in 7% vs 20%. Conclusions: Pts with gBRCAm PSR OC receiving olaparib monotherapy had a significant, clinically relevant improvement in ORR and PFS vs TPC, with no new safety signals. Clinical trial information: NCT

* NCT Phase II data* of olaparib (200 or 400 mg capsules BID, n=32 per arm) vs pegylated liposomal doxorubicin (PLD, n=33) in gBRCAm ovarian cancer patients with recurrence ≤12 months after prior platinum therapy indicated efficacy for olaparib1 However, the efficacy of PLD was higher than previously reported in this setting Presented here is a confirmatory Phase III, open-label study** of olaparib vs non- platinum chemotherapy in gBRCAm PSROC patients BID, twice daily gBRCAm, BRCA germline mutation ** NCT PSROC, platinum-sensitive recurrent ovarian cancer Patients (n=266) were randomized (2:1) to olaparib tablets (300 mg bid) or chemotherapy treatment of physician’s choice (TPC): paclitaxel, topotecan, gemcitabine or PLD Stratification by: TPC, prior lines of chemotherapy (2–3 vs ≥4) and platinum-free interval (6–12 vs >12 months) Primary endpoint: ORR (blinded independent central review [BICR]) Secondary endpoints included PFS and safety 1. Kaye et al. JCO 2012 Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial Penson RT et al., ASCO 2019, abstract 5506 (oral presentation)

SOLO3 − Study design Primary endpoint Secondary endpoint Olaparib tablets 300 mg bid (n=178) PFS PFS2 OS TFST TSST HRQoL Safety Non-platinum chemotherapy§ (n=88) PLD (n=47) Paclitaxel (n=20) Gemcitabine (n=13) Topotecan (n=8) Study treatment administered until disease progression Relapsed, high-grade serous or endometrioid ovarian, primary peritoneal, and/or fallopian tube cancer Germline BRCAm ECOG performance status 0-2 ≥2 previous lines of platinum-based chemotherapy* Platinum sensitive† Open-label 2:1 randomization Stratified by: Selected chemotherapy‡ Number of prior lines of chemotherapy Time to progression after previous platinum-based chemotherapy ORR by BICR (RECIST v1.1) *Prior treatment with a PARP inhibitor was not permitted; †Fully platinum sensitive: progression >12 months after platinum-based chemotherapy; partially platinum sensitive: progression 6-12 months after platinum-based chemotherapy; ‡For each patient, the investigator declared their choice of non-platinum chemotherapy before randomization §PLD, 50mg/m2 on day 1 q4w; paclitaxel, 80mg/m2 on days 1, 8, 15, and 22 q4w; gemcitabine, 1000 mg/m2 on days 1, 8, and 15 q4w; topotecan, 4 mg/m2 on days 1, 8, and 15 q4w BICR, blinded independent central review; BRCAm, BRCA1 or BRCA2 mutation; ECOG, Eastern Cooperative Oncology Group; HRQoL, health-related quality of life; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PFS2, second progression-free survival; PLD, pegylated liposomal doxorubicin; q4w, every 4 weeks; RECIST, response evaluation criteria in solid tumors; TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial Penson RT et al., ASCO 2019, abstract 5506 (oral presentation)

Patient characteristics
Olaparib (n=178) Chemotherapy (n=88) Primary tumor location, n(%) Ovary Fallopian tube Primary peritoneal Other* 160 (90) 7 (4) 10 (6) 1 (1) 74 (84) 8 (9) 3 (3) 3 (3) gBRCAm by Myriad testing, n(%) BRCA1 BRCA2 Negative or missing† 120 (67) 50 (28) 8 (4) 52 (59) 32 (36) 4 (5) Platinum sensivity, n(%) Progressed ≤ 6 months after platinum Progressed > 6 to ≤ 12 months after platinum Progressed >12 months after platinum 114 (64) 64 (36) 1 (1) 50 (57) 37 (42) Number of previous chemotherapy regimens, n(%) 2 3 ≥4 92 (52) 41 (23) 45 (25) 47 (53) 24 (27) 17 (19) *Other primary tumor locations were “rectal wall” in the olaparib arm, and “uterus”, “liver metastasis”, and “pleura” in the chemotherapy arm; †Central Myriad results were either unavailable or negative, but patients had been shown to have a gBRCAm by local testing Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial Penson RT et al., ASCO 2019, abstract 5506 (oral presentation)

Results − primary endpoint
Objective response rate (ORR) by blinded independent central review (BICR) 63% ORR 72% 9% Olaparib n=151 90 80 70 60 50 40 30 20 10 Chemotherapy n=72 49% ORR 51% 3% ORR 85% 73% 12% Olaparib n=78 90 80 70 60 50 40 30 20 10 Chemotherapy n=39 56% 5% ORR 62% ORR 59% 52% 7% Olaparib n=73 90 80 70 60 50 40 30 20 10 Chemotherapy n=33 39% ORR 39% Complete response Partial response Percentage of patients with response All patients* OR 2.53 (1.40, 4.58) P=0.002 Patients with 2 prior lines of chemotherapy* OR 3.44 (1.42, 8.54) Patients with ≥3 prior lines of chemotherapy* OR 2.21 (0.96, 5.20) *Patients with measurable disease at baseline Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial Penson RT et al., ASCO 2019, abstract 5506 (oral presentation)

Results − PFS Progression-free survival (PFS) in Intention-To-Treat (ITT) population 100 100 BICR Investigator-assessed 90 90 80 80 Olaparib Chemotherapy 70 70 Olaparib Chemotherapy 60 60 Patients free from disease progression and death (%) Patients free from disease progression and death (%) 50 50 40 40 30 30 20 20 10 10 3 6 9 12 15 18 21 24 27 30 33 36 39 3 6 9 12 15 18 21 24 27 30 33 36 39 No. at risk Olaparib 178 156 126 108 71 47 30 25 18 14 8 5 2 Chemotherapy 88 63 31 9 3 Months since randomization No. at risk Olaparib 178 155 126 110 72 48 31 26 19 12 8 6 2 Chemotherapy 88 62 43 34 18 9 5 3 1 Months since randomization Olaparib (n=178) Chemotherapy (n=88) PFS events, n (%) 110 (62) 49 (56) Median PFS, month 13.4 9.2 HR (95% CI), P value 0.62 (0.43, 0.91); P=0.013 Olaparib (n=178) Chemotherapy (n=88) PFS events, n (%) 123 (69) 63 (72) Median PFS, month 13.2 8.5 HR (95% CI), P value 0.49 (0.35, 0.70); P<0.001 BICR, Binded indepedent Central Review Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial Penson RT et al., ASCO 2019, abstract 5506 (oral presentation)

Results − safety Most common AEs* and selected AEs of interest in either treatment arm Olaparib (n=178) Chemotherapy (n=76) Median total treatment duration 11.3 months 6.0 (PLD), 5.1 (paclitaxel), 3.3 (gemcitabine) and 6.2 (topotecan) months Nausea 64.6 1.1 1.3 34.2 All grades Grade ≥3 Fatigue/asthenia 52.2 4.5 1.3 42.1 Anemia† 51.1 21.3 25.0 Vomiting 38.2 1.1 2.6 22.4 Diarrhea 28.1 17.1 Neutropenia† 23.0 9.6 15.8 42.1 Abdominal pain 21.3 1.1 14.5 Thrombocytopenia† 11.8 3.9 2.6 10.5 Constipation 12.4 22.4 Alopecia 6.2 1.3 15.8 Peripheral neuropathy 2.8 2.6 10.5 Palmar-plantar erythrodysesthesia 0.6 11.8 35.5 100 75 50 25 25 50 75 100 AEs (%) *All grades, frequency ≥20%; grade ≥3, frequency ≥5%; †Grouped terms AE, Adverse Event Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial Penson RT et al., ASCO 2019, abstract 5506 (oral presentation)

SUMMARY & CONCLUSIONS SOLO3 is the first Phase Ill randomized trial of a PARP inhibitor vs a non-platinum-based chemotherapy in women with platinum-sensitive recurrent ovarian cancer and a germline BRCA mutation A statistically significant and clinically relevant improvement in ORR and PFS was observed with olaparib versus non-platinum-based chemotherapy The tolerability profiles of olaparib and chemotherapy were consistent with previous data Patients in the chemotherapy arm were more than twice as likely to discontinue study treatment because of an adverse event SOLO3 provides important prospective data on the efficacy of these treatment options for women with heavily pre-treated platinum-sensitive recurrent ovarian cancer and a germline BRCA mutation Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial Penson RT et al., ASCO 2019, abstract 5506 (oral presentation)

Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer (oral abstract 5507) Adriaan Vanderstichele, Els Van Nieuwenhuysen, Sileny Han, Nicole Concin, Toon Van Gorp, Patrick Berteloot, Patrick Neven, Pieter Busschaert, Diether Lambrechts, Ignace Vergote Abstract 5507: Background: The CLIO trial (NCT ) evaluated olaparib single-agent therapy versus standard of care chemotherapy in platinum-resistant (recurrence within 6 months after last platin) ovarian cancer (PROC). Methods: Eligible patients with measurable disease and ≥1 prior line of chemotherapy were randomized 2:1 to Olaparib (OLA) monotherapy (300 mg tablets, BID) or physician’s choice chemotherapy (CT; PLD 40 mg/m2 q 4 wks; Topotecan 1.25 mg/m2 day 1—5 q 3 wks; Paclitaxel 80 mg/m2 day 1, 8,15 q 3 wks; Gemcitabine 1000 mg/m2 day 1, 8 and 15 q 4 wks). Primary endpoint was objective overall response (ORR) per RECIST v1.1. Germline BRCA status was available for all patients. Disease control rate (DCR) was defined as response for at least 12 wks. Results: 100 patients with PROC were randomized 2:1 to OLA (N = 67) or CT (N = 33). Median prior lines of treatment was 3 (range: 1—8). ORR (unconfirmed) was 18% (12/67) for OLA and 6% (2/33) for CT. ORR for OLA was 38% (5/13) in gBRCAm and 13% (7/54) in gBRCAwt patients. Of note, 2 patients with gBRIP1 mutation had no response under OLA. DCR was 35.8% (24/67) for OLA and 42% (14/33) for CT. DCR under OLA in gBRCAm was 62% (8/13) compared to 30% (16/54) in gBRCAwt disease. The median duration of response (DOR) and the median progression-free survival (PFS) was similar: 5.4 months vs 4.5 months (DOR) and 2.9 vs 3.4 months (PFS) for OLA and CT, respectively. Grade ≥3 treatment-related AEs occurred in 60% vs 52% for OLA and CT, respectively. Somatic HRR mutation analysis is ongoing and will be presented. Conclusions: Olaparib monotherapy showed a favorable response rate in PROC compared with chemotherapy also in gBRCAwt patients. Analysis of clinical endpoints in relation to HRR is ongoing and will be presented. Clinical trial information: NCT

The CLIO phase II trial* evaluated single-agent therapy with PARP inhibitor olaparib versus standard of care chemotherapy in platinum-resistant ovarian cancer (PROC) patients (recurrence within 6 months after last platinum treatment) * NCT BID, twice daily Eligible patients (n=100) with measurable disease and ≥1 prior line of chemotherapy were randomized 2:1 to olaparib* monotherapy (300 mg tablets, BID) or physician’s choice chemotherapy (PLD, topotecan, paclitaxel, or gemcitabine) Primary endpoint was objective overall response (ORR) per RECIST v1.1. Germline BRCA status was available for all patients. Disease control rate (DCR) was defined as response for at least 12 weeks PLD, pegylated liposomal doxorubicin Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer Vanderstichele A et al., ASCO 2019, abstract 5507 (oral presentation)

CLIO Trial − Study design
Randomized open-label study ENGOT MODEL A Relapsed ovarian cancer: at least 1 previous line of chemotherapy Histology: High-grade serous, Endometrioid, Clear-Cell, Carcinosarcoma, Undifferentiated Measurable disease Previous PARPi allowed Platinum-sensitive / PSOC (N=60) Relapse ≥ 6 months after platinum-based chemotherapy Exclusion of patients with known germline or somatic BRCA mutation prior to screening R crossover OLAPARIB 300 mg BID (4 tablets/day) Physician‘s choice CHEMOTHERAPY (Carbo-Gemic/Carbo-Paclitaxel/Carbo-PLD) Platinum-resistant / PROC (N=100) Relapse < 6 months after platinum-based chemotherapy, exclusion primary platinum-refractory disease (i.e. relapse during or < 28 days after first-line platinum) Germline or somatic BRCA mutation allowed 2:1 randomisation R crossover OLAPARIB 300 mg BID (4 tablets/day) Physician‘s choice CHEMOTHERAPY Paclitaxel 80 mg/m² PLD 40 mg/m² Topotecan 1.25 mg/m² Gemcitabine 1000 mg/m² BID, twice daily; PARPi, PARP inhibitor; PLD, Pegylated Liposomal Doxorubicin; PROC, platinum-resistant Ovarian Cancer; PSOC, platinum-sensitive Ovarian Cancer Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer Vanderstichele A et al., ASCO 2019, abstract 5507 (oral presentation)

Baseline characteristics
Prior treatment (PROC, n= 100) BRCA status (PROC, n= 100) Olaparib Chemotherapy Number of patients 67 33 Median years since diagnosis 3.7 (95%CI: 2.8−5.0) 3.2 (95%CI: 2.2−3.9) Median prior lines 4 (IQR: 3−5, Range: 1−8) 3 (IQR: 2−4, Range: 1−8) 1 3 (5%) 3 (9%) 2 10 (15%) 12 (36%) 3 19 (28%) 4 (12%) 4 or more 35 (52%) 14 (42%) Prior bevacizumab 36 (54%) Prior PARPi 5 (8%) 2 (6%) (incl. placebo-controlled trials) 6 (18%) Imbalance ín frequency of known BRCA mutations between both groups (p=0.03) (no stratification performed, incomplete somatic testing mainly in chemotherapy arm) gBRCAmut, germ cell BRCA mutation, IQR, Interquartile Range; PARPi, PARP inhibitor; PROC, platinum-resistant Ovarian Cancer; sBRCAmut, somatic BRCA mutation Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer Vanderstichele A et al., ASCO 2019, abstract 5507 (oral presentation)

2 responses under chemotherapy (both paclitaxel weekly)
Efficacy Results Objective response rate (ORR for PROC, n=100)* 140 33.3% (11/33) Paclitaxel 30.3% (10/33) PLD 18.2% (6/33) Topotecan 18.2% (6/33) Gemcitabine Olaparib Chemotherapy 120 100 80 60 40 Best Percentage Change from Baseline 20 + 20% -20 2 responses under chemotherapy (both paclitaxel weekly) - 30% -40 -60 -80 -100 Olaparib Chemotherapy All patients 18% (12/67) 6% (2/33) p=0.13 * unconfirmed PLD, Pegylated Liposomal Doxorubicin Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer Vanderstichele A et al., ASCO 2019, abstract 5507 (oral presentation)

Median duration of clinical benefit
Efficacy Results Duration of clinical benefit 1.00 AAAAAAAAAAAAAA Median duration of clinical benefit 0.75 All patients (n=100) months (95% CI: ) Olaparib (n=67) months (95% CI: NA) Chemotherapy (n=33) months (95% CI: ) Survival probability 0.50 p= 0.73 0.25 0.00 30 60 90 120 150 180 210 240 270 300 330 360 390 Time Similar duration of clinical benefit (CR, PR or SD) under olaparib and standard chemotherapy treatment in PROC CR, Complete Response; PR, Partial Response; SD, Stable Disease Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer Vanderstichele A et al., ASCO 2019, abstract 5507 (oral presentation)

Safety results Treatment emergent adverse events (TEAEs)
MedDRA System Preferred Term Olaparib (n=67) Chemotherapy (n=33) Any CTCAE Grade ≥3 TEAE (>5%) n (%) Anaemia 24 (36) 6 (18) Neutrophil count decreased 2 (3) 10 (30) Platelet count decreased 3 (5) 3 (9) Vomiting 5 (7) 0 (0) Malaise 4 (6) 1 (3) TEAE (any grade) leading to dose reduction 14 (21) 5 (15) TEAE (any grade) leading to dose discontinuation CTCAE, Common Terminology Criteria for Adverse Events Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer Vanderstichele A et al., ASCO 2019, abstract 5507 (oral presentation)

SUMMARY & CONCLUSIONS Olaparib monotherapy showed a favourable objective response rate of 18% in patients with platinum- resistant ovarian cancer (PROC) compared to 6% with standard chemotherapy BRCA-mutated PROC patients had a response rate of 36% under olaparib treatment, with a clinical benefit rate at 12 weeks of 64% The studied population was heavily pre-treated, with 49% having received ≥4 prior lines of treatment, 16% of patients received prior PARP inhibitor therapy (including placebo-controlled studies) No new TEAEs were noted; TEAEs leading to dose discontinuation were rare TEAE, Treatment Emergent Adverse Event Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer Vanderstichele A et al., ASCO 2019, abstract 5507 (oral presentation)

EWOC-1: A randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer: A GCIG-ENGOT-GINECO study (oral abstract 5508) Claire Falandry, Aude Marie Savoye, Laetitia Stefani, Fabien Tinquaut, Domenica Lorusso, Jorn Herrstedt, Emmanuelle Bourbouloux, Anne Floquet, Pierre Emmanuel Brachet, Alain Zannetti, Marie-Ange Mouret-Reynier, Robert Sverdlin, Veronique D'hondt, Olivier Guillem, Oana Cojocarasu, Laurence Venat-Bouvet, Frederique Rousseau, Alain Lortholary, Eric Pujade-Lauraine, Gilles Freyer Abstract 5508: Background: The Geriatric Vulnerability Score (GVS) combining albumin, lymphocyte count, ADL, IADL and HADS scores has been reported (Falandry C Ann Oncol 2013) to identify vulnerable elderly OC patients (pts) as those with a GVS≥3. For such pts, Carboplatin (Cb) monotherapy or weekly Cb plus paclitaxel (Pa) are often proposed as an alternative to Cb-Pa given every 3 weeks. Methods: Pts ≥70 yrs with first line FIGO stage III/IV epithelial OC were screened for GVS. Those with GVS≥3 were randomized to receive either arm A: Cb AUC5-6 + Pa 175mg/m², d1q3week or arm B: Cb AUC5-6 d1q3week or arm C:weekly Cb AUC2 + Pa 60mg/m² d1-d8-d15 q4week. Primary endpoint is treatment feasibility defined as the ability to complete 6 chemotherapy courses without disease progression, early treatment stopping due to unacceptable toxicity or death. Inclusion of 240 pts was planned. Results: Among 444 screened pts, 120 were randomized from 12/2013 to 04/2017 (armA = B = C = 40). Pts characteristics were well balanced between arms A-B-C respectively: median age ( yrs), FIGO stage IV ( %), primary surgery ( %), absence of macroscopic residuals (CC-0) (7-5-7%), ECOG≥2 ( %). Feasibility per protocol for arms A-B-C is 65%, 47% and 60% (p = 0.15). Main reasons for treatment arrest are treatment toxicity (A:20%; B:15%; C:22.5%; p = 0.771) and disease progression (A:7.5%; B:30%; C:2%; p = 0.004). Median PFS for arm A-B-C are 12.5 mos (95%CI ), 4.8 ( ) and 8.3 ( ), respectively (p < 0.001) and median OS for arm A-B-C is not reached (NR) (21, NR), 7.4 (5.3-NR) and 17.3 (10.8-NR), respectively (p = 0.001). At the pre-planned intermediate analysis, the IDMC recommended to prematurely close the study as survival in armB was found significantly worse and the number of potential pts required to find a significant difference between both Cb-Pa regimens (arms A&C) was out of reach. Conclusions: Compared to 3-weekly and weekly Cb-Pa regimens, Cb single agent was reported to be less active with significant worse survival outcome in vulnerable elderly pts. In this population Cb-Pa combination remains a standard. Clinical trial information: NCT

The Geriatric Vulnerability Score (GVS) combining albumin, lymphocyte count, ADL, IADL and HADS scores has been reported to identify vulnerable elderly ovarian cancer patients when GVS ≥3 1 For such patients, carboplatin (Cb) monotherapy or weekly Cb plus paclitaxel (Pa) are often proposed as an alternative to Cb-Pa given every 3 weeks ADL, activities of daily living IADL, instrumental activities of daily living HADS, Hospital Anxiety and Depression Scale Patients ≥70 years with first-line FIGO stage III/IV epithelial OC were screened for GVS Those with GVS≥3 were randomized to receive one of three carboplatin-based chemotherapy regimes Primary endpoint is treatment feasibility defined as the ability to complete 6 chemotherapy courses without disease progression, early treatment stopping due to unacceptable toxicity or death. Inclusion of 240 patients was planned 1: Falandry C et al. Ann Oncol 2013 EWOC-1: A randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-ENGOT-GINECO study Falandry C et al., ASCO 2019, abstract 5508 (oral presentation)

Background − geriatric vulnerability score
GVS developed by GINECO to discriminate vulnerable vs fit elderly patients1 GVS Items Activity of daily living (ADL-Katz) score < 6 Instrumental activities of daily living (IADL-Lawton) score < 25 Hospital Anxiety and Depression score (HADS) > 14 Albuminemia < 35 g/L Lymphocyte count < 1G/L GVS = Σ scores GVS ≥ 3 defines vulnerable older patients ( > 70 years) 1: Falandry C et al. Ann Oncol 2013 EWOC-1: A randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-ENGOT-GINECO study Falandry C et al., ASCO 2019, abstract 5508 (oral presentation)

ewoc-1 study design Arm A: 3-weekly carboplatin-paclitaxel
Carboplatin AUC paclitaxel mg/m² q21 Arm B: 3-weekly carboplatin Carboplatin AUC 5-6 q21 Arm C: weekly carboplatin-paclitaxel Carboplatin AUC 2 + paclitaxel 60 mg/m² d1, d8, d15 q28 Primary endpoint: To evaluate the feasibility of the 3 different chemotherapy regimens Secondary endpoints: Safety, PF, OS, QoL, interval debulking and post-operative adjuvant therapy feasibility, geriatric covariates and aging biomarkers Eligible for EWOC-1 trial R 6 cycles follow up Stratification parameters Country Initial debulking surgery outcome Randomization according to minimization All patients had: GVS ≥ 3; FIGO 3 or 4; no clinically relevant organ dysfunction EWOC-1: A randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-ENGOT-GINECO study Falandry C et al., ASCO 2019, abstract 5508 (oral presentation)

EWOC-1 Patient characteristics
Arm A (3wCb-P) n=40 Arm B (3wCb) n=40 Arm C (wCb-P) n=40 Median age, years (range) 79 (71-90) 82 (70-94) 80 (70-90) GVS global, N (%) 3 24 (60) 19 (48) 21 (53) 4 14 (35) 15 (37) 5 2 (5) 7 (17) 4 (10) GVS per item, N (%) Albuminemia < 35 G/L 32 (80) 33 (82) 34 (85) ADL score < 6 36 (90) IDAL score < 25 37 (92) HADS > 14 23 (57) 28 (70) Lymphocyte count < /L 16 (40) 13 (32) Histology, N (%) Serous Others 12 (30) FIGO stage, N (%) III 26 (65) 29 (72) IV 11 (28) Debulking surgery, N (%) None or macroscopic residue 38 (95) Complete surgical resection 3 (7) ADL, Activities of Daily Living; GVS, Geriatric Vulnerability Score; HADS, Hospital Anxiety and Depression Scale; IADL, Instrumental Activities of Daily Living EWOC-1: A randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-ENGOT-GINECO study Falandry C et al., ASCO 2019, abstract 5508 (oral presentation)

Results EWOC-1 toxicity Toxicity Arm A (3wCb-P) Arm B (3wCb)
Arm C (wCb-P) Haematological toxicity (%) Grade ≥ 3 Anemia 10 32.5 7.5 Thrombopenia 5 15 Neutropenia 12.5 20 Febrille neutropenia 7.5 (1†) Non-haematological toxicity (%) All grades Nausea/vomiting 52.5 37.5 2.5 55 Constipation 45 Diarrhea 35 17.5 Neuropathy sensory Total alopecia Fatigue 70 72.5 85 Pain 42.5 47.5 50 General physical health deterioration 2.5 (1†) 10.0 Treatment stopping due to toxicity N (%) 8 (20) 6 (15) 9 (22.5) EWOC-1: A randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-ENGOT-GINECO study Falandry C et al., ASCO 2019, abstract 5508 (oral presentation)

Results EWOC-1 Progression-free survival Completed 6 cycles — A - 65%
Arm A Arm B Arm C Events, N (%) 34 (85) 38 (95) Median, mos (95% CI) 12.5 (10.3 – 15.3) 4.8 (3.6 – 15.3) 8.3 (6.6 – 15.3) HR (95% CI) 1 2.51 (1.56,4.04) 1.41 (0.87,2.28) P Wald test – < 0.001 0.162 P Log-Rank 1.0 — A - 65% — B % — C - 60% 0.8 0.6 Survival Probability 0.4 Arm A: 3wCb-P 0.2 Arm C: w Cb-P Arm B: 3wCb 0.0 5 10 15 20 25 30 35 Time (month) 10 20 30 At Risk: A 40 25 2 B 6 3 C 16 5 EWOC-1: A randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-ENGOT-GINECO study Falandry C et al., ASCO 2019, abstract 5508 (oral presentation)

SUMMARY & CONCLUSIONS Compared to 3-weekly and weekly carboplatin-paclitaxel regimens, carboplatin single agent was less active with significantly worse survival outcome in vulnerable older patients (> 70 yrs) with a GVS ≥ 3 These findings were also observed in the most vulnerable patients (GVS 4 & 5) Even vulnerable older ovarian cancer patients should be offered a carboplatin-paclitaxel regimen GVS, geriatric vulnerability score EWOC-1: A randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-ENGOT-GINECO study Falandry C et al., ASCO 2019, abstract 5508 (oral presentation)

Results of a phase 2 trial of ribociclib and letrozole in patients with either relapsed estrogen receptor (ER)-positive ovarian cancers or relapsed ER-positive endometrial cancers (oral abstract 5510) Gerardo Colon-Otero, S. John Weroha, Valentina Zanfagnin, Nathan R. Foster, Erik Asmus, Andrea Elisabeth Wahner Hendrickson, Aminah Jatoi, Matthew Stephen Block, Carrie L Langstraat, Gretchen Elizabeth Glaser, Tri Dinh, Matthew Robertson, John Kelly Camoriano, Kristina Butler, John A. Copland Abstract 5510: Background: Single agent aromatase inhibitor (AI) therapy is associated with limited clinical activity in ovarian cancer (OC) and endometrial cancers (EC). AI therapy was associated with a progression free survival (PFS) at 12 weeks of only 20% in relapsed OC (Bowman et al, 2002) and a median PFS of 1 month in relapsed EC (Rose et al, 2000). In Estrogen Receptor (ER) positive metastatic breast cancer, clinical studies had shown a significant prolongation of PFS with the addition of the cyclin kinase 4/6 inhibitor ribociclib to AI (Hortobagyi et al, 2016). Here, we report the results of a phase 2 clinical trial of the combination of ribociclib and letrozole in patients with relapsed ER positive OC or EC. Objectives: Primary endpoint was the proportion of patients with relapsed ER positive OC or EC alive and progression-free after 12 weeks of therapy (PFS12) with the combination of ribociclib given at a dose of 400 mg orally daily and letrozole 2.5 mg orally daily. A PFS of 45% was considered a favorable result based on the data referenced above from Bowman et al. Methods: Eligibility criteria included patients with relapsed ER positive OC or EC, with measurable disease, not previously treated with ribociclib or AIs. Xenografts were created from CT guided tumor biopsies at baseline to assess feasibility. Results: A total of 40 patients were enrolled (20 with OC and 20 with EC) ) with a median age of 61 years (range: 30-82) and 64.5 (range: 52-75) in the OC and EC groups respectively. Among the OC patients, 17 had high grade serous carcinomas and 3 had low grade serous carcinomas. 11 EC patients had endometrioid cancers (3 with grade 1 tumors) and 9 had high grade serous tumors. Ten out of 20 OC patients and 11/20 EC patients were alive and progression-free at 12 weeks (PFS12 of 50 and 55%, respectively). The most common grade 3 or higher adverse events (occurring in at least 5 pts) were leukopenia (18%), lymphopenia (18%), neutropenia (13%), and fatigue (13%). 34 tumor biopsies were suitable for injection into mice and 44% engrafted. ER expression persisted through multiple passages in mice. Two of three EC PDX models exhibited improved PFS with letrozole/ribociclib compared to letrozole alone. Conclusions: The combination of ribociclib and letrozole is associated with a promising 50% and 55% PFS12 in patients with ER positive relapsed OC or EC respectively. Creation of xenograft tumor models from CT guided biopsies of OC and EC tumors was feasible. Clinical trial information: NCT

Single agent aromatase inhibitor (AI) therapy has limited clinical activity in ovarian cancer (OC) and endometrial cancers (EC). AI therapy was associated with a CA-125 RR of 8% and a PFS at 12 weeks of only 20% in relapsed OC1 and a RR of 9% with a median PFS of 1 month in relapsed EC2 In estrogen receptor (ER) positive metastatic breast cancer, clinical studies had shown a significant prolongation of PFS with the addition of the cyclin kinase 4/6 inhibitor ribociclib to AI3 Presented here are the results of a phase II clinical trial of the combination of ribociclib and aromatase inhibitor letrozole in patients with relapsed ER positive ovarian or endometrial cancer RR, response rate PFS, progression-free survival Eligibility criteria included patients with relapsed ER positive OC or EC, with measurable disease, not previously treated with ribociclib or AIs. Xenografts were created from CT guided tumor biopsies at baseline to assess feasibility Primary endpoint was the proportion of patients with relapsed ER positive OC or EC alive and progression-free after 12 weeks of therapy (PFS-12) with the combination of ribociclib given at a dose of 400 mg orally daily and letrozole 2.5 mg orally daily 1. Bowman et al., 2002; 2. Rose et al., 2000; 3. Hortobagyi et al., 2016 Results of a phase 2 trial of ribociclib and letrozole in patients with either relapsed estrogen receptor (ER)-positive ovarian cancers or relapsed ER-positive endometrial cancers Colon-Otero G et al., ASCO 2019, abstract 5510 (oral presentation)

Rationale derived from breast cancer
Estrogen receptor positivity is present in % of all ovarian cancers and 80% of all endometrial cancers In the treatment of ER positive breast cancer, Cyclin Kinase (CDK 4/6) inhibitors (palbociclib, ribociclib, abemaciclib) have been shown to significantly prolong PFS when combined with aromatase inhibitors1 1.0 Hortobagyi et al. 2016 0.9 0.8 0.7 Ribociclib group 0.6 Probability of Progression-free Survival 0.5 0.4 0.3 Hazard ratio, 0.56 (95% CI, ) P=3.29x10-6 for superiority 0.2 Placebo group 0.1 0.0 2 4 6 8 10 12 14 16 18 20 22 24 Months No. at risk Ribociclib 334 294 277 257 240 226 164 119 68 20 6 1 Placebo 279 264 237 217 192 143 88 44 23 5 1. Hortobagyi et al. N Engl J Med Nov 3;375(18): Results of a phase 2 trial of ribociclib and letrozole in patients with either relapsed estrogen receptor (ER)-positive ovarian cancers or relapsed ER-positive endometrial cancers Colon-Otero G et al., ASCO 2019, abstract 5510 (oral presentation)

Study design AND Patient population
Pre-Registration For determination of ER and RB Patients Characteristics Ovarian cohort (n=20) Endometrial cohort (n=20) Age (median, range) 61 (30-82) 64.5 (52-75) Performance Score (ECOG scale); No. (%) 0= 60%; 1= 35%; 2= 5% 0= 55%; 1= 30%; 2= 15% Cell Type High grade serous = 17 (85%) Low grade serous = 3 (15%) Gr 1-2 = 11(55%) Gr 3 = 9(45%) Number of previous chemo regimens 0-6 (median 3) 0-6 (median 2) Platinum resistance Sensitive = 7 (36.8%) Resistant = 12 (63%) Sensitive = 8 (44%) Resistant = 10 (55%) Registration Cohort A Ovarian, primary peritoneal, fallopian tube ACA Cohort B Endometrial cancer Treatment Letrozole 2.5 mg PO daily Ribociclib 400 mg PO daily ACA, Adenocarcinoma; PO, orally Results of a phase 2 trial of ribociclib and letrozole in patients with either relapsed estrogen receptor (ER)-positive ovarian cancers or relapsed ER-positive endometrial cancers Colon-Otero G et al., ASCO 2019, abstract 5510 (oral presentation)

Results Clinically significant benefit (PFS ≥ 23 weeks and ON STUDY for ≥ 23 weeks) Total patients 14 / 40 (35%) Ovarian Group 5 / 20 (25%) Low-grade serous 3 / 3 (100%)* High-grade serous 2 / 17 (12%) Endometrial Group 9 / 20 (45%) Grade 1-2 7 / 11 (64%) Grade 3 2 / 9 (22%) * These patients are still on rx for 28+ months, 24+ months, and 19+ months * These patients are still on rx for 28+ months, 24+ months, and 19+ months. Results of a phase 2 trial of ribociclib and letrozole in patients with either relapsed estrogen receptor (ER)-positive ovarian cancers or relapsed ER-positive endometrial cancers Colon-Otero G et al., ASCO 2019, abstract 5510 (oral presentation)

SUMMARY & CONCLUSIONS The combination of ribociclib + letrozole is active against ER positive endometrial and ovarian cancers: PFS ≥ 23 weeks achieved in 9/20 (45%) of endometrial cancers and 5/20 (25%) of ovarian cancers The greatest benefit was seen in low grade serous ovarian cancers (3/3 PR,PFS over 18 months) and grade 1-2 endometrial cancers (7/11, 64%, with PFS of ≥ 23 weeks) Lesser benefit was seen in G3 endometrial cancers with 2/9 (22%) showing a PFS ≥ 23 weeks and in high grade serous ovarian cancers with 2/17 (12%) patients achieving a PFS ≥ 23 weeks Additional studies of ribociclib and letrozole in ER positive low grade serous ovarian cancers and G1-2 endometrial cancers are indicated ER, Estrogen Receptor Results of a phase 2 trial of ribociclib and letrozole in patients with either relapsed estrogen receptor (ER)-positive ovarian cancers or relapsed ER-positive endometrial cancers Colon-Otero G et al., ASCO 2019, abstract 5510 (oral presentation)

Adavosertib with chemotherapy in patients with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study (poster discussion abstract 5513) Kathleen N. Moore, Setsuko K. Chambers, Erika Paige Hamilton, Lee-may Chen, Amit M. Oza, Sharad A. Ghamande, Gottfried E. Konecny, Steven C. Plaxe, Daniel Lewis Spitz, Jill J.J. Geenen, Tiffany A. Troso-Sandoval, Janiel M. Cragun, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh M. Mugundu, Zhongwu Lai, Juliann Chmielecki, Suzanne Fields Jones, David R. Spigel, Karen Anne Cadoo Abstract 5513: Background: Adavosertib (AZD1775; A), a highly selective WEE1 inhibitor, demonstrated activity and tolerability in combination with carboplatin (C) in primary PROC. This study (NCT ) assessed the objective response rate (ORR) and safety of A in PROC. Methods: Pts with recurrent RECIST v1.1 measurable PROC received A with C, gemcitabine (G), weekly paclitaxel (P), or pegylated liposomal doxorubicin (PLD) in 3- (C) or 4-week (G, P, PLD) cycles (Table). Tumor assessments were performed every 2 cycles until disease progression. Primary objective: ORR; other objectives: disease control rate (DCR), progression-free survival (PFS) and safety. Results: In the 94 pts treated (median treatment duration 3 months; range 0–16 months), outcomes were greatest with A (weeks [W]1–3) + C (Table), with ORR of 67% and median PFS (mPFS) of 10.1 months for this cohort. Most common grade ≥3 treatment-emergent adverse events (TEAEs) are shown in the Table, with hematologic toxicity most notable with A (W1–3) + C. TEAEs led to A dose interruptions, reductions and discontinuations in 63%, 30% and 13% of the whole cohort, respectively. A possible positive relationship between CCNE1 amplification and response warrants further investigation. Conclusions: A shows preliminary efficacy when combined with CT. Pts receiving A (W1–3) + C showed greatest benefit. The increased but not unexpected hematologic toxicity is a challenge and could be further studied to optimize the dose schedule and supportive medications. Clinical trial information: NCT

Adavosertib is a highly selective WEE-1 inhibitor that demonstrated activity and tolerability in combination with carboplatin (C) in primary platin-resistant ovarian cancer (PROC) This study* assessed the objective response rate (ORR) and safety of adavosertib in patients with PROC * NCT Patients with recurrent RECIST v1.1 measurable PROC received adavosertib with either carboplatin (C), gemcitabine (G), weekly paclitaxel (P), or pegylated liposomal doxorubicin (PLD) in 3- (C) or 4-week (G, P, PLD) cycles Tumor assessments were performed every 2 cycles until disease progression Primary objective: ORR; other objectives: disease control rate (DCR), progression-free survival (PFS) and safety Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study Moore KN et al., ASCO 2019, abstract 5513 (poster discussion presentation)

(combination therapy)
Background Adavosertib Suggested mode of action WEE-1 inhibitor Impairs cell cycle G2 DNA damage checkpoint May lead to apoptosis upon treatment with DNA damaging agents Most p53 deficient or mutated cancers lack G1 checkpoint, thus cells rely on checkpoint at G2 May lead to mitotic catasthrophe 4-arm phase II trial, ≤ 4 prior regimens G2 M G1 S WEE1 Repair prevention Damage maximization (combination therapy) Damage manifestation Adavosertib (AZD1775) Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study Moore KN et al., ASCO 2019, abstract 5513 (poster discussion presentation)

Adavosertib treatment days Chemotherapy dose and treatment days
Treatment schedules Treatments and dosing schedules in four treatment arms, across six cohorts Adavosertib dosing regimens varied across the four treatment arms (table) A more dose-dense adavosertib schedule (cohort 225 mg twice daily [bid] in weeks [W]1–3 + C) and two adavosertib dose levels (175 mg bid and 225 mg bid) with PLD were also included for evaluation The number of patients enrolled in each cohort was determined by the protocol according to the level of clinical activity in the emerging data Cohorts 225 mg bid + P and 225 mg bid W1 + C enrolled additional patients because they showed the most promising results at the interim analysis Cohorts Adavosertib treatment days (cycle length) Adavosertib dose Chemotherapy dose and treatment days 175 mg qd + G 1–2, 8–9 and 15–16 (28 days) 175 mg qd G: 800 mg/m2 IV days 1, 8 and 15 (28 days)* 225 mg bid + P 1–3, 8–10 and 15–17 (21 days) 225 mg bid P: 80 mg/m2 IV days 1, 8 and 15 (28 days) 225 mg bid W1 + C 1–3 (21 days) C: AUC of 5 mg/mL·min, IV, day 1 (21 days) 225 mg bid W1–3 + C 175 mg bid + PLD 1–3 (28 days) 175 mg bid PLD: 40 mg/m2 IV day 1 (28 days) 225 mg bid + PLD Patients in all cohorts, except for 175 mg qd + G, received adavosertib for 2.5 days (five doses total) per dosing week. *Initial dose level was 1000 mg/m2; owing to toxicity, this was reduced to 800 mg/m2 in five out of nine patients in this cohort. AUC, area under the concentration–time curve;IV, intravenous; qd, once daily Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study Moore KN et al., ASCO 2019, abstract 5513 (poster discussion presentation)

Results Antitumor activity - Response to treatment
ORR was 31.9% (table ) 3 patients achieved a complete response (in the P and C cohorts) The highest ORR (66.7%) was recorded in the 225 mg bid W1–3 + C cohort Median DoR and PFS were 10.8 and 5.5 months, respectively (table) The longest median DoR was captured in the P cohort (12.0 months) Median PFS was highest in the 225 mg bid W1–3 + C cohort at 12.0 months (table and figure next slide). DCR and CA-125 RR were 73.4% and 42.9%, respectively (table) The highest DCR and CA-125 RR were recorded in the 225 mg bid W1–3 + C cohort (100% and 63.6%, respectively). 175 mg qd + G (n=9) 225 mg bid + P (n=38) W1 + C (n=23) W1–3 + C (n=12) 175 mg bid + PLD (n=6) Overall (N=94) ORR,* n (%) 1 (11.1) 11 (28.9) 7 (30.4) 8 (66.7) 2 (33.3) 1 (16.7) 30 (31.9) CR 1 (2.6) 1 (4.3) 1 (8.3) 3 (3.2) PR 1 (11.1)† 10 (26.3) 6 (26.1) 7 (58.3) 27 (28.7) SD ≥7 weeks‡ 2 (22.2) 16 (42.1) 12 (52.2) 4 (33.3) 4 (66.7) 39 (41.5) PD 6 (66.7) 7 (18.4) 3 (13.0) 3 (50.0) 19 (20.2) NE Median DoR, months 4.4 12.0 NC 10.4 10.8 Median PFS, months 1.7 5.5 4.2 2.7 DCR,§ n (%) 3 (33.3) 27 (71.1) 19 (82.6) 12 (100.0) 5 (83.3) 69 (73.4) CA-125 RR,¶ n (%) 2 (25.0) 15 (53.6) 4 (26.7) 7 (63.6) 1 (25.0) 30 (42.9) The greatest treatment benefit appeared to be in the 225 mg bid W1–3 + C cohort (highlighted in blue). *Number (%) of patients with measurable disease with ≥1 confirmed CR or PR; †Patient received G 800 mg/m2 IV; ‡≥5 weeks for the C cohorts; §Number (%) of patients with measurable disease with ≥1 CR, PR or SD response; ¶Patient numbers per cohort were: 8 (175 mg qd + G), 28 (225 mg bid + P), 15 (225 mg bid W1 + C), 11 (225 mg bid W1–3 + C), 4 (both PLD cohorts), 70 (overall). CR, complete response; NC, not calculated; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study Moore KN et al., ASCO 2019, abstract 5513 (poster discussion presentation)

Results Response rates in PROC - Overview of results from different studies Study Agent N Response Rate (%) 126-J Docetaxel 58 22 126-N Weekly Paclitaxel 48 21 126-Q Pemetrexed 126-R Nab-Paclitaxel 47 23 170-D Bevacizumab 62 AURELIA Chemo + Bev Chemo Alone 179 181 27.3 11.8 Gordon Ph 3 PLD Topo D1-5 239 235 19.7 17 Study 10 and ARIEL 2 subset PROC Rucaparib 20 25 QUADRA subset BRCAm, PROC Niraparib 37 27 Current Study Carbo + Adavosertib 35 42.9 Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study Moore KN et al., ASCO 2019, abstract 5513 (poster discussion presentation)

Results Most commonly occurring TEAEs of grade ≥3 in >10% of patients (CTCAE definition) All 94 patients experienced at least one TEAE 38 (40.4%) patients experienced a grade 3 TEAE and 39 (41.5%) patients a grade 4 TEAE Overall, TEAEs led to dose interruptions, dose reductions and discontinuations of adavosertib in 63.8%, 38.3% and 12.8% of patients, respectively During the study, 31 (33.0%) patients died; of these, 25 (80.6%) deaths were related to pPROC only Of 34 patients in the DLT analysis set, five (14.7%) experienced a total of seven DLTs Number of patients (%) 175 mg qd + G (n=9) 225 mg bid + P (n=38) W1 + C (n=23) W1–3 + C (n=12) 175 mg bid + PLD (n=6) Overall (N=94) Anemia/hemoglobin decreased 1 (11.1) 10 (26.3) 13 (56.5) 7 (58.3) 31 (33.0) Diarrhea 4 (10.5) 4 (17.4) 1 (8.3) 10 (10.6) Neutropenia/neutrophil count decreased 7 (77.8) 20 (52.6) 5 (21.7) 9 (75.0) 2 (33.3) 43 (45.7) Thrombocytopenia/ platelet count decreased 3 (33.3) 12 (52.2) 10 (83.3) 1 (16.7) 30 (31.9) Vomiting 3 (13.0) bid, twice daily; CTCAE, Common Terminology Criteria for Adverse Events; PLD, Pegylated Liposomal Doxorubicin; qd, once daily Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study Moore KN et al., ASCO 2019, abstract 5513 (poster discussion presentation)

SUMMARY & CONCLUSIONS Adavosertib showed preliminary efficacy and tolerability when combined with chemotherapy Adavosertib 225 mg bid (2.5 days on weeks 1, 2 and 3 each) with carboplatin IV AUC5 every 21 days appeared to be the most promising regimen of all study treatment combinations At a median of 12 months, PFS was higher than usually observed in patients with primary PROG (3-4 months)1 ORR (66.7%) was higher than commonly seen in patients with primary PROC who received P, G, or PLD monotherapy (range, 5-21%)2-5 Hematologic toxicity was more frequent in this cohort than the other evaluated cohorts or would be expected for single-agent chemotherapy; this remains a challenge, which may be mitigated by further optimization of dosing, schedule and supportive medications No genetic biomarkers correlating clearly with tumor type or clinical outcomes have been identified so far 1. Davis A et al. Gynecol Oncol 2014;133:624–31; 2. Naumann RW, Coleman RL. Drugs 2011;71:1397–412; 3. Gynecologic Oncology Group et al. Gynecol Oncol 2006;101:436–40; 4. Markman M et al. Gynecol Oncol 2003;90:593–6; 5. D’Agostino G et al. Gynecol Oncol 2003;88:266–9 Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study Moore KN et al., ASCO 2019, abstract 5513 (poster discussion presentation)

Pembrolizumab with low dose carboplatin for recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer-interim results (poster discussion abstract 5519) John B. Liao, William Rayford Gwin, Renata Urban, Katie Hitchcock-Bernhardt, Andrew L. Coveler, Doreen Higgins, Jennifer S Childs, Hania Shakalia, Sasha E. Stanton, Anna Tinker, Tanya A. Wahl, Richard G. Ancheta, Kathryn F. McGonigle, James Dai, Mary L. Disis, Barbara Ann Goff Abstract 5519: Background: Pembrolizumab has shown activity in advanced recurrent ovarian cancer (AOC) with an 8% response rate and median progression-free survival (PFS) of 2.1 months reported in KEYNOTE-100. Because platinum chemotherapies also induce T cell proliferation and enhance tumor cell recognition through PD-1/PD-L, we assessed the safety and activity of pembrolizumab with carboplatin in platinum resistant AOC. Methods: Key eligibility criteria for this Phase 1/2 single arm trial were platinum resistant AOC, fallopian tube, or peritoneal cancer, progression after subsequent systemic therapy, and ECOG PS 0-1. Pembrolizumab 200mg was given on Day 1 and carboplatin AUC 2 on Day 8 and 15 of a 3 week cycle until progression, unacceptable toxicity, or consent withdrawal. Imaging was done before cycles 4 and 8, then every 3 months and unconfirmed objective response assessed by blinded independent review per RECIST 1.1. Adverse events (AEs) were reported per Common Terminology for Adverse Events v5.0. PD-L1 expression was assessed by immunohistochemistry. Results: 27 patients (median age: 64) had received a median of 5 (range: 2-9) prior lines of systemic therapy, which included bevacizumab in 74% of patients. The most common treatment related (TR) AEs were lymphopenia (18%) and anemia (9%). The majority of TR AEs were grade 1 or 2 (93%). 6% of AEs were grade 3 with lymphopenia the most common. Two grade 4 AEs were neutropenia and lymphopenia. Of 23 patients evaluable for best objective response, 13.0% (95% CI, ) had partial response (PR), 65.2% (95% CI, ) had stable disease (SD), and 21.7% (95% CI, ) had progression. 7 of the 23 evaluable patients (30.4%) had archival tumor with modified percent scoring ≥5 for PD-L1 and all achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Overall median PFS was 4.6 months (95% CI, ). Rate of PFS at 6 months was 40.4% (95% CI, ). Median follow-up is 6.2 months and PFS is based on current data, but 8 patients remain on study and estimates will be updated. Conclusions: Pembrolizumab with low dose carboplatin was well tolerated and showed activity in heavily pretreated platinum resistant AOC. Survival and biomarker analyses are ongoing. Clinical trial information: NCT

Pembrolizumab demonstrated activity in advanced recurrent ovarian cancer (AOC) with an 8% response rate and median PFS of 2.1 months reported in KEYNOTE-100 Platinum based chemotherapies also induce T cell proliferation and enhance tumor cell recognition through PD-1/PD-L Therefore the safety and activity of pembrolizumab with carboplatin was assessed in patients with platinum resistant AOC in a phase 1/2 single arm trial Key eligibility criteria were platinum resistant AOC, fallopian tube, or peritoneal cancer, progression after subsequent systemic therapy, and ECOG PS 0-1 Pembrolizumab 200 mg was given on Day 1 and carboplatin AUC 2 on Day 8 and 15 of a 3 week cycle until progression, unacceptable toxicity, or consent withdrawal Imaging was done before cycles 4 and 8, then every 3 months and unconfirmed objective response assessed by blinded independent review per RECIST 1.1. Adverse events (AEs) were reported per Common Terminology for Adverse Events v5.0. PD-L1 expression was assessed by immunohistochemistry ECOG, Eastern Cooperative Oncology Group Pembrolizumab with low dose carboplatin for recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer-interim results Liao JB et al., ASCO 2019, abstract 5519 (poster discussion presentation)

Background Study scheme Patient characteristics Median (range) n %
AUC2 carboplatin Median (range) n % Age, yr 65 (41-80) - Stage III 21 72% IV 7 24% Other 1 3% Time from initial dx, mo 45.7 (29-107) Time from last chemo, mo 1 (0-10) # previous regimes 5 (2-9) Prior bevacizumab therapy Histology 90% serous Platinum susceptibility Resistant 25 86% Refractory 4 14% pembro pembro pembro Screening/ enrollment (n=27) Repeat cycles for 2 years or until prog./tox Cycle 1 Cycle 2 Cycle 3 Day Phase 1/2 single institution single arm study First objective: PFS, RR, safety Second objective: PD-L1 expression, OS CT scans performed at baseline, and q3 cycle Pembrolizumab with low dose carboplatin for recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer-interim results Liao JB et al., ASCO 2019, abstract 5519 (poster discussion presentation)

REsults 29 patients (median age 65 years) had received a median of 5 prior lines of systemic therapy, which included bevacizumab in 72.4% of patients Most common TEAEs were lymphopenia (18%) and anemia (9%), the majority of TEAEs were grade 1 or 2 (93%). 6% of TEAEs were grade 3 with lymphopenia the most common event. Two TEAEs were grade 4 (lymphopenia, neutropenia) Of 23 patients evaluable for best objective response, 13.0% had partial response (PR), % had stable disease (SD) and 21.7% showed disease progression (PD) 7 of 23 evaluable patients (30.4%) had archival tumor with modified percent scoring ≥5 für PD-L1 and all achieved PR (3/7, 42.8%) or SD (4/7, 57.2%) Overall median PFS was 4.63 months, rate of PFS at 6 months (PFS6) was 44.14% Median follow-up is 8.83 months nd PFS is based on current data, but 2 patients remain on study and estimates will be updated Pembrolizumab with low dose carboplatin for recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer-interim results Liao JB et al., ASCO 2019, abstract 5519 (poster discussion presentation)

RESULTS Best % change in tumor size*
Longitudinal change in tumor size from baseline* 6 mo * by RECIST 1.1; PD, Progressive Disease; PR, Partial Response; SD, Stable Disease Pembrolizumab with low dose carboplatin for recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer-interim results Liao JB et al., ASCO 2019, abstract 5519 (poster discussion presentation)

RESULTs Adverse events (AEs) Most Common
Possibly, Probably, or Definitely Related No % of Related AEs All AEs No % of all AEs Lymphocyte count decreased 43 17.84% 49 11.01% Anemia 24 9.96% 42 9.44% Hypoalbuminemia 19 7.88% 34 7.64% Hypocalcemia 4 1.66% 27 6.07% Neutrophil count decreased 18 7.47% 20 4.49% White blood cell decreased 16 6.64% 4.27% Hypokalemia 3 1.24% 4.04% Platelet count decreased 14 5.81% 17 3.82% Nausea 15 6.22% Vomiting 10 4.15% 13 2.92% AE Gradings 1 162 68% 309 70% 2 60 25% 103 23% 7% 6% 1% 0% 5 Pembrolizumab with low dose carboplatin for recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer-interim results Liao JB et al., ASCO 2019, abstract 5519 (poster discussion presentation)

SUMMARY & CONCLUSIONS Pembrolizumab with low dose carboplatin was well tolerated in this phase 1/2 single arm trial and showed activity in heavily pre-treated platinum resistant advanced ovarian cancer (PR 13%, SD 65%) Survival and biomarker analyses are ongoing What is the investigator’s hypothesized mechanism through which to re-sensitize to platinum? What is the g/sBRCA status of the patients, and did it bias response? Was PD-L1 measured on temporally proximate tissue samples? Do these findings warrant a randomized controlled trial? Pembrolizumab with low dose carboplatin for recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer-interim results Liao JB et al., ASCO 2019, abstract 5519 (poster discussion presentation)

ovarian CAncer (OC) OVERVIEW OF ASCO 2019 POSTER PRESENTATIONS (I)
Efficacy of maintenance olaparib for newly diagnosed, advanced ovarian cancer patients (pts) by BRCA1 or BRCA2 mutation in the phase III SOLO1 trial (Friedlander M, et al. ASCO 2019, abstract 5551) Maintenance olaparib after platinum-based chemotherapy in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Efficacy by surgical and tumor status in the Phase III SOLO1 trial (Mathews CA, et al. ASCO 2019, abstract 5541) Adverse events (AEs) with maintenance olaparib in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Phase III SOLO1 trial (Colombo N, et al. ASCO 2019, abstract 5539) Results of the VENUS study: Bevacizumab efficacy and safety in platinum-sensitive recurrent ovarian cancer (OC)—A real-life ambispective study (Ray-Coquard I, et al. ASCO 2019, abstract 5540) Modeled CA-125 kinetics during neoadjuvant chemotherapy for predicting the likelihood of optimal interval debulking surgery in ovarian cancer patients: Data from CHIVA trial (a GINECO study) (Robelin P, et al. ASCO 2019, abstract 5546) Recurrence of ovarian cancer in BRCAwt patients without maintenance therapy: Real-world evidence (Louie-Gao M, et al. ASCO 2019, abstract 5547)

ovarian CAncer (OC) OVERVIEW OF ASCO 2019 POSTER PRESENTATIONS (II)
Risk factors for progression or death in ovarian cancer patients who completed first-line platinum treatment (Neville Westin S, et al. ASCO 2019, abstract 5548) Bevacizumab beyond progression: Impact of subsequent bevacizumab retreatment in patients with ovarian, fallopian tube, and peritoneal cancer after progression (Previs RA, et al. ASCO 2019, abstract 5557) Bevacizumab or PARP-inhibitors maintenance therapy for platinum-sensitive (PS) recurrent ovarian cancer (rOC)? A network meta- analysis (NMA) (Bartoletti M, et al. ASCO 2019, abstract 5564) Real-world bevacizumab utilization and outcomes in first-line ovarian cancer (Monberg MJ, et al. ASCO 2019, abstract 5578) ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC) (Hardy-Bessard AC, et al. ASCO 2019, abstract TPS5600)

Efficacy of maintenance olaparib for newly diagnosed, advanced ovarian cancer patients by BRCA1 or BRCA2 mutation in the phase III SOLO1 trial (poster abstract 5551) Michael Friedlander, Kathleen N. Moore, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Alla Sergeevna Lisyanskaya, Anne Floquet, Alexandra Leary, Gabe S. Sonke, Charlie Gourley, Susana N. Banerjee, Amit M. Oza, Antonio González-Martín, Carol Aghajanian, William Hampton Bradley, Elizabeth S. Lowe, Ralph Bloomfield, Paul Disilvestro Abstract 5551: Background: In SOLO1 (NCT ), maintenance olaparib resulted in a significant improvement in progression-free survival (PFS) for newly diagnosed, BRCA1- and/or BRCA2-mutated, advanced ovarian cancer pts compared with placebo (HR 0.30, 95% CI 0.23–0.41; median not reached vs 13.8 months; Moore et al. N Engl J Med 2018). We investigated PFS in SOLO1 for the subgroups of pts with BRCA1 mutations (BRCA1m) or BRCA2 mutations (BRCA2m). Methods: All pts were in clinical complete or partial response to platinum-based chemotherapy and were randomized to maintenance olaparib (300 mg twice daily; tablets) or placebo. After 2 years, pts with no evidence of disease discontinued study treatment, but pts with evidence of disease could continue study treatment. PFS by BRCAm was a predefined analysis. BRCAm were identified by central germline (Myriad or BGI) or local testing; Foundation Medicine testing confirmed tumor BRCAm. Results: Median follow-up for PFS was ~41 months in the olaparib and placebo arms. Of 391 randomized pts, 282 had BRCA1m (72%), 106 had BRCA2m (27%) and three (1%) had both (Table). Two pts in the olaparib arm had somatic BRCAm (one BRCA1m, one BRCA2m); all others had germline BRCAm. At the primary data cut-off, 155 pts in the BRCA1-mutated group (55%), 43 in the BRCA2-mutated group (41%) and none in the BRCA1/2-mutated group had disease progression. The percentage of BRCA1-mutated pts who received olaparib and were progression-free at 1, 2 and 3 years was 86%, 69% and 53% (vs 52%, 36% and 26% receiving placebo) and for BRCA2-mutated pts was 92%, 85% and 80% (vs 50%, 32% and 29%, respectively). Conclusions: Significant PFS benefit with olaparib versus placebo was demonstrated for all pts, regardless of whether they had BRCA1m or BRCA2m. Statistical tests were not used to compare BRCA1- and BRCA2-mutated pts, but those with BRCA2m appeared to receive greater benefit from maintenance olaparib than those with BRCA1m. Clinical trial information: NCT

In SOLO1, maintenance olaparib resulted in a significant improvement in progression- free survival (PFS) for newly diagnosed, BRCA1- and/or BRCA2-mutated, advanced ovarian cancer patients compared with placebo (HR 0.30, 95% CI 0.23–0.41; median not reached vs 13.8 months)1 The present analysis investigated the PFS in SOLO1 for the subgroups of patients with BRCA1 or BRCA2 mutations * NCT CR, complete response PR, partial response All patients were in clinical CR or PR to platinum-based chemotherapy and were randomized to maintenance olaparib (300 mg twice daily; tablets) or placebo After 2 years, patients with no evidence of disease discontinued study treatment, but those with evidence of disease could continue study treatment PFS by BRCAm was a predefined analysis. BRCAm were identified by central germline (Myriad or BGI) or local testing; Foundation Medicine testing confirmed tumor BRCAm 1. Moore KN et al. New Engl J Med 2018 Efficacy of maintenance olaparib for newly diagnosed, advanced ovarian cancer patients (pts) by BRCA1 or BRCA2 mutation in the phase III SOLO1 trial Friedlander M et al., ASCO 2019, abstract 5551 (poster presentation)

SOLO1 study design and results
Investigator-assessed PFS by BRCA1m or BRCA2m N=391 BRCA1m BRCA2m Olaparib (n=191) Placebo (n=91) Olaparib (n=66) Placebo (n=40) Median PFS, months 41.4 13.8 NR HR (95% CI) 0.41 (0.300.56) 0.20 (0.10037) Kaplan-Meier estimates of progression-free patients (%) 1 year 2 years 3 years 86 69 53 52 36 26 92 85 80 50 32 29 2:1 randomization Stratified by response to platinum-based chemotherapy Olaparib tablets 300 mg bid N=260 Placebo N=131 Treat for 2 years or until disease progression At 2 years: No evidence of disease stop treatment Ongoing partial response could continue treatment until disease progression Primary endpoint Investigator assessed PFS (modified RECIST 1.1) bid, twice daily; HR, hazard ratio; PFS, progression-free survival; RECIST; Response Evaluation Criteria in Solid Tumors; NR, not reached Efficacy of maintenance olaparib for newly diagnosed, advanced ovarian cancer patients (pts) by BRCA1 or BRCA2 mutation in the phase III SOLO1 trial Friedlander M et al., ASCO 2019, abstract 5551 (poster presentation)

SUMMARY & CONCLUSIONS In SOLO1, a significant PFS benefit with olaparib maintenance therapy versus placebo was demonstrated for all patients regardless of whether they had a BRCA1m or a BRCA2m Patients with BRCA2m appeared to receive an even greater benefit in PFS from maintenance olaparib than those with a BRCA1m, although statistical tests were not used to directly compare these subgroups. This trend was not observed in SOLO2 and further studies are needed In terms of patient selection, all BRCA-mutated ovarian cancer patients receive substantial benefit from maintenance olaparib in the newly diagnosed setting Efficacy of maintenance olaparib for newly diagnosed, advanced ovarian cancer patients (pts) by BRCA1 or BRCA2 mutation in the phase III SOLO1 trial Friedlander M et al., ASCO 2019, abstract 5551 (poster presentation)

Think out of the Box PARP inhibition also demonstrates efficacy in gBRCAm patients with advanced pancreatic cancer POLO3 was a randomized, double-blind, placebo-controlled, phase 3 trial Aim: To evaluate the efficacy of olaparib as maintenance therapy in patients (n=154) with gBRCAmut and metastatic pancreatic cancer and disease that had not progressed during 1L platinum-based CT Result: PFS benefit for olaparib vs placebo (7.4 mos vs 3.8 mos, HR 0.53, p=0.004) PFS efficacy did not translate into significant benefit for overall survival (18.9 mos vs mos) Nevertheless these data can be regarded as clinically relevant due to lack of treatment alternatives Two randomized phase 2 trials evaluating PARP-inhibitor niraparib in advanced pancreatic cancer are ongoing* * ASCO 2019 abstract TPS 4161 (NCT ); ASCO 2019 abstract TPS 4168 (NCT ) Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial. Kindler HL et al., ASCO 2019, late breaking abstract LBA4 (oral presentation)

Maintenance olaparib after platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (BRCAm): Efficacy by surgical and tumor status in the Phase III SOLO1 trial (poster abstract 5541) Cara Amanda Mathews, Kathleen N. Moore, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Michael Friedlander, Alla Sergeevna Lisyanskaya, Anne Floquet, Alexandra Leary, Gabe S. Sonke, Charlie Gourley, Susana N. Banerjee, Amit M. Oza, Antonio González-Martín, Carol Aghajanian, William Hampton Bradley, Elizabeth S. Lowe, Ralph Bloomfield, Paul Disilvestro Abstract 5541: Background: In SOLO1 (NCT ), maintenance olaparib significantly improved progression-free survival (PFS) vs placebo (HR 0.30; 95% CI 0.23–0.41; Moore et al. N Engl J Med 2018) in pts with newly diagnosed advanced OC and a BRCAm. This analysis evaluates olaparib efficacy by timing of surgery, presence of residual tumor following surgery and response status after completion of chemotherapy in SOLO1. Methods: Pts underwent cytoreductive surgery and were in clinical complete response (CR) or partial response (PR) after platinum-based chemotherapy. Pts were stratified by response and received olaparib tablets 300 mg twice daily or placebo. Investigator-assessed PFS and objective response were assessed using modified RECIST v1.1. Results: 260 pts were randomized to olaparib and 131 to placebo; one pt did not receive placebo. Median follow-up was 41 months in both arms. 63% and 35% of pts underwent upfront and interval surgery, 21% and 76% had residual and no residual macroscopic disease after surgery, and 74% and 26% entered the study in clinical CR and PR (based on electronic case report form [eCRF] data). PFS was significantly improved regardless of the timing of surgery, residual disease status after surgery or response after platinum-based chemotherapy (Table). In pts with baseline radiologic evidence of disease (n=80; eCRF), the objective response rate was 43% for olaparib (CR, 28%) and 23% for placebo (CR, 12%). Conclusions: Maintenance olaparib improved outcomes compared with placebo in pts with newly diagnosed advanced OC and a BRCAm, regardless of surgical or tumor status. Clinical trial information: NCT

* NCT In SOLO1, maintenance olaparib significantly improved progression-free survival (PFS) vs placebo (HR 0.30; 95% CI 0.23–0.41) in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation1 The present analysis evaluates olaparib efficacy by timing of surgery, presence of residual tumor following surgery and response status after completion of chemotherapy in SOLO1 SOLO1 patients underwent cytoreductive surgery and were in clinical complete response (CR) or partial response (PR) after platinum-based chemotherapy Patients were stratified by response and received olaparib tablets 300 mg twice daily or placebo Investigator-assessed PFS and objective response were assessed using modified RECIST v1.1 1. Moore KN et al. New Engl J Med Maintenance olaparib after platinum-based chemotherapy in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Efficacy by surgical and tumor status in the Phase III SOLO1 trial Mathews CA et al., ASCO 2019, abstract 5541 (poster presentation)

Results Kaplan-Meier (KM) estimate of investigator-assessed PFS based on timing of surgery 100 Olaparib: Upfront surgery Placebo: Upfront surgery 90 Olaparib: Interval surgery 80 Placebo: Interval surgery 70 60 Patients free from disease progression and death (%) 50 40 30 20 10 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Months since randomization Num. patients at risk: Olaparib: Upfront surgery Placebo: Upfront surgery Olaparib: Interval surgery Placebo: Interval surgery PFS, progression-free survival Maintenance olaparib after platinum-based chemotherapy in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Efficacy by surgical and tumor status in the Phase III SOLO1 trial Mathews CA et al., ASCO 2019, abstract 5541 (poster presentation)

Results KM estimate of investigator-assessed PFS based on residual disease status following surgery 100 Olaparib: No residual disease Placebo: No residual disease Olaparib: Residual disease Placebo: Residual disease 90 80 70 60 Patients free from disease progression and death (%) 50 40 30 20 10 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Months since randomization Num. patients at risk: Olaparib: No residual disease Placebo: No residual disease Olaparib: Residual disease Placebo: Residual disease PFS, progression-free survival Maintenance olaparib after platinum-based chemotherapy in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Efficacy by surgical and tumor status in the Phase III SOLO1 trial Mathews CA et al., ASCO 2019, abstract 5541 (poster presentation)

SUMMARY & CONCLUSIONS Maintenance treatment with PARP inhibitor olaparib improved outcomes vs placebo in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1 study) Median follow-up was 41 months in both arms Maintenance treatment with olaparib was associated with a PFS benefit regardless of the timing of surgery, residual disease status after surgery, or response following platinum-based chemotherapy Maintenance olaparib after platinum-based chemotherapy in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Efficacy by surgical and tumor status in the Phase III SOLO1 trial Mathews CA et al., ASCO 2019, abstract 5541 (poster presentation)

Adverse events with maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation (BRCAm): Phase III SOLO1 trial (poster abstract 5539) Nicoletta Colombo, Kathleen N. Moore, Giovanni Scambia, Ana Oaknin, Michael Friedlander, Alla Sergeevna Lisyanskaya, Anne Floquet, Alexandra Leary, Gabe S. Sonke, Charlie Gourley, Susana N. Banerjee, Amit M. Oza, Antonio González-Martín, Carol Aghajanian, William Hampton Bradley, Jae-Weon Kim, Elizabeth S. Lowe, Ralph Bloomfield, Paul Disilvestro Abstract 5539: Background: In SOLO1 (NCT ), maintenance olaparib provided a substantial progression-free survival benefit vs placebo in newly diagnosed pts with advanced OC, a BRCAm and clinical complete or partial response to platinum therapy (HR 0.30; 95% CI 0.23–0.41) and was well tolerated (Moore et al.NEJM 2018). We analysed the most common AEs and hematologic AEs in SOLO1. Methods: Pts received olaparib tablets 300 mg twice daily or placebo until progression unless they had no evidence of disease at 2 years, in which case treatment stopped. AEs were graded using CTCAE v4.0. Results: Of 391 pts randomized, 390 (olaparib, 260; placebo, 130) were treated and included in the safety analysis. Median treatment duration was approximately 25 months for olaparib vs 14 for placebo. Median time to first onset of the most common AEs (nausea, vomiting, fatigue/asthenia, anemia) and neutropenia and thrombocytopenia was < 3 months; the first event lasted a median of < 2 months, apart from fatigue/asthenia, which lasted a median of < 4 months (Table). AEs were usually managed with supportive therapy and/or dose modification; few pts discontinued. Conclusions: AEs in newly diagnosed pts with advanced OC treated with olaparib usually occurred early and were manageable, with few discontinuations. Clinical trial information: NCT

* NCT In the SOLO1 trial*, maintenance therapy with olaparib provided a substantial PFS benefit vs placebo in newly diagnosed patients with advanced ovarian cancer, a BRCAm and clinical CR or PR to platinum therapy (HR 0.30), and was well tolerated1 The present study analysed the most common adverse events (AE) and hematologic AEs in SOLO1 PFS, progression-free survival CR, complete response PR, partial response Patients (n=391) received olaparib tablets 300 mg twice daily or placebo until progression unless they had no evidence of disease at 2 years, in which case treatment stopped AEs were graded using CTCAE v4.0. CTCAE, Common Terminology Criteria for Adverse Events 1. Moore KN et al. New Engl J Med 2018 Adverse events (AEs) with maintenance olaparib in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Phase III SOLO1 trial Colombo N et al., ASCO 2019, abstract 5539 (poster presentation)

Results − Overview of adverse events (AEs)
Summary of the first occurrence of most commonly reported non-hematologic and hematologic AEs* Non-hematologic AEs Nausea Fatigue/asthenia§ Vomiting Olaparib Placebo Patients with events (all grades), n (%) 201 (77) 49 (38) 165 (63) 54 (42) 104 (40) 19 (15) Median time to first onset, months (range) 0.13 (0.03–21.49) 0.69 (0.03–17.51) 0.72 (0.03–33.91) 1.54 (0.03–20.24) 1.46 (0.03–20.60) 1.94 (0.03–21.91) Patients with a first event with a resolution date (all grades),† n (%) 194 (75) 47 (36) 126 (48) 44 (34) 101 (39) Median duration of first event,‡ months 1.41 0.43 3.48 2.30 0.07 0.03 Hematologic AEs Anemia§ Neutropenia§ Thrombocytopenia§ Olaparib Placebo Patients with events (all grades), n (%) 101 (39) 13 (10) 60 (23) 15 (12) 29 (11) 5 (4) Median time to first onset, months (range) 1.94 (0.03–44.52) 1.81 (0.26–24.15) 1.77 (0.26–29.57) 0.49 (0.26–12.02) 2.83 (0.30–25.76) 7.39 (0.26–10.38) Patients with a first event with a resolution date (all grades),† n (%) 93 (36) 12 (9) 57 (22) 14 (11) 25 (10) 4 (3) Median duration of first event,‡ months 1.87 1.64 0.76 0.95 * The safety analysis set comprised 260 patients in the olaparib group and 130 in the placebo group; † Number (%) of patients with a first event that has a resolution date; ‡ AEs with no end date were censored at the end of the safety follow-up or at data cut-off, as applicable; § Grouped-term events. Adverse events (AEs) with maintenance olaparib in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Phase III SOLO1 trial Colombo N et al., ASCO 2019, abstract 5539 (poster presentation)

Results − dose reductions
Olaparib dose reductions over time 100 90 80 70 60 Patients (%) 50 40 30 20 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Treatment time (months) Num. patients at risk: 260 248 242 234 226 224 215 214 212 204 201 198 193 188 187 181 180 176 174 173 172 171 169 162 No dosing† Other regimen* 200 mg bid 250 mg bid 300 mg bid Number of patients treated at the start of each month. * ‘Other regimen’ includes 150 mg qd, 150 mg bid, 200 mg qd, 250 mg qd, 300 mg qd, and 450 mg bid; † The category of ‘no dosing’ was assigned if the patient had dosing interrupted for the entire month window. qd, once daily Adverse events (AEs) with maintenance olaparib in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Phase III SOLO1 trial Colombo N et al., ASCO 2019, abstract 5539 (poster presentation)

SUMMARY & CONCLUSIONS In patients with newly diagnosed advanced ovarian cancer treated with PARP inhibitor olaparib, adverse events (AE) usually occurred early and were manageable with supportive therapy and / or dose modifications The tolerability profile of olaparib in patients with newly diagnosed OC was consistent with that reported in the relapsed-disease setting, with no new safety signals identified Most common AEs were nausea, vomiting, fatigue/asthenia, anemia, neutropenia and thrombocytopenia Given that anemia predominantly occurred early, stricter monitoring is required at the beginning of treatment Treatment discontinuations were rare Adverse events (AEs) with maintenance olaparib in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Phase III SOLO1 trial Colombo N et al., ASCO 2019, abstract 5539 (poster presentation)

Results of the VENUS study: Bevacizumab efficacy and safety in platinum-sensitive recurrent ovarian cancer - A real-life ambispective study (poster abstract 5540) Isabelle Laure Ray-Coquard, Jerome Alexandre, Francois Goldwasser, Jean-Philippe Spano, Dominique Berton-Rigaud, Aude-Marie Savoye, Michel Fabbro, Fernando Bazan, Elsa Kalbacher, Nadia Raban, Claire Giraud, Virginie Pottier, Frédéric Selle, Anne Patsouris, Claire Garnier-Tixidre, Anne Mercier Blas, Jocelyne Provencal, Fabien Brocard, Jessica Berdougo-Tritz, Vincent Launay-Vacher Abstract 5540: Background: The VENUS study reports on the efficacy/safety of bevacizumab (Bev) in patients (pts) treated in the real-life setting. Methods: In this multicentric observational ambispective VENUS study, all Pts were naive of any antiVEGF and received Bev +/- chemotherapy. Pts were followed until progression or death, for a maximum of 3 years since Bev initiation. De novo side effects were defined as symptoms for which patients were naïve at baseline. Results: 148 OC pts were included (27 centres), 10 excluded and 8 were lost of follow-up. 52 were retrospective. Median age 64 years (55-70). 84.1% were advanced. Median duration of Bev was 8.6 months, min 1 max 36 months. Initial Bev dose was 15 mg/kg Q3W for 65.3%, 10.0 for 22.5%, 7.5 for 10.2% and 5.0 for 2%. 2 pts presented with thrombotic micro-angiopathy (1.4%). Before Bev, hypertension (HTN) was present in 28.9%; proteinuria in 11.3%. Incidence of de novo HTN was 25%. 43 pts (31.2%) experienced de novo Grade 1-2 Pu, for a total of 56 events, no grade 3-4 was observed. A total of 12 Grade 4 events occurred: 9 neutropenia and 3 thrombopenia. Mean overall survival (OS) and progression free survival (PFS) were 30.0 and 13.3 months, respectively. Conclusions: 1) 1/3 of pts were treated at low doses in this real-life study; 2) safety of Bev in real-life was manageable and as expected, 3) OS and PFS were consistent with those reported in the OCEANS study: PFS 12.4 and OS 33.6 months but lower than in the GOG-0213 study: PFS 13.8 and OS 42.6 months. De novo events recorded during follow-up.

The VENUS study reports on the efficacy and safety of bevacizumab (BEV) in patients with platinum-sensitive recurrent ovarian cancer (PSROC) treated in a real-life setting 148 PSROC patients were included (27 centres), 10 excluded and 8 were lost to follow-up. 52 patients were retrospective In this multicentric observational ambispective study, all patients were naive for any anti-VEGF agents and received BEV +/- chemotherapy All patients were followed until progression or death, for a maximum of 3 years after BEV initiation De novo side effects were defined as symptoms for which patients were naïve at baseline VEGF, Vascular Endothelial Growth Factor Results of the VENUS study: Bevacizumab efficacy and safety in platinum-sensitive recurrent ovarian cancer (OC)—A real-life ambispective study Ray-Coquard I et al., ASCO 2019, abstract 5540 (poster presentation)

Results & CONCLUSIONS Results Conclusions
Mean overall survival (OS) in the VENUS study was 30.0 months Mean progression-free survival (PFS) in the VENUS study was 13.3 months Conclusions In this real-life study, 1/3 of patients with PSROC were treated with low doses of bevacizumab The safety of bevacizumab under real-life conditions was manageable and as expected Results of OS and PFS were consistent with those reported in the OCEANS study (PFS 12.4 months, OS 33.6 months) but lower than in the GOG-0213 study (PFS 13.8 months, OS 42.6 months) PSROC, Platinum-sensitive Recurrent Ovarian Cancer Results of the VENUS study: Bevacizumab efficacy and safety in platinum-sensitive recurrent ovarian cancer (OC)—A real-life ambispective study Ray-Coquard I et al., ASCO 2019, abstract 5540 (poster presentation)

Modelled CA-125 kinetics during neoadjuvant chemotherapy for predicting the likelihood of optimal interval debulking surgery in ovarian cancer patients: Data from CHIVA trial (a GINECO study) (poster abstract 5546) Patrick Robelin, Michel Tod, Olivier Colomban, Christophe Louvet, Jean-Pierre Lotz, Sophie Abadie Lacourtoisie, Michel Fabbro, Christophe Desauw, Nathalie Bonichon, Jean Emmanuel Kurtz, Philippe Follana, Marianne Leheurteur, Francesco Del Piano, Carol René Alliot, Gaetan De Rauglaudre, Isabelle Laure Ray-Coquard, Pierre Combe, Annick Chevalier, Florence Joly, Benoit You Abstract 5546: Background: A pre-operative predictive biomarker of CC0 interval debulking surgery (IDS) likelihood would be helpful. The modeled CA125 elimination rate constant KELIM predicts OS in 1st line setting (You et al. Clin Cancer Res 2019). The predictive/prognostic values of KELIM regarding CC scores at IDS, and survivals, during neo-adjuvant chemotherapy were assessed. Methods: The data of the CHIVA randomized phase II trial, comparing carboplatin-paclitaxel +/- nintedanib before IDS (NCT ), were used. A semi-mechanistic model was built to describe CA125 longitudinal kinetics during the first 100 treatment days. The relationships between KELIM and IDS CC scores, PFS & OS, were assessed with other major prognostic factors (grade, histology, GCIG CA125 response, FIGO stage, and arm) using multivariate logistic regression (logit), C-index & survival tests. Results: The longitudinal kinetics of 529 CA125 values, assessed every 3 weeks during neo-adj chemotherapy, were modeled in 133 patients (out of 188). KELIM (as a continuous covariate) was the only significant predictive factor of CC0 IDS likelihood using multivariate analyses (OR = 12.37, 95% CI [ ]). CC0 IDS probability can be estimated with patient KELIM: ≥ 90 % if standardized KELIM ≥ Non-parametric survival models confirmed the independent predictive values of KELIM categorized by terciles regarding PFS & OS (Table). The parametric model linking KELIM (as a continuous covariate) with OS allows to predict the patient survivals (months) based on their estimated KELIM (HR = 0.20, [ ]). Conclusions: The prognostic & predictive values of the modeled CA125 KELIM are also confirmed regarding CC0 IDS likelihood, PFS and OS with neo-adjuvant chemotherapy. Patient KELIM is calculable online, based on observed CA125 values, on Clinical trial information:

A pre-operative predictive biomarker of CC0 interval debulking surgery (IDS) likelihood would be helpful in patients with ovarian cancer The modelled CA125 kinetic parameter KELIM predicts PFS and OS in 1st line setting in patients treated with primary surgery1 The modeled CA125 elimination rate constant KELIM predicts OS in 1st line setting1 The predictive/prognostic values of KELIM regarding CC scores at IDS, and survivals, during neo-adjuvant chemotherapy were assessed Data of the CHIVA randomized phase II trial*, comparing carboplatin-paclitaxel +/- nintedanib before IDS was used A semi-mechanistic model was built to describe CA125 longitudinal kinetics during the first 100 treatment days The relationships between KELIM and IDS CC scores, PFS & OS, were assessed with other major prognostic factors (grade, histology, GCIG CA125 response, FIGO stage, and arm) using multivariate logistic regression (logit), C-index & survival tests * NCT 1. Colomban O et al. Clin Cancer Res 2019; CC, Completeness of Cytoreduction (CC0, no macroscopic residual tumor after surgery) Modelled CA-125 kinetics during neoadjuvant chemotherapy for predicting the likelihood of optimal interval debulking surgery in ovarian cancer patients: Data from CHIVA trial (a GINECO study) Robelin P et al., ASCO 2019, abstract 5546 (poster presentation)

KELIM and tumor response rates (RECIST 1.1)
Standardized KELIM 0.5 1.0 1.5 Complete responses Partial responses Stable diseases Progressions Modelled CA-125 kinetics during neoadjuvant chemotherapy for predicting the likelihood of optimal interval debulking surgery in ovarian cancer patients: Data from CHIVA trial (a GINECO study) Robelin P et al., ASCO 2019, abstract 5546 (poster presentation)

Risk prediction of subsequent PR relapses
Platinum Resistant (PR) Recurrence Score Probability of Platinum Resistant Relapse Standardized KELIM CC1-CC2 cytoreductive surgery and standardized KELIM Standardized KELIM alone Complete CC0 cytoreductive surgery and standardized KELIM 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 1.4 1.2 1.6 1.8 2 2.2 2.4 The patients with CC0 interval debulking surgery and standardized KELIM = 0.2 have 35% risk of subsequent platinum resistant relapse CC, Completeness of Cytoreduction Modelled CA-125 kinetics during neoadjuvant chemotherapy for predicting the likelihood of optimal interval debulking surgery in ovarian cancer patients: Data from CHIVA trial (a GINECO study) Robelin P et al., ASCO 2019, abstract 5546 (poster presentation)

SUMMARY & CONCLUSIONS Data of the CHIVA randomized phase II trial in patients with ovarian cancer were used to evaluate the predictive and prognostic values of KELIM (a modelled CA125 elimination rate constant) regarding CC scores at interval debulking surgery (IDS), and survivals, during neo-adjuvant chemotherapy The results of this analysis confirm the prognostic and predictive values of the modelled CA125 KELIM regarding CC0 IDS likelihood, PFS and OS with neo-adjuvant chemotherapy Patient KELIM is calculable online, based on observed CA125 values ( Modelled CA-125 kinetics during neoadjuvant chemotherapy for predicting the likelihood of optimal interval debulking surgery in ovarian cancer patients: Data from CHIVA trial (a GINECO study) Robelin P et al., ASCO 2019, abstract 5546 (poster presentation)

Recurrence of ovarian cancer in BRCAwt patients without maintenance therapy: Real-world evidence (poster abstract 5547) Melinda Louie-Gao, Ebru Aydin, Premal H. Thaker; TESARO, Inc., Waltham, MA; Washington University School of Medicine, St. Louis, MO Abstract 5547: Background: Development of platinum resistance is a major clinical challenge in ovarian cancer (OC) treatment. In the phase 3 ENGOT-OV16/NOVA trial of the poly(ADP-ribose) polymerase inhibitor (PARPi) niraparib, 55% of BRCA wild-type (BRCAwt) patients (pts) receiving placebo developed platinum resistance after their last platinum-based therapy (ie, progressive disease within 6 months of their last chemotherapy [CT] dose). Niraparib, a PARPi approved for the maintenance treatment of adult pts with recurrent OC following platinum-based CT, significantly prolongs progression-free survival (PFS). This real-world data analysis investigated the risk of platinum eligibility loss for BRCAwt pts who did not receive maintenance therapy after platinum treatment. Methods: This retrospective study identified 5,535 pts with OC from January 2011–October 2018 using data from Flatiron, a longitudinal, demographically and geographically diverse database derived from records of > 265 cancer clinics and > 2 million US cancer pts. BRCAwt pts who had received ≥2 lines of platinum-based CT, had disease progression ≥6 months after their previous line of therapy, and had no maintenance therapy (PARPi, bevacizumab, or CT agents) after their current treatment were included. Kaplan-Meier analysis was used to estimate the probability of pts initiating next treatment or death, whichever occurred first, within 6 months. Results: Of 5,535 pts diagnosed with OC, 147 BRCAwt pts met the inclusion/exclusion criteria of this analysis (similar to ENGOT-OV16/NOVA placebo arm). An estimated 56% of pts received the next treatment or died within 6 months after their last platinum-based therapy. Median time to next therapy or death was 5.1 months (95% confidence interval, 3.1–7.2). Conclusions: Our real-world data analysis shows that 56% of BRCAwt pts who received platinum-based treatment without maintenance therapy had recurrent OC within 6 months, classifying them as platinum resistant. Use of maintenance treatment options, such as niraparib, has been shown to significantly prolong PFS after platinum-based CT and may be beneficial in extending the platinum-free interval, enabling pts to remain eligible for further platinum therapy.

Development of platinum resistance is a major clinical challenge in ovarian cancer (OC) treatment. In the phase 3 ENGOT-OV16/NOVA trial of PARP inhibitor niraparib, 55% of BRCAwt patients receiving placebo developed platinum resistance after their last platinum- based therapy (ie, PD within 6 months of their last chemotherapy dose). Niraparib has been shown to significantly prolong PFS This real-world data analysis investigated the risk of platinum eligibility loss for BRCAwt pts who did not receive maintenance therapy after platinum treatment BRCAwt, BRCA wild type PD, disease progression PFS, progression-free survival This retrospective study identified 5,535 patients with OC from using data from Flatiron database* BRCAwt patients who had received ≥2 lines of platinum-based CT, had disease progression ≥ 6 months after their previous line of therapy, and had no maintenance therapy (PARPi, bevacizumab, or CT agents) after their current treatment were included Kaplan-Meier analysis was used to estimate the probability of patients initiating next treatment or death, whichever occurred first, within 6 months * a longitudinal, demographically & geographically diverse database derived from records of > 265 cancer clinics and > 2 million US cancer pts ENGOT, European Network for Gynecological Oncological Trial groups Recurrence of ovarian cancer in BRCAwt patients without maintenance therapy: Real-world evidence Louie-Gao M et al., ASCO 2019, abstract 5547 (poster presentation)

Study design* Lx-1 platinum
* reflects a real-world data situation Lx+1, treatment, death, or lost to follow-up Estimate probability of PD <6 months after Lx Active surveillance PD Lx-1 platinum Active surveillance ≥6 months Lx platinum CR or PR <6 months ≥6 months CR, Complete Response; Lx, Last line of Chemotherapy; Lx-1, Penultimate Line of Chemotherapy; Lx+1, Next Line of Chemotherapy; PD, Progressive Disease; PR, Partial Response Recurrence of ovarian cancer in BRCAwt patients without maintenance therapy: Real-world evidence Louie-Gao M et al., ASCO 2019, abstract 5547 (poster presentation)

Probability of time to next treatment
Results Time to next treatment in BRCAwt patients 1.0 + Censored 0.9 Event /N: 99/147 mTTNT (95% CI): 5.1 months ( ) 0.8 0.7 0.6 Probability of PD at 6 months: 56% Probability of time to next treatment 0.5 0.4 0.3 0.2 0.1 0.0 6 12 18 24 30 Months BRCAwt, BRCA wild-type; CI, Confidence Interval; mTTNT, median Time To Next Treatment; PD, Progressive Disease Recurrence of ovarian cancer in BRCAwt patients without maintenance therapy: Real-world evidence Louie-Gao M et al., ASCO 2019, abstract 5547 (poster presentation)

SUMMARY & CONCLUSIONS Results of this real-world data analysis revealed that 56% ovarian cancer (OC) patients with BRCA wild-type who received platinum-based treatment without maintenance therapy had recurrent OC within 6 months, classifying them as platinum resistant Median time to next therapy or death was 5.1 months Use of maintenance treatment options, such as niraparib, has been shown to significantly prolong PFS after platinum-based CT and may be beneficial in extending the platinum-free interval, enabling patients to remain eligible for further platinum-based therapy Recurrence of ovarian cancer in BRCAwt patients without maintenance therapy: Real-world evidence Louie-Gao M et al., ASCO 2019, abstract 5547 (poster presentation)

Risk factors for progression or death in ovarian cancer patients who completed first-line platinum treatment (poster abstract 5548) Shannon Neville Westin, Melinda Louie-Gao, Enkhe Badamgarav, Mohan V. Bala, Premal H. Thaker; The University of Texas MD Anderson Cancer Center, Houston, TX; TESARO, Inc., Waltham, MA; Washington University School of Medicine, St. Louis, MO Abstract 5548: Background: Limited real-world information is available in ovarian cancer (OC) regarding prognostic factors for disease progression or death after initial treatment. Here, we assessed potential prognostic risk factors in OC patients (pts) who completed first-line (1L) platinum-based chemotherapy (CT) using real-world data. Methods: This retrospective study identified 5535 pts diagnosed with OC from January 2011–October 2018 from the Flatiron database, a longitudinal, demographically and geographically diverse database derived from health records from > 265 cancer clinics and > 2 million US cancer pts. Stage III/IV OC pts who completed 1L platinum-based CT after primary debulking or interval debulking surgery were included. Pts who received a poly(ADP-ribose) polymerase inhibitor (PARPi) in 1L treatment or as maintenance therapy after 1L treatment were excluded. Cox proportional hazards model was used to assess the association between baseline factors (neoadjuvant CT, disease stage, residual disease, BRCA status, ECOG, age, platelet count, hemoglobin, and neutrophil count) and time to next treatment (TTNT; a proxy for progression-free survival) or overall survival (OS) in these pts. Results: 1064 of 5535 pts were eligible per our inclusion/exclusion criteria. Neoadjuvant treatment, stage of disease, residual disease after surgery, and BRCA mutation (BRCAmut) status were significant prognostic factors for either TTNT or OS. Neoadjuvant chemotherapy pts had a shorter TTNT (hazard ration [HR] = 1.37; P= .001) and OS (HR = 1.64; P= .0002) than pts who underwent primary surgery after adjusting for other covariates. Stage IV pts had a shorter TTNT (HR = 1.26; P= .01) and OS (HR = 1.24; P= .09) than stage III pts. OS was also worse in pts with vs without residual disease (HR = 1.27; P= .04) and worse in BRCAwt than BRCAmut pts (HR = 1.37; P= .10). Conclusions: In this retrospective analysis of a real-world data set, BRCAwt status was associated with higher risk of death. Receipt of neoadjuvant CT, higher stage of disease at diagnosis, or presence of residual disease after surgery were also associated with a shorter TTNT or higher risk of death. These real-world data confirm previously identified prognostic factors.

There is limited real-world information available in ovarian cancer (OC) regarding prognostic factors for disease progression or death after initial treatment The present study assessed potential prognostic risk factors in OC patients who completed first-line (1L) platinum-based chemotherapy (CT) using real-world data This retrospective study identified 5,535 OC patients from using Flatiron database* Stage III/IV OC pts who completed 1L platinum-based CT after primary debulking or interval debulking surgery were included. Patients who received PARPi in 1L treatment or as maintenance therapy after 1L treatment were excluded Cox proportional hazards model was used to assess the association between baseline factors (neoadjuvant CT, disease stage, residual disease, BRCA status, ECOG, age, platelet count, hemoglobin, and neutrophil count) and time to next treatment or overall survival in these patients * a longitudinal, demographically & geographically diverse database derived from records of > 265 cancer clinics and > 2 million US cancer pts Risk factors for progression or death in ovarian cancer patients who completed first-line platinum treatment Neville Westin S et al., ASCO 2019, abstract 5548 (poster presentation)

Results Patient attrition Study attrition Attrition Patients, n (%)
Ovarian cancer cohort (1/1/2011–10/31/2018) 5535 (100) Patients received 1L treatment 4081 (74) Patients received 1L platinum-based CT 3499 (63) Patients had stage III/IV disease 2314 (42) Excluded patients whose surgery date was unknown 2312 (42) Platinum-based CT criteria: a. Patients without surgery in the 1L must have had ≥3 and ≤10 cycles of platinum-based CT; b. Patients treated with primary debulking surgery must have had ≥5 and ≤10 cycles of platinum-based CT; c. Patients must have had ≥2 and ≤10 postoperative cycles of platinum based CT following interval debulking surgery 1346 (24) Excluded patients who received 1L PARP inhibitor treatment 1345 (24) Patients who had active surveillance after 1L treatment 1217 (22) Excluded patients who started 2L treatment within 2 months 1064 (19) Sensitivity analysis Excluded patients who started 2L treatment within 3 months 1018 (18) 1L, First-Line; 2L, Second-Line; CT, Chemotherapy; PARP, Poly(ADP-Ribose) Polymerase Risk factors for progression or death in ovarian cancer patients who completed first-line platinum treatment Neville Westin S et al., ASCO 2019, abstract 5548 (poster presentation)

Results Kaplan-Meier analysis (TTNT)
Patients receiving neoadjuvant CT had a shorter TTNT than those who did not* 1.0 Events Median (95% CI) BRCAmut: 90/144 14.2 mo (13−18) BRCAwt: 292/469 11.6 mo (10−12) P=0.10 BRCAwt vs BRCAmut: HR, 1.2 (95% CI, 1.0–1.5) 1.0 Events Median (95% CI) Stage III: 449/775 12.9 mo (12−15) Stage IV: 169/289 8.9 mo (8−10) P<0.0001 Stage IV vs III: HR, 1.5 (95% CI, 1.3–1.8) 1.0 Events Median (95% CI) PDS: 393/667 13.8 mo (12−16) IDS: 165/261 10.2 mo (9−12) No surgery: 87/136 6.1 mo (4−8) P<0.0001 IDS vs PDS: HR, 1.5 (95% CI, 1.2–1.8) No surgery vs PDS: HR, 2.7 (95% CI, 2.2–3.5) 0.9 0.9 0.9 0.8 0.8 0.8 0.7 0.7 0.7 0.6 0.6 0.6 Probability of time to next treatment Probability of time to next treatment Probability of time to next treatment 0.5 0.5 0.5 0.4 0.4 0.4 0.3 0.3 0.3 0.2 0.2 0.2 PDS 0.1 BRCAmut BRCAwt 0.1 Stage III 0.1 IDS Stage IV No surgery 0.0 0.0 0.0 6 12 18 24 30 36 42 48 54 60 6 12 18 24 30 36 42 48 54 60 6 12 18 24 30 36 42 48 54 60 Months Months Months BRCmut BRCAwt Stage III Stage IV PDS IDS No surgery *after adjusting for other covariates BRCAmut, BRCA mutated; BRCAwt, BRCA wild-type; CI, Confidence interval; HR, Hazard Ratio; IDS, Interval Debulking Surgery; mo, months; PDS, Primary Debulking Surgery; TTNT, Time To Next Treatment Risk factors for progression or death in ovarian cancer patients who completed first-line platinum treatment Neville Westin S et al., ASCO 2019, abstract 5548 (poster presentation)

Results Patients receiving neoadjuvant CT had a shorter TTNT than those who did not* The multivariable model adjusted for all variables shown in the forest plot. A hazard ratio greater than 1.0 indicates a shorter TTNT. BRCAmut, BRCA mutated; BRCAwt, BRCA wild-type; BRCAunk, BRCA unknown; CI, Confidence Interval; ECOG, Eastern Cooperative Oncology Group; HR, Hazard Ratio; IDS, Interval Debulking Surgery; PDS, Primary Debulking Surgery; R0, No Residual Disease after Surgery; R1, Presence of Residual Disease after Surgery; TTNT, Time To Next Treatment *after adjusting for other covariates Risk factors for progression or death in ovarian cancer patients who completed first-line platinum treatment Neville Westin S et al., ASCO 2019, abstract 5548 (poster presentation)

SUMMARY & CONCLUSIONS The findings of this retrospective real-world study confirm previously identified prognostic factors for ovarian cancer The following factors were associated with higher risk of death or shorter time to next treatment: BRCA wild-type status Receipt of neoadjuvant chemotherapy Higher stage of disease at diagnosis Presence of residual disease after surgery Risk factors for progression or death in ovarian cancer patients who completed first-line platinum treatment Neville Westin S et al., ASCO 2019, abstract 5548 (poster presentation)

Bevacizumab beyond progression: Impact of subsequent bevacizumab retreatment in patients with ovarian, fallopian tube, and peritoneal cancer after progression (poster abstract 5557) Rebecca Ann Previs, Daniel Spinosa, Bryan M. Fellman, Amelia Lorenzo, Isabelle Mulder, May Mahmoud, Ahmed Enbaya, Jean M. Hansen, Lauren Patterson Cobb, Pamela T. Soliman, Robert L. Coleman, Angeles Alvarez Secord, Shannon Neville Westin Abstract 5557: Background: The Food and Drug Administration approved the use of bevacizumab for treatment of recurrent epithelial ovarian, fallopian tube, and primary peritoneal carcinoma (OC) in combination with chemotherapy. This study evaluates whether patients immediately retreated with bevacizumab derive benefit after progressing on a bevacizumab-containing regimen. Methods: This multi-institutional, retrospective study compared patients with high grade non-mucinous epithelial OC who received bevacizumab followed directly by another bevacizumab-containing treatment regimen to patients who received bevacizumab followed by a regimen that did not contain bevacizumab (or received no further treatment). All patient retreated with bevacizumab had stable or progressive disease on prior bevacizumab containing regimen. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan and Meier product-limit estimator and modeled via Cox proportional hazards regression. PFS was measured from the date of first bevacizumab treatment to the date of first progression, date of death or date of last clinic visit. OS was measured from the date of first bevacizumab treatment after progression to the date of death or date of last contact/clinic visit. Statistical significance was defined at the 0.05 level. Results: 275 patients received bevacizumab, of which 226 were evaluable; 102 received sequential treatment with bevacizumab and 124 received a bevacizumab containing regimen followed by a non-bevacizumab containing regimen at the time of progression. There was no significant difference between tumor grade, stage, or BRCA mutation. Median follow-up for all subjects was 17 months (range: months). Median PFS was months (95%CI: ) and median OS was months (95%CI: 17.1 – 27.4). Median PFS for patients who received bevacizumab without retreatment was 5.1 months (95%CI: 4.3 – 6.3) and 17.6 months (95%CI: 14.3 – 21.3) for patients who received sequential bevacizumab retreatment (p < 0.001). Median OS for patients who received bevacizumab without retreatment was 12.9 months (95%CI: 9.3 – 16.7) and 30.1 months (95%CI: 26.1 – 35.4) for patients who received sequential bevacizumab retreatment (p < 0.001). Conclusions: Our study shows OC patients treated with bevacizumab-containing regimens sequentially at the time of progression have significantly prolonged survival outcomes compared to those patients who received no re-treatment with bevacizumab.

The FDA approved the use of bevacizumab (BEV) for treatment of recurrent epithelial ovarian, fallopian tube, and primary peritoneal carcinoma (OC) in combination with chemotherapy This study evaluates whether patients immediately retreated with BEV derive benefit after progressing on a bevacizumab-containing regimen SD, stable disease PD, progressive disease Retrospective study comparing OC patients who received BEV followed directly by another BEV- containing treatment regimen to patients who received BEV followed by a non-BEV regimen (or no further treatment). All patients retreated with BEV had SD or PD on prior BEV-containing regimen PFS and OS were estimated using KM product-limit estimator and modelled via Cox regression. PFS was measured from date of first BEV treatment to date of first progression, date of death or last clinic visit OS was measured from date of first BEV treatment after progression to date of death or last contact/clinic visit. Statistical significance was defined at the 0.05 level KM, Kaplan-Meier OS, overall survival PFS, progression-free survival Bevacizumab beyond progression: Impact of subsequent bevacizumab retreatment in patients with ovarian, fallopian tube, and peritoneal cancer after progression Previs RA et al., ASCO 2019, abstract 5557 (poster presentation)

Non Bev after Bev (n=124) N (%)
Methods AND results Consort diagram Descriptive statistics 275 ovarian cancer patients received Bevacizumab (Bev) containing regimen Non Bev after Bev (n=124) N (%) Bev after Bev (n=102) N P-value Age N Mean (SD) Median (Min-Max) (12.11) 56.0 (20-82) (10.33) (32-80) P =0.263 Tumor grade 1 Grade 2 Grade 3 9 (7.7) 3 (2.6) 105 (89.7) 4 (4.3) 4 (4.3) 86 (91.5) P =0.501 Tumor stage I II III IV Unstaged 8 (7.5) 4 (3.8) 63 (59.4) 23 (21.7) 8 (7.5) 1 (1) 6 (6.2) 62 (63.9) 27 (27.8) 1 (1) P =0.001 BRCA status None BRCA 1 mutation BRCA 2 mutation 52 (82) 9 (13.9) 4 (6.1) 53 (73.6) 13 (18.1) 6 (8.3) P =0.684 Primary treatment Surgery Neoadjuvant 74 (67.9) 35 (32.1) 63 (68.5) 29 (31.5) P =0.929 226 evaluable 102 received Bev after Bev 124 received non Bev after Bev Bevacizumab beyond progression: Impact of subsequent bevacizumab retreatment in patients with ovarian, fallopian tube, and peritoneal cancer after progression Previs RA et al., ASCO 2019, abstract 5557 (poster presentation)

Months since start of initial Bev
Results Overall survival of OC patients treated and retreated with bevacizumab 1.00 Impact of bevacizumab treatment and retreatment on PFS and OS Non Bev after Bev Bev after Bev P-value Median PFS Months (95% CI) 5.1 (4.3−6.3) 17.6 (14.3−21.3) P<0.001 Median OS Months (95% CI) 12.9 (9.3−16.7) 30.1 (26.1−35.4) 0.80 0.60 Overall survival 0.40 P<0.001 0.20 Bev/No Bev Bev/Bev 0.00 24 48 72 96 120 144 Months since start of initial Bev n at risk (events) Bev/No Bev (76) (14) (2) (1) (0) (0) Bev/Bev (32) (23) (8) (4) (0) (0) Bevacizumab beyond progression: Impact of subsequent bevacizumab retreatment in patients with ovarian, fallopian tube, and peritoneal cancer after progression Previs RA et al., ASCO 2019, abstract 5557 (poster presentation)

SUMMARY & CONCLUSIONS In this retrospective study, ovarian cancer patients treated with bevacizumab-containing regimens sequentially at the time of disease progression had significantly prolonged survival outcomes compared to patients who received no re-treatment with bevacizumab Bevacizumab beyond progression: Impact of subsequent bevacizumab retreatment in patients with ovarian, fallopian tube, and peritoneal cancer after progression Previs RA et al., ASCO 2019, abstract 5557 (poster presentation)

Bevacizumab or PARP-inhibitors maintenance therapy for platinum-sensitive recurrent ovarian cancer? A network meta-analysis (poster abstract 5564) Michele Bartoletti, Giacomo Pelizzari, Lorenzo Gerratana, Silvio Ken Garattini, Debora Basile, Camilla Lisanti, Lucia Bortot, Carla Corvaja, Mattia Garutti, Simona Scalone, Milena Nicoloso, Silvia Bolzonello, Elena Torrisi, Lucia Da Ros, Paola Di Nardo, Davide Lombardi, Giorgio Giorda, Gustavo Baldassarre, Roberto Sorio, Fabio Puglisi Abstract 5564: Background: Patients (pts) experiencing a PS rOC are generally re-exposed to a platinum based-chemotherapy (CT). In this setting, the addition of a targeted agent like bevacizumab (BEV) or PARP inhibitors (PARPi) as concomitant and/or maintenance therapy has shown to improve progression free survival (PFS). In the absence of direct comparison in randomized trials (RCTs), we have performed a NMA to evaluate differences in terms of efficacy between BEV and PARPi in pts with PS rOC, according to BRCA status. Methods: We searched PubMed, Embase and Medline for RCTs involving pts with PS rOC treated with BEV (n = 3, 1563 pts) or PARPi (n = 5, 1839 pts). Only trials with PFS as primary endpoint were included. Trials in first line setting were excluded. Analyses have been done pooling pts who had received PARPi in three groups, according to the available data on BRCA genes status: all comers (AC), BRCA mutated pts (BRCAm) and BRCA wild-type pts (BRCAwt). A frequentist approach has been used with R statistical software. To rank the effect size of treatments, surface under the cumulative ranking value (SUCRA) has been applied. Results: In AC pts, PARPi improved PFS compared to BEV (hazard ratio [HR] = 0.70, 95% CI , test of heterogeneity [I2] = 40.5%). In BRCAm pts the gain in PFS for PARPi was even higher compared to BEV (HR = 0.46, 95% CI , I2= 17.2%). In BRCAwt pts the benefit of PARPi over BEV was not statistically significant (HR = 0.87, 95% CI , I2= 35.7%) but PARPi had the highest likelihood of being ranked as the best treatment in terms of efficacy according to SUCRA (90% and 60%, respectively for PARPi and BEV). Hazard ratio for PFS between PARPi, BEV and CT in the three cohorts are reported in the table. Conclusions: According to indirect comparisons, PARPi performed the best for the treatment of PS rOC, especially in BRCAm pts who had not previously received PARPi. BEV could be still an option in BRCAwt pts.

Patients experiencing relapse of a platinum sensitive ovarian cancer (PSROC) are generally re-exposed to a platinum based-chemotherapy (CT) In this setting, the addition of a targeted agent like bevacizumab (BEV) or PARP inhibitors (PARPi) as concomitant and/or maintenance therapy has shown to improve PFS In the absence of direct comparison in randomized trials (RCTs), a network meta-analysis (NMA) was performed to evaluate differences in terms of efficacy between BEV and PARPi in patients with PSROC, according to BRCA status PFS, progression-free survival A database* search identified RCTs involving patients with PSROC treated with BEV (n=3, patients) or PARPi (n=5, 1839 patients) Only trials with PFS as primary endpoint were included, trials in first-line setting were excluded Analyses was performed by pooling patients who had received PARPi in three groups, according to available BRCA status: (1) all comers, (2) BRCA mutated patients and (3) BRCA wild-type patients A frequentist approach was used with R statistical software. To rank the effect size of treatments, surface under the cumulative ranking value (SUCRA) has been applied * PubMed, Embase and Medline Bevacizumab or PARP-inhibitors maintenance therapy for platinum-sensitive (PS) recurrent ovarian cancer (rOC)? A network meta-analysis (NMA) Bartoletti M et al., ASCO 2019, abstract 5564 (poster presentation)

Study inclusion and results
Prospective clinical studies (PSROC) included in this network meta-analysis: 6 phase III studies1-6 2 phase II studies7,8 HRs of PFS for PARPi and BEV compared with CT in BRCA 1-2 mutated patients Treatment HR 95%-CI CT 1.00 CT-BEV 0.55 [0.48;0.63] CT-PARPi 0.25 [0.21;0.31] 0.5 1 2 HRs of PFS for PARPi and BEV compared with CT in all comers patients HRs of PFS for PARPi and BEV compared with CT in BRCA 1-2 wild type patients Treatment HR 95%-CI CT 1.00 CT-BEV 0.55 [0.46;0.64] CT-PARPi 0.38 [0.31;0.47] 0.5 1 2 Treatment HR 95%-CI CT 1.00 CT-BEV 0.55 [0.47;0.64] CT-PARPi 0.48 [0.36;0.63] 0.5 1 2 1. Aghajanian et al., JCO 2012; 2. Coleman et al., Lancet 2017; 3. Pignata et al., JCO 2018; 4. Mirza et al., NEJM 2016; 5. Coleman et al., Lancet 2017; 6. Pujade-Lauraine et al., Lancet Oncol 2017; 7. Lederman et al., Lancet 2014; 8. Oza et al., Lancet Oncol 2015 CI, Confidence Interval; HR, Hazard Ratio; PSROC, platinum-sensitive recurrent ovarian cancer Bevacizumab or PARP-inhibitors maintenance therapy for platinum-sensitive (PS) recurrent ovarian cancer (rOC)? A network meta-analysis (NMA) Bartoletti M et al., ASCO 2019, abstract 5564 (poster presentation)

SUMMARY & CONCLUSIONS According to indirect comparisons of this network meta-analyis, PARP inhibtors performed the best for the treatment of platinum-sensitive recurrent ovarian cancer (PSROC) This finding was most pronounced in patients with BRCA mutations who had not previously received a PARP inhibitor Bevacizumab could still be an option in PSROC patients with BRCA wild-type Bevacizumab or PARP-inhibitors maintenance therapy for platinum-sensitive (PS) recurrent ovarian cancer (rOC)? A network meta-analysis (NMA) Bartoletti M et al., ASCO 2019, abstract 5564 (poster presentation)

Real-world bevacizumab utilization and outcomes in first-line ovarian cancer (poster abstract 5578)
Matthew J. Monberg, Jennifer P Hall, Rebecca Moon, Olivia Higson, Kimmie McLaurin, Tapashi Dalvi; Merck & Co., Inc., Kenilworth, NJ; Adelphi Real World, Manchester, United Kingdom; AstraZeneca Pharmaceuticals, LP, Gaithersburg, MD Abstract 5578: Background: Bevacizumab (B) is approved in combination with carboplatin and paclitaxel, followed by B monotherapy, for the treatment of advanced ovarian cancer (OC) following surgery. We sought to describe B utilization and outcomes of B in first-line (1L) OC within the US and EU. Methods: This cross-sectional study included patients who were actively receiving treatment for OC. Data were collected at a single time point from 2496 patient forms between December 2017 and March 2018 from 340 oncologists/ gynecologists across the US, France, Germany, Italy, Spain, and the UK. Patients were platinum sensitive if progression was noted > 6 months after frontline platinum therapy and resistant if the interval was 0-6 months. This analysis included patients who received 1L chemotherapy (chemo) with no maintenance or 1L chemo with bevacizumab maintenance. Results: B was used in combination with chemo at 1L and as 1L maintenance monotherapy in 11% total study patients. Those receiving 1L + B were more likely to have Stage IV disease, have good performance status (PS) at diagnosis, and receive BRCA testing than patients receiving chemo only. Treatment response, platinum sensitivity, and activities of daily living are shown in the Table. Results did not vary by BRCA status. Conclusions: This study highlights differences in patient characteristics and outcomes between patients receiving/ who received 1L chemo only and those receiving/ who received B, however, this study was not designed to formally compare 1L treatment options.

Bevacizumab (BEV) is approved in combination with carboplatin plus paclitaxel, followed by BEV monotherapy, for the treatment of advanced ovarian cancer (OC) following surgery The present study analyses the utilization and outcomes of BEV in the first-line (1L) treatment of advanced ovarian cancer within the US and EU Cross-sectional study including OC patients on active treatment Patient data (n=2,496) collected at a single time point from 340 oncologists / gynecologists across the US, France, Germany, Italy, Spain, and the UK Patients regarded as platinum sensitive if PD was noted > 6 months after frontline platinum therapy and resistant if interval was 0-6 months. Analysis included patients who received 1L chemotherapy (CT) with no maintenance or 1L CT with BEV maintenance PD, progressive disease Real-world bevacizumab utilization and outcomes in first-line ovarian cancer Monberg MJ et al., ASCO 2019, abstract 5578 (poster presentation)

Methods AND Patient demographics
Total (N=1498) 1L Chemo Only Treatment + No 1L Maintenance (N=1232) 1L Chemo + B, + B Maintenance (N=266) Mean age (patients <90), years 64 61 Family history of OC, n (%) 139 (9) 98 (8) 41 (15) Serous epithelial histology, n (%) 975 (65) 791 (64) 184 (69) Stage III/IV disease, n (%) 473 (32) / 981 (65) 409 (33) / 779 (63) 64 (24) / 202 (76) ECOG score at diagnosis 0-1, n (%) 1213 (81) 969 (79) 244 (92) 2+, n (%) 250 (17) 234 (19) 16 (6) Unknown, n (%) 35 (2) 29 (2) 6 (2) BRCA tested, n (%) 773 (52) 584 (47) 189 (71) Positive for BRCA (% of those screened) 187 (24) 145 (25) 42 (22) Some decrease in activities of daily living, % 1092 (73) 904 (73) 188 (71) Full DSP Sample Patient demographics, clinical characteristics and BRCA-screening Initiated 1L Chemo Only + No 1L Maintenance (N=1232) Completed 1L (N=742) Confirmed BRCA wildtype (N=252) Total current analysis population (N=1498) Initiated 1L Chemo + B + B Maintenance (N=266) Completed 1L (N=203) Confirmed BRCA wildtype (N=108) Patient demographics, clinical characteristics and BRCA screening 1L, first-line Real-world bevacizumab utilization and outcomes in first-line ovarian cancer Monberg MJ et al., ASCO 2019, abstract 5578 (poster presentation)

Results Treatment outcomes among all BRCAwt patients completing first-line All BRCA wildtype patients who completed 1L 1L Chemo Only Treatment + No 1L Maintenance (N=252) 1L Chemo + Bev + Bev Maintenance (N=108) Complete response, partial response or stable disease at completion of 1L, n (%) 201 (80) 104 (96) Platinum sensitive, n (%) 117 (46) 68 (63) Platinum resistant, n (%) 25 (10) 17 (16) Platinum refractory, n (%) 49 (19) 3 (3) Unknown, n (%) 61 (24) 20 (19) Received 2L platinum chemo, n (%) 163 (65) 79 (73) Received 2l non-platinum chemo, n (%) 88 (35) 29 (27) 1L, first-line; 2L, second-line Real-world bevacizumab utilization and outcomes in first-line ovarian cancer Monberg MJ et al., ASCO 2019, abstract 5578 (poster presentation)

SUMMARY & CONCLUSIONS This real-world cross-sectional study highlights differences in patient characteristics between patients with advanced ovarian cancer who received first-line chemotherapy (1L CT) alone or those who received 1L CT plus bevacizumab (BEV) plus BEV maintenance Regardless of BRCA status, most patients who received 1L CT with BEV were considered to be platinum sensitive and were able to receive platinum CT at the time of recurrence (among patients who were able to receive 2L therapy). Compared with patients receiving 1L CT alone, patients receiving 1L plus BEV / BEV maintenance were more likely to have: stage IV disease good performance status at diagnosis undergone BRCA-testing Real-world bevacizumab utilization and outcomes in first-line ovarian cancer Monberg MJ et al., ASCO 2019, abstract 5578 (poster presentation)

ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (poster abstract TPS5600) Anne-Claire Hardy-Bessard, Kathleen N. Moore, Mansoor Raza Mirza, Bernard Asselain, Andres Redondo, Jacobus Pfisterer, Sandro Pignata, Diane M. Provencher, David Cibula, Anna K.L. Reyners, Lubomir Bodnar, Rosalind Margaret Glasspool, Christos A. Papadimitriou, Rami Eitan, Sileny Han, Linda R. Duska, Bj Rimel, Sebastien Hazard, Jian Chen, Eric Pujade-Lauraine Abstract TPS5600: Background: Despite surgery and SOC therapy (paclitaxel and carboplatin ± bevacizumab[bev]), 5-year survival rates remain low for patients (pts) with FIGO stage 3/4 OC. Niraparib (ZEJULA) is the first selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the US and Europe for maintenance treatment in pts with recurrent OC regardless of BRCAmut status. Preclinical data suggest synergy with PARPi + anti-PD-1 blockade. Niraparib + pembrolizumab has shown clinical efficacy in pts with platinum-resistant or secondary refractory OC regardless of biomarker status. Dostarlimab is an anti–PD-1 humanized monoclonal with clinical activity as monotherapy in early phase trials. The primary objective of the currently enrolling FIRST trial is to compare PFS (per RECIST v1.1) in pts treated with SOC + dostarlimab + niraparib to SOC. Methods: Eligible pts (up to 912) are FIGO stage 3 (with residual disease, CC0 high risk, or planned neoadjuvant therapy) or stage 4, non-mucinous epithelial OC and ECOG score < 2. After 1 cycle of SOC, pts are stratified by concurrent bev use, BRCAmut/HRR status, and disease burden then randomized as 1:1:2 to 1 of 3 arms (Table). An innovative feature of ENGOT-OV44/FIRST (NCT ; EUDRACT ) is the pre-planned adaptive study design to adapt the control arm to the evolving SOCs in OC, allowing pts in the control arm to receive up to date SOC. These adaptations will occur when practice-changing data are released. Following publication of SOLO1 results, BRCAmut pts will only be randomized to arm 2 or 3 to ensure they receive niraparib. Further adaptations may be incorporated as new data become available, leading to stop randomization in arm 1 or 2 of pts based on their biomarker status. Clinical trial information: NCT

For patients with FIGO stage 3/4 ovarian cancer (OC), 5-year survival rates remain low despite surgery and standard of care (SOC) therapy (paclitaxel plus carboplatin ± BEV) Preclinical data suggest synergy of PARP inhibitors (PARPi) with anti-PD-1 blockade Niraparib + pembrolizumab combination therapy has demonstrated clinical efficacy in platinum- resistant or secondary refractory OC regardless of biomarker status Dostarlimab is an anti–PD-1 humanized monoclonal antibody with clinical activity as monotherapy in early phase trials. The primary objective of the currently enrolling FIRST trial is to compare PFS* in patients treated with SOC + dostarlimab + niraparib to SOC * per RECIST v1.1 ** with residual disease, CC0 high risk, or planned neoadjuvant therapy Eligible patients (up to 912) are FIGO stage 3** or 4, non-mucinous epithelial OC and ECOG score < 2 After 1 cycle of SOC, patients are stratified by concurrent BEV use, BRCAmut/HRR status, and disease burden then randomized as 1:1:2 to 1 of 3 arms An innovative feature of ENGOT-OV44/FIRST‡ is the pre-planned adaptive study design to adapt the control arm to the evolving SOCs in OC These adaptations will occur when practice-changing data are released (e.g. after SOLO1 results, BRCAmut patients will only be randomized to niraparib arms. Further adaptations may be incorporated in the future, leading to stop randomization in arm 1 or 2 of patients based on their biomarker status HRR, homologous recombination repair ‡ NCT CC, Completeness of Cytoreduction (CC0, no macroscopic residual tumor after surgery) ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC) Mirza MR et al., ASCO 2019, abstract TPS5600 (poster presentation)

ENGOT-OV44/FIRST − trial Design
BRCAmut, BRCA mutated; HRR, homologous recombination repair; PFS, progression-free survival; Q3D, every 3 weeks; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1. ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC) Mirza MR et al., ASCO 2019, abstract TPS5600 (poster presentation)

SUMMARY & CONCLUSIONS The ENGOT-OV44/FIRST study is an ongoing study evaluating the efficacy and safety of the combination of PARP inhibitor niraparib plus PD-1 antibody dorstalimab added to standard-of-care (SOC) therapy vs SOC alone in patients with stage III/IV non-mucinous epithelial OC treated with platinum-based therapy Safety, pharmacokinetics, and patient reported outcomes will also be evaluated Projected enrollment is up to 912 patients Patients will be stratified by concurrent bevacizumab use, HRR mutation status, and disease burden A special feature of this study is its adaptive design, allowing patients in the control arm to receive up-to-date SOC therapy This study is currently recruiting patients Contact with questions ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC) Mirza MR et al., ASCO 2019, abstract TPS5600 (poster presentation)

Ovarian cancer ASCO 2019 Fazit Oral Abstract 5505 Oral Abstract 5506
Die Kombination aus Niraparib und Bevacizumab scheint einen synergistischen Effekt über die reine Addition zu haben, ähnlich wie in der Liu Studie. Spannend bleibt, ob sich dieser Effekt auch in Kombination mit Chemotherapie in den laufenden First-line-Studien zeigt. Auch scheint der Effekt bei den BRCAwt Patientinnen sowie den intermediär platinsensiblen und damit prognostisch ungünstigen am stärksten zu sein. Oral Abstract 5506 Auch wenn hier eine Wirksamkeit durch PARPi-Monotherapie gezeigt werden kann, bleibt zu bemängeln, dass der Kontrollarm platinfrei und damit Substandard gewählt war. Damit lassen sich die Ergebnisse nicht ohne Weiteres in die klinische Routine übertragen. Oral Abstract 5507 Ob wirklich ein Therapie-Benefit durch PARPi Monotherapie mit Olaparib vorhanden war, lässt sich durch die starke Imbalance beider Arme hinsichtlich der Anzahl der Patientinnen mit BRCAmut (21% im experimentellen Arm vs. 3% im Standard-Arm) nur eingeschränkt beurteilen. Zudem ist die Dauer des anhaltenden klinischen Benefits mit 3 Monaten unter der in vorangegangenen Studien.

Ovarian cancer ASCO 2019 Fazit Oral Abstract 5508 Oral Abstract 5510
Ältere Patientinnen (>70 Jahre) sollten auf den Überlebensgewinn durch die Kombination aus Carboplatin- Paclitaxel trotz relevanter Toxizität (z.B. in Form von Neuropathien) hingewiesen werden. Oral Abstract 5510 Beim fortgeschrittenen Endometriumkarzinom mit Hormonrezeptor-Positivität stellt die Kombination eines CDK4/6- Inhibitors in Form des Ribociclib zusammen mit Letrozol eine relevante Therapieoption dar. Poster Discussion Abstract 5513 Adavosertib, ein hochselektiver WEE1-Hemmer, weist eine signifikante Effektivität beim platinresistenten Ovarialkarzinomrezidiv auf. Neutropenie und Thrombozytopenie sind besonders zu beachten. Poster Discussion Abstract 5519 Wöchentliches Carboplatin in Kombination mit Pembrolizumab zeigt bei Platinresistenz ein mäßiges Tumoransprechen bei einem medianen progressionsfreien Überleben von 4,1 Monaten.

Ovarian cancer ASCO 2019 Fazit Poster Abstract 5539
Die Analyse fand keine neuen Sicherheitssignale bzw. Toxizität durch den PARPi Einsatz (Olaparib). Poster Abstract 5540 Bevacizumab weist auch im „Real Life Setting“ Effektivität und Toxizität wie in der OCEANS-Studie auf. Poster Abstract 5541 Auch unter PARPi Therapie bleibt der Resektionsstatus der Patientin der wichtigste Prognosefaktor. Poster Abstract 5546 Die Kombination aus CA-125 und internetbasiertem KELIM Score ist eine weitere Option zur Prädiktion für den Erfolg einer neoadjuvanten Chemotherapie mit Carboplatin/Paclitaxel +/- Niraparib bei OC. Poster Abstract 5547 Eine Erhaltungstherapie mit Niraparib verlängert bei Patientinnen mit Ovarialkarzinomrezidiv und BRCAwt signifikant die Zeit bis zur nächsten Platin-basierten Chemotherapie.

Die Studie bestätigt die bekannten Risikofaktoren für Progression oder Tod nach platinhaltiger Erstlinientherapie beim Ovarialkarzinom. Poster Abstract 5551 Möglicherweise gibt es auch Unterschiede im Ansprechen des PARP Inhibitors (Olaparib) abhängig von der BRCA Mutation. Diese Daten sollten aber nicht überbewertet werden. Poster Abstract 5557 PFS und OS werden durch Bevacizumab nach Bevacizumab („Treatment beyond Progression“) beim Ovarialkarzinom verbessert. Poster Abstract 5564 Bei BRCAmut Patientinnen sollte dem PARP Inhibitor der Vorzug gegeben werden, Bevacizumab bleibt aber eine Option für Patientinnen mit BRCAwt.

Die Gabe einer Erhaltungstherapie mit Bevacizumab ist häufiger verbunden mit einem höheren Tumorstadium und der Durchführung einer BRCA Testung. Poster Abstract TPS5600 Die Kombination aus PARPi und Bevacizumab scheint synergistische Wirkung zu haben (s. a. oral abstract 5505). Ob die Addition einer Immuntherapie (Dorstalimab) einen Benefit bringt, bleibt abzuwarten.

Endometrial, cervical & rare gyn. CANCER
OVERVIEW OF ASCO 2019 ORAL & POSTER PRESENTATIONS A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG oncology trial (Powell MA et al. ASCO 2019, oral abstract 5500) Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601) (Antill YC et al. ASCO 2019, oral abstract 5501) Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC) (Konstantinopoulos PA et al. ASCO 2019, oral abstract 5502) Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC (Kenter G et al. ASCO 2019, oral abstract 5503) Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi- institutional analysis of 700 cases (Uppal S et al. ASCO 2019, oral abstract 5504) Surveillance in stage I MOGCTs (malignant ovarian germ cell tumors): A MITO prospective study (multicenter Italian trials in ovarian cancer) (Bergamini A et al. ASCO 2019, poster discussion abstract 5516)

Endometrial, cervical & rare gyn. CANCER
OVERVIEW OF ASCO 2019 ORAL & POSTER PRESENTATIONS Recurrence and survival after robotic-assisted radical hysterectomy (RRH) for early-stage cervical cancer (CC): Experience may matter (Fitzsimmons CK et al. ASCO 2019, poster abstract 5535) Mismatch repair deficiency as a predictor of adjuvant radiotherapy response in endometrioid endometrial carcinoma (Kommoss S et al. ASCO 2019, poster abstract 5586) p53 and p16 expression profiles reveal three prognostically relevant subgroups in vulvar cancer: A TMA based study by the AGO- CaRE-translational study group (Woelber LL et al. ASCO 2019, poster abstract 5592)

A randomized phase 3 trial of paclitaxel plus carboplatin versus paclitaxel plus ifosfamide in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG oncology trial (oral abstract 5500) Matthew A. Powell, Virginia L. Filiaci, Martee Leigh Hensley, Helen Q Huang, Kathleen N. Moore, Krishnansu Sujata Tewari, Larry J. Copeland, Angeles Alvarez Secord, David G Mutch, Alessandro Santin, William Richards, David Philip Warshal, Nicola M. Spirtos, Paul Disilverstro, Olga Ioffe, David S. Miller Abstract 5500: Background: Gynecologic carcinosarcomas (CS) are rare yet aggressive epithelial malignancies for which optimal therapy is debated. PI was shown to be superior to I. PC demonstrated compelling phase 2 activity with improved safety and convenience. Methods: Main inclusion: ≥18 y; chemotherapy naïve stage I-IVB or recurrent uterine (U) or ovarian (O) CS. Treatment randomised 1:1 to PC (P 175mg/m2 with C: AUC 6 or 5 if prior RT on D1) or PI (P: 135 mg/m2; I 1.6 g/m2 D1-3; G-CSF support with dose escalation & de-escalation based on nadir counts) q21days for 6-10 cycles. Quality of life (QOL) (FACT-En TOI) and neurotoxicity (FACT/GOG-Ntx subscale) administered at 4 timepoints. A stratified log-rank test compared primary endpoint of overall survival (OS) from entry between treatment groups for non-inferiority (NI) of PC to PI. With 264 events, power was 80% for a null hazard ratio of 1.2 against a 13% greater death rate on PI when type I error is limited to 5% for a one-tail test. NCT Results: 637 pts accrued with a median follow-up of 61 months. The primary (U, n = 536) and secondary (O, n = 101) cohorts are analyzed separately and included 449 and 90 pts eligible pts, respectively. For the U cohort:PC and PI were randomly assigned to 228 and 221 eligible pts. Stage distribution: I (40%), II (6%), III (31%), IV (15%) and recurrent (8%). The study met its primary objective withPC not inferior to PI (intention-to-treat analysis;Median OS 37 vs. 29 mo, HR = 0.87; 90% CI = 0.70 to 1.075; p < 0.01 for NI, p > 0.1 for superiority (S)).PFS (median on PC 16mo vs PI 12mo; HR = 0.73; p = < 0.01 for NI, p < 0.01 for S). Toxicity (grade 1/2/3/4/5: PC 1/8/40/48/2%; PI 1/32/39/25/1%). Most of increase toxicity for PC was hematologic with G-CSF rarely used (N = 6). Confusion and genitourinary hemorrhage were significantly worse with PI. Both groups had decline in QOL and neurotoxicity scores. Similar trends were noted for the O cohort (OS: PC 30mo vs PI 25mo; and PFS: 15 mo vs 10 respectively). Conclusions: PC was not inferior to PI for OS with longer PFS and similar QOL and neurotoxicity. These results establish a new standard regimen for women with CS. Clinical trial information: NCT

Gynecologic carcinosarcomas (CS) are rare yet aggressive epithelial malignancies for which optimal therapy is debated Paclitaxel plus ifosfamide (PI) was shown to be superior to ifosfamide (I) alone In phase II, paclitaxel plus carboplatin (PC) demonstrated compelling activity with improved safety and convenience Overview of study results in advanced stage uterine carcinosarcoma on next slide Main inclusion: chemotherapy naïve stage I-IVB or recurrent uterine or ovarian CS (637 pts) Treatment randomised 1:1 to PC or PI q21days for 6-10 cycles (G-CSF support with dose escalation/de-escalation based on nadir counts) Quality of life and neurotoxicity administered at 4 timepoints Comparison of primary endpoint of overall survival (OS) from entry between treatment groups for non-inferiority (NI) of PC to PI A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG oncology trial Powell MA et al., ASCO 2019, abstract 5500 (oral presentation)

Background Treatment of advanced stage uterine carcinosarcoma Adjuvant
Advanced, Recurrent, Metastatic, Chemo, Naïve, Measurable Study N 5y relapse rate 5y survival GOG150 WAI: 105 CIM: 101 58% vs 52% 35% vs 45% Study Agents N ORR mPFS (months) mOS (months) GOG108 Ifos vs Ifos + Cis 102 vs 92 36% vs 54% 4 vs 6 (P=0.02) 7.6 vs 9.4 (P=0.07) GOG161 Ifos + Pac 91 vs 88 29% vs 45% (P=0.02) 3.6 vs 5.8 (P=0.03) 8.4 vs 13.5 (P=0.03) GOG232B Pac + Carbo 46 54% 7.6 14.7 WAI – Whole abdominal radiation CIM – Cisplatin/Ifosfamide/Mesna Gynecol Oncol.2006 Sep 5;107: ; Gynecol Oncol.2000 Apr 4: 9: ; J Clin Oncol.2007 Feb 10;25(5): ; J Clin Oncol.2010 Jun 01;28(16): A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG oncology trial Powell MA et al., ASCO 2019, abstract 5500 (oral presentation)

GOG 0261 − Study design Regime I
Paclitaxel 175 mg/m²* IV over 3 hours day 1 Carboplatin (AUC=6*) IV day 1 Repeat q 3 weeks x 6 cycles (up to 4 additional cycles may be given to patients who entered study with measurable disease and have partial response after 6 cycles) Stage I-IV, Persistent or Recurrent Uterine, Fallopian Tube, Peritoneum or Ovarian Carcinosarcoma (chemotherapy-naïve) Patients may have prior pelvic and/or vaginal radiation therapy Stratification: History of Pelvic Radiation Disease Status/Stage at time of Study registration Measurable Disease R A N D O M I Z E Regime II Ifosfamide 1.6 g/m²** IV days 1, 2, 3, Mesna*** Paclitaxel 135 mg/m² by 3-hour infusion on day 1 Repeat q 3 weeks x 6 cycles (up to 4 additional cycles may be given to patients who entered study with measureable disease and have partial response after 6 cycles) G-CSF Support: Filgrastim or Pegfilgrastim begins day 4-6 Endpoints: Primary endpoint: OS Secondary endpoints: PFS, AEs, QoL * Inital dose reduced to Paclitaxel 135 mg/m² and Carboplatin (AUC=5) if prior whole pelvic radiotherapy (may be escalated if patient tolerates lower dose) ** Inital dose reduced to Ifosfamide 1.2 g/m²/day x 3 days if prior whole pelvic radiotherapy (subsequent dosing MAY INCREASE OR DECREASE EACH CYCLE BASED ON NADIR COUNTS) ***PLEASE NOTE THAT REGIME II UTILIZES DOSE ESCALATIONS A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG oncology trial Powell MA et al., ASCO 2019, abstract 5500 (oral presentation)

GOG 0261 − Patient characteristics
Uterine Cohort Characteristic Regime Total PC PI n % Age (median) 65 64 BMI (median) 30.4 30.7 Race White 150 65.8 133 60.2 283 63.0 Black/African American 66 28.9 72 32.6 138 Asian 9 3.9 4.1 18 4.0 Am Indian/Alaskan Native 2 0.9 1 0.5 3 0.7 Performance Status 149 65.4 119 53.8 268 59.7 68 29.8 94 42.5 162 36.1 11 4.8 8 3.6 19 4.2 Primary Site Uterine Corpus 228 100.0 221 449 Disease status (verified) Clin/Surg Stage I/II 103 45 102 46.2 205 45.7 Stage III/IV 106 46.6 209 46.5 Recurrent/Persistent 46 16 7.2 35 7.8 Prior RT (verified) No 197 8.3 192 86.9 389 86.6 Yes 31 86.4 29 13.1 60 13.4 Measurable Disease (verifed) 153 13.6 147 66.5 300 66.8 75 67.1 74 33.5 32.2 Regime PC PI Total n % Number of cycles 0 cycles 4 1.8 17 7.7 21 4.7 1-3 cycles 44 19.3 33 14.9 77 17.1 4-6 cycles 160 70.2 159 71.9 319 71.0 7-10 cycles 20 8.8 12 5.4 32 7.1 228 50.8 221 49.2 449 100 Protocol Violations Paclitaxel, Carboplatin Ifosfamide Paclitaxel n % Minor 38 14.2 55 20.5 Major 21 7.8 32 11.9 A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG oncology trial Powell MA et al., ASCO 2019, abstract 5500 (oral presentation)

GOG 0261 − Overview of Adverse events
Uterine chohort: 9 deaths on therapy* Paclitaxel + Carboplatin (PC) Paclitaxel + Ifosfamide (PI) Grades 3-4 System Organ Class/Term N % Constitutional 11 5% 13 6% Fatigue 9 4% Cardiac Gastrointestinal 21 9% 19 Genitourinary/Renal 7 3% Hemorrhage 0% 3 1% Hematologic 184 82% 101 50% Infection 17 8% 14 7% Lymphatics 2 Musculoskeletal 1 Metabolic 29 13% 33 16% Neurological 16 23 11% Pulmonary 6 Pain * two deaths “possible” due to PC A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG oncology trial Powell MA et al., ASCO 2019, abstract 5500 (oral presentation)

Proportion Alive, Progression-Free
Outcomes Primary outcome uterine cohort: OS Secondary outcomes uterine cohort: PFS 37 mo PC vs. 29 mo PI Adjusted treatment death hazard ratio is 0.87 The 90% CI 0.70 to 1.075 p-value < Rejects the null hypothesis: inferiority Superiority: Not significant (p=0.14); one-tailed 1 16.3 mo PC vs mo PI HR=0.735 (95% CI: 0.58 to 0.93) The p-value < The test rejects the null hypothesis of inferiority. PFS (superiority) was statistically significant (p<0.01) 1 0.8 0.8 0.6 0.6 Proportion Alive Proportion Alive, Progression-Free 0.5 0.5 0.4 0.4 Regimen PC PI Regimen PC PI 0.2 Event Total Median 129 228 37.3 130 221 29.0 0.2 Event Total Median 141 228 16.3 148 221 11.7 12 24 36 48 60 72 12 24 36 48 60 72 Months on Study Months on Study PC PI PC, Paclitaxel + Carboplatin; PI, Paclitaxel + Ifosfamide A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG oncology trial Powell MA et al., ASCO 2019, abstract 5500 (oral presentation)

Proportion Alive, Progression-Free
Outcomes Primary outcome ovarian cohort: OS Secondary outcomes ovarian cohort: PFS 1 1 Event Total Median 31 44 30.0 30 46 24.7 Event Total Median 33 44 14.6 34 46 10.3 0.8 0.8 0.6 0.6 Proportion Alive 0.5 Proportion Alive, Progression-Free 0.5 0.4 0.4 Regimen PC PI Regimen PC PI 0.2 0.2 12 24 36 48 60 72 12 24 36 48 60 72 Months on Study Months on Study PC PI PC PI No significant outcome differences were observed for the two regimens in the ovarian cohort PC, Paclitaxel + Carboplatin; PI, Paclitaxel + Ifosfamide A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG oncology trial Powell MA et al., ASCO 2019, abstract 5500 (oral presentation)

SUMMARY & CONCLUSIONS In chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary, the combination of paclitaxel (P) plus carboplatin (C) was not inferior to paclitaxel plus ifosfamide for overall survival Treatment with P+C resulted in prolonged PFS with similar quality of life (QoL) and neurotoxicity These phase III results establish a new standard regimen for women with carcinosarcoma These results confirm the approach already practiced in many German centers today A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG oncology trial Powell MA et al., ASCO 2019, abstract 5500 (oral presentation)

Activity of durvalumab in advanced endometrial cancer according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601) (oral abstract 5501) Yoland Catherine Antill, Peey Sei Kok, Kristy Robledo, Elizabeth Barnes, Michael Friedlander, Sally E. Baron-Hay, Catherine M. Shannon, Jermaine Coward, Philip James Beale, Geraldine Goss, Tarek Meniawy, Sonia Yip, Deborah Smith, Amanda B. Spurdle, Michelle Parry, John Andrews, Marzena Kelly, Martin R. Stockler, Linda R. Mileshkin Abstract 5501: Background: Deficient DNA mismatch repair (dMMR) occurs in approximately 15% of AEC and is associated with a high tumour mutation burden. Expression of PD-1 and PD-L1 has been reported in up to 90% of ECs, including those with proficient DNA mismatch repair (pMMR). We report here preliminary results of PHAEDRA, a single-arm phase 2 trial designed to determine the activity of single-agent durvalumab, an antibody to PD-L1, in 2 cohorts of women with AEC. Methods: Participants (pts) had pMMR AEC progressing after 1-3 lines of chemotherapy, or dMMR AEC progressing after 0-3 lines of chemotherapy, and were treated with durvalumab 1500mg IV Q4W. The primary endpoint was objective tumour response (OTR = complete response [CR] or partial response [PR] by iRECIST). Secondary endpoints included disease control at 16 weeks (DC16w = CR, PR, or stable disease at 16 weeks [SD16w]), immune-related adverse events (irAEs), PD-L1, germline mutations and MLH1 methylation. Other secondary endpoints include: OTR and DC by RECIST1.1, other AE, PFS, OS & quality of life will be reported later. Results: 71 pts with AEC were recruited from Feb 2017 to Sep 2018: 35 dMMR and 36 pMMR. Median follow-up were 8.3 vs 14.8 months in dMMR vs pMMR pts. Median age: 67 (range 36-81); ECOG PS: 0-1 in 68, and 2 in 3. Pathology: endometrioid in 94% and 58%; serous in 0% and 31%; grade: high in 42% and 83% (dMMR and pMMR respectively). Durvalumab was the 1st, 2nd and subsequent line of non-hormonal therapy in 15, 14, and 6 pts with dMMR and 0, 21, and 15 pts with pMMR. Among dMMR pts, the OTR rate was 40% (14/35, 95% CI 26-56), with 4 CR and 10 PR; 7 others had SD 16w for a DC16w rate of 60% (21/35, 95% CI 44-74). OTR rate was 40% as 1st line, 43% as 2nd line, and 33% as subsequent line treatment. Among pMMR pts, the OTR rate was 1/36 (3%, 95% CI 1-14) with 1 PR; 6 others had SD16w for a DC16w rate of 19% (7/36; 95% CI 10-35). IrAEs occurred in 14 pts: hyperthyroidism in 6, hypothyroidism in 6, pneumonitis in 1 and hepatitis in 1. Conclusions: Durvalumab monotherapy showed promising activity and safety in AEC with dMMR regardless of prior lines of chemotherapy, but there was limited evidence of activity in AEC with pMMR. Clinical trial information: ACTRN

Deficient DNA mismatch repair (dMMR) occurs in ~15% of advanced endometrial cancers (AEC) and is associated with a high tumour mutation burden and DNA hypermethylation Expression of PD-1 and PD-L1 has been reported in 25-90% of ECs, including those with proficient DNA mismatch repair (pMMR)1 AEC progressing after ≥ 1 lines of chemotherapy is an area of unmet medical need (OTRRs with current therapeutics are ≤ 20%) OTRR, objective tumour response rate Participants had pMMR AEC progressing after 1-3 lines of chemotherapy, or dMMR AEC progressing after 0-3 lines of chemotherapy, all were treated with durvalumab* Primary endpoint - objective tumour response (OTR = CR or PR) by iRECIST) Secondary endpoints included disease control at 16 weeks (DC16w = CR, PR, or stable disease at 16 weeks [SD16w]), immune-related adverse events (irAEs), PD-L1, germline mutations and MLH1 methylation * 1500 mg IV Q4W CR, complete response PR, partial response 1. Mittica et al. Oncotarget Oct 27; 8(52): 90532– Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601) Antill YC et al., ASCO 2019, abstract 5501 (oral presentation)

Study scheme Design: Open-label, multicenter, Phase II, non-comparative trial with 2 cohorts MMR proficient − normal MMR protein expression on IHC MMR deficient − loss of expression of at least one MMR protein on IHC Advanced or recurrent endometrial adenocarcinoma not amenable to curative surgery n=70 Cohort 1 (n=35) MMR proficient 1-3 lines of chemotherapy prior Durvalumab 1500 mg IV Q4w Until PD Cohort 2 (n=35) MMR deficient 0-3 lines of chemotherapy prior Tumor assessment 8-12 weekly until PD Aim − to determine the activity and safety of anti-PD-L1 durvalumab in AEC Primary objective − objective tumour response (OTRR) according to iRECIST AEC, advanced endometrial cancer; MMR, mismatch repair; PD, progressive disease Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601) Antill YC et al., ASCO 2019, abstract 5501 (oral presentation

Study objectives Primary Secondary Tertiary
Objective tumour response rate (OTRR) according to iRECIST Secondary OTRR according to RECIST 1.1 Disease control rates at weeks 16 an 24 PFS OS Durations of OTR and DC Adverse events (CTCAE v4.03) HRQoL (EORTC QLQ-C30) Tertiary Biomarkers predicting response including: PD-L1 expression, MMR status, MSI status Genomic, proteomic and immune characteristics associated with outcomes (immune cell infiltration, autoimmunity) Exploratory DNA methylation and ctDNA studies CTCAE; Common Terminology Criteria for Adverse Events; EORTC, European Organisation for Research and Treatment of Cancer; MMR, Mismatch Repair; MSI, Microsatellite Instability Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601) Antill YC et al., ASCO 2019, abstract 5501 (oral presentation

Patient characteristics
Baseline characteristics Baseline characteristics − Previous therapy Characteristic n=71 MMR deficient (n=35) MMR proficient (n=36) Median age (range) 66 (36-76) 69 (37-81) ECOG 18 (51%) 17 (47%) 1 14 (40%) 19 (53%) 2 3 (9%) - Grade at diagnosis 9 (26%) 6 (17%) 16 (47%) 4 (11%) 3 26 (72%) Pathology Endometrioid 33 (94%) 21 (58%) Serous 11 (31%) Others 2 (6%) Prior surgery 31 (89%) 32 (89%) Prior radiotherapy 26 (74%) Characteristic n=71 MMR deficient (n=35) MMR proficient (n=36) Previous chemotherapy Platinum doublets 18 (51%) 34 (94%) Platinum monotherapy 3 (9%) 5 (14%) Taxane monotherapy - - 3 (8%) Doxorubicin / liposomal doxorubicin 1 (3%) 4 (11%) Other cytotoxic chemotherapy 2 (6%) Previous hormonal therapy Previous bevacizumab - - Hormone status ER+ 26 (93%) 19 (66%) PR+ 21 (84%) 14 (58%) Lines of prior systemic treatment for advanced disease* 21 (60%) 1 13 (37%) 23 (64%) ≥ 2 10 (27%) * Excluding hormone, bevacizumab, adjuvant an dneo-adjuvant chemotherapy received ≥ 12 months prior to registration Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601) Antill YC et al., ASCO 2019, abstract 5501 (oral presentation

Results Primary objective: OTRR (iRECIST)
Adverse events (AEs) − patients (n) dMMR (n=35) pMMR (n=35) OTRR 15 (43%) 1 (3%) DCR 23 (66%) 10 (29%) CR 5 (14%) 0 (0%) PR 19 (29%) SD 8 (23%) 9 (26%) Non-evaluable* All AEs n=71 All grade 64 24 Immune-related AEs Any Grade ≥ Grade 3 Hyperthyroidism 8 Hypothyroidism 7 Hepatitis 1 Pneumonitis 2 No. of patients who had treatment-related AEs 14 patients 1 patient 1 non-evaluable as no RECIST assessment after registration dMMR-MMR deficient, pMMR- MMR proficient OTRR, Objective Tumour Response Rate; DCR, Disease Control Rate Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601) Antill YC et al., ASCO 2019, abstract 5501 (oral presentation

SUMMARY & CONCLUSIONS Monotherapy with durvalumab (PD-L1 antibody) showed promising activity and safety in patients with advanced endometrial cancer (AEC) and deficient DNA mismatch repair (dMMR) regardless of prior lines of chemotherapy Overall response rate 43% (52% in first-line, 31% in second-line) In AEC patients with proficient DNA mismatch repair (pMMR), the evidence for activity of durvalumab was limited Overall response rate 3% Only few immune-related adverse events were noted These results warrant further exploration of immune therapy in the setting of AEC Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601) Antill YC et al., ASCO 2019, abstract 5501 (oral presentation)

Phase 2, two-group, two-stage study of avelumab in patients with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent / persistent endometrial cancer (oral abstract 5502) Panagiotis A. Konstantinopoulos, Joyce F. Liu, Weixiu Luo, Carolyn N. Krasner, Jeffrey Joseph Ishizuka, Allison Ann Gockley, Mary K. Buss, Susana M. Campos, Elizabeth Stover, Alexi A. Wright, Whitfield Board Growdon, Jennifer Curtis, Ariana Peralta, Patrice Basada, Roxanne Quinn, Kathryn P. Gray, Richard T. Penson, Stephen A. Cannistra, Gini F. Fleming, Ursula A. Matulonis Abstract 5502: Background: This non-randomized phase 2 study evaluated the PD-L1 inhibitor avelumab in two cohorts of EC: i) MSI/POLE cohort including ECs with immunohistochemical (IHC) loss of expression of at least one of the mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE and ii) MSS cohort including ECs with normal IHC expression of all MMR proteins. Methods: Eligibility criteria included measurable disease, unlimited prior therapies, and any EC histology. Co-primary endpoints were confirmed objective response (OR) and progression-free survival rate at 6 months (PFS6). Avelumab 10 mg/kg IV was given every 2 weeks until progression or unacceptable toxicity. In the 1st stage, 16 pts were enrolled in each cohort; if there were ≥2 ORs or ≥2 PFS6 responses, accrual would continue to the 2nd stage with enrollment of 19 additional pts. Overall, if there are ≥4 ORs or ≥8 PFS6 responses, avelumab would be considered worthy of further study in each cohort. Results: As of 12/2018, 33 pts were enrolled. The MSS cohort was closed at the 1st stage due to futility; of 16 pts in the MSS cohort, only 1 pt exhibited an OR and PFS6 response [ORR and PFS6 rate 6.25% (95% CI 0.16%-30.2%)]. Conversely, the MSI/POLE cohort reached the primary endpoint of 4 ORs after accrual of only 17 pts. Two pts in the MSI/POLE cohort did not initiate protocol therapy and were excluded from all analyses. Of 15 pts in the MSI/POLE cohort, 4 pts exhibited OR [1CR+3PRs, OR rate (ORR) 26.7% (95% CI 7.8%-55.1%)] and 6 pts (including the 4 pts with OR) exhibited PFS6 responses [PFS6 rate 40.0% (95% CI 16.3%-66.7%)], 4 ongoing and 3 approaching 2 yrs. Twenty-two pts (71%) reported treatment related toxicities, 6 patients (19%) G3 toxicities; there were no treatment-related G4 and G5 toxicities. In the MSI/POLE cohort, 5 of 6 PFS6 responses were observed in pts with ≥3 lines of prior therapy (p = 0.011) and in tumors who were PD-L1 negative by IHC. Further correlative work will be reported at the meeting. Conclusions: In EC pts stratified by MSI/POLE status, MSI vs MSS status appears to be correlated with avelumab response even in PD-L1 negative tumors. Responses in the MSI/POLE cohort were more frequent in more heavily pretreated patients, a finding that warrants further investigation. Clinical trial information: NCT

A non-randomized phase 2 study evaluating PD-L1 inhibitor avelumab in two endometrial cancer (EC) cohorts: 1- MSI/POLE cohort: including ECs with immunohistochemical loss of expression of at least one of the mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE 2- MSS cohort: including ECs with normal IHC expression of all MMR proteins MSI, microsatellite instable MSS, microsatellite stable Eligibility criteria included measurable disease, unlimited prior therapies, and any EC histology Co-primary endpoints - confirmed objective response (OR) and PFS rate at 6 months (PFS-6) Avelumab* was given until progression / unacceptable toxicity. In stage1, 16 pts were enrolled in each cohort; if there were ≥2 ORs or ≥2 PFS-6 responses, accrual would continue to stage 2 with 19 additional patients Overall, if there were ≥4 ORs or ≥8 PFS-6 responses, avelumab would be considered worthy of further study in each cohort *10 mg/kg IV given every 2 weeks Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC) Konstantinopoulos PA et al., ASCO 2019, abstract 5502 (oral presentation)

Patient stratification AND Design
Avelumab study in EC stratified by mutational status MMRD or POLE-mutated cohort* (N=15) IV Avalumab q2weeks until disease progression Co-primary endpoints Progression-free survival ≥ 6 months (PFS6) after initiating therapy Objective response rate (ORR) by RECIST 1.1 Key eligibility criteria Recurrent EC of any histology (including carcinosarcoma) No upper limit of prior therapies No prior immune checkpoint blockade Patients (n=31) with recurrent or persistent Endometrial Cancer (EC) * All were MMRD by IHC No POLE-mutated tumors Stratification based on IHC MMRP cohort (n=16) IV Avelumab q2weeks until disease progression ECs with unknown POLE-mutation status which were MMRP were included in the MMRP cohort POLE-mutation status was determinded subsequently for all these tumors *POLE-mutated ECs: Mutations involving the exonuclease domain (amino acid residues ) IHC, Immunohistochemistry; MMRD, Mismatch Repair Deficient; MMRP, Mismatch Repair Proficient; POLE, exonuclease domain of DNA Polymerase Epsilon Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC) Konstantinopoulos PA et al., ASCO 2019, abstract 5502 (oral presentation)

Demographics AND baseline characteristics
MMRD (N=15) MMRP/non-POLE (N=16) Overall N % Age (yrs) 63.2 65.9 64.6 Stage at diagnosis 8 53.3 5 31.3 13 41.9 I II 2 13.3 1 6.3 3 9.7 III 4 26.7 18.8 7 22.6 IV 6.7 43.8 25.8 Histology 14 93.3 6 37.5 20 64.5 Endometrioid Mixed 12.9 Adenocarcinoma not otherwise specified - 12.5 6.5 Carcinosarcoma Serous Number of prior lines 40.0 9 29.0 20.0 3 or more MMRD, Mismatch Repair Deficient; MMRP, Mismatch Repair Proficient; POLE, exonuclease domain of DNA Polymerase Epsilon Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC) Konstantinopoulos PA et al., ASCO 2019, abstract 5502 (oral presentation)

MMRP/non-POLE Cohort (N=16)
Results Confirmed objective response and PFS6 RESPONSE Patients MMRD cohort (N=15) MMRP/non-POLE Cohort (N=16) Best Overall Response CR 1 PR 3 SD 4 PD 9 Not evaluable 2 ORR, % (95% CI) 26.7 ( ) 6.25 ( ) PFS6 Response Yes 6 No 15 PFS6 Response, % 40 ( ) MMRD, Mismatch Repair Deficient; MMRP, Mismatch Repair Proficient; PFS6, Progression-free Survival Rate at 6 months Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC) Konstantinopoulos PA et al., ASCO 2019, abstract 5502 (oral presentation)

Percent alive and progression-free
Results PFS and OS in both cohorts (median follow up 18.6 months) Progression-free survival Overall survival 100 100 Median PFS MMRD: 4.4 months MMRP: 1.9 months / non-POLE Median OS MMRD: not reached MMRP: 6.6 months / non-POLE 80 80 Percent alive and progression-free 60 60 Percent alive MMRD MMRD 40 40 MMRP/ non-POLE 20 20 MMRP/ non-POLE MMRD, mismatch repair deficient MMRP, mismatch repair proficient 3 6 9 12 15 18 21 3 6 9 12 15 18 21 24 Months Months Number at risk Number at risk MMRD MMRP/ non-POLE Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/ persistent endometrial cancer (EC) Konstantinopoulos PA et al., ASCO 2019, abstract 5502 (oral presentation)

IHC did not miss any case of MMRD determined by PCR or Oncopanel
Results MMRP cohort: Perfect correlation of IHC, PCR & NGS Responses were observed irrespective of PD-L1 Status Cohort (IHC) PCR NGS (Oncopanel) MSS MSI-H Total MMRD MMRP cohort (n=16) 13 − 15 4 MMRD (33%) and 3 MMRP/non-POLE (23%) were PD-L1 positive Treatment response was irrespective of: line of therapy PD-L1 status tumor mutation burden (TMB) CD8+ tumor infiltrating lymphocytes (TILs) No unexpected side effects were observed IHC did not miss any case of MMRD determined by PCR or Oncopanel Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC) Konstantinopoulos PA et al., ASCO 2019, abstract 5502 (oral presentation)

SUMMARY & CONCLUSIONS Mismatch repair deficiency (MMRD) by IHC correlates with response to avelumab in endometrial cancer (EC) with durable responses observed irrespective of PD-L1 status, multiple prior lines of therapy and somatic or germline MMRD Avelumab did not demonstrate activity worthy of further study in MMRP/non-POLE mutated ECs Findings support routine use of IHC to determine MMRD in EC when considering therapy with immune checkpoint inhibitors IHC; immunohistochemistry; MMRP, Mismatch Repair Proficient; POLE, exonuclease domain of DNA Polymerase Epsilon Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC) Konstantinopoulos PA et al., ASCO 2019, abstract 5502 (oral presentation)

Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC (oral abstract 5503) Gemma Kenter, Stefano Greggi, Ignace Vergote, Dionyssios Katsaros, Juliusz Kobierski, Leon Massuger, H. C. van Doorn, Fabio Landoni, Jacobus Van Der Velden, Nicholas Simon Reed, Corneel Coens, Iske van Luijk, P. B. Ottevanger, Antonio Casado Abstract 5503: Background: Conflicting evidence on the value of neoadjuvant chemotherapy followed by surgery compared to concomitant chemoradiation in Stage IB2-IIB cervical carcinoma led to this multinational multicenter trial. As the trial is approaching completion of its follow-up, preliminary results are presented. Methods: Between May 2002 and June 2014 a total of 620 patients with FIGO stage Ib2-IIb were randomized between neoadjuvant chemotherapy followed by surgery (NACTS, arm 1, N=311) with standard concomitant chemoradiotherapy (CCRT, arm 2, N=309) . In arm 1, radical hysterectomy was required within 6 weeks after completion of cisplatin-based chemotherapy with a cumulative minimum of 225mg/m2, in arm 2, radiation consisted of Gy plus boost concurrent with weekly cisplatin chemotherapy (40 mg/m2 per week). Primary endpoint was 5-yrs overall survival (OS). Results: Median follow-up time was 8.2 years ( 95% CI = 7.8 yrs – 8.6 yrs)) and similar between both arms. A total of 191 deaths (31%) occurred. Age, stage and histological cell type were balanced in both arms. Protocol treatment was completed in 459 (74%) patients (71% for NACTS; 82% for CCRT). In arm (76%) patients underwent surgery. Main reasons for not having surgery as per protocol, were toxicity (25/74, 34%), progressive disease (18/74, 24%) and insufficient response to NACT (12/74, 16%). Additional radiotherapy was given to 113 patients (36.3%) in arm 1; additional surgery performed in 9 patients (2.9%) in arm 2. Short term severe adverse events (≥G3) occurred more frequently in arm 1 than in arm 2 (35% vs 21%, p < 0.001). The 5 year OS was 72% in arm 1 and 76% in arm 2 (not statistically significant, difference = 4.0% (95%CI: -4% - 12%); HR 0.87, 95%CI: , p=0.332). Conclusions: These preliminary results revealed no difference in 5-year OS between NACTS and CCRT, indicating that quality of life and long term toxicity are important to decide optimal treatment. The final results will be available by April 2019, including long-term toxicity and treatment effect across prognostic factors. Clinical trial information: NCT

There is conflicting evidence on the value of neoadjuvant chemotherapy followed by surgery compared to concomitant chemoradiation in Stage IB2-IIB cervical carcinoma EORTC a multinational multicenter trial is approaching completion of its follow-up, preliminary results are presented here Between , a total of 620 patients (FIGO IB2-IIB) were randomized between neoadjuvant chemotherapy followed by surgery (NACTS, arm 1, N=311) and standard concomitant chemoradiotherapy (CCRT, arm 2, N=309) In arm 1, radical hysterectomy was required within 6 weeks after completion of cisplatin- based chemotherapy (cumulative minimum of 225 mg/m2), in arm 2, radiation consisted of Gy plus boost concurrent with weekly cisplatin chemotherapy (40 mg/m2 per week) Primary endpoint was 5-years overall survival (OS) EORTC, European Organisation for Research and Treatment of Cancer Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC 55994 Kenter G et al., ASCO 2019, abstract 5503 (oral presentation)

EORTC 55994 − trial design Endpoints:
Cervical carcinoma of squamous or adeno (squamous) cell type FIGO stage Ib2, IIa >4 cm, or IIb Arm 1: NACT + Sy Neoadjuvant cisplatin-based chemotherapy (≥225 mg/m2) followed by radical hysterectomy* n=314 R Arm 2: CTRTx Concomitant radiation and chemotherapy Gy plus boost + weekly ≥40 mg/ m2 cisplatin n=312 + n=626 Endpoints: Primary: overall survival (OS) at 5 years Secondary: PFS, toxicity & Qol Stratification: Age (<50 vs >50 years), cell type, FIGO stage (1994), and Institution * radical hysterectomy was required within 6 weeks after completion of chemotherapy; PFS, Progression-free Survival Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC 55994 Kenter G et al., ASCO 2019, abstract 5503 (oral presentation)

Baseline characteristics
NACT + Sy (n=314) CTRTx (n=312) Median age, years 46 47 ECOG PS 0/1 88% / 12% FIGO stage: Ib2 26% 28% IIa >4 cm 15% IIb 57% Type of cervical carcinoma squamous cell 85% adenocarcinoma 10% 11% adenocarcinoma cell 5% 4% BMI ≤25 / / >30 38% / 27% / 23% 40% / 31% / 15% 3 FIGO III; 1 FIGO IV; 2 FIGO stage unknown 1 clear cell; 2 unknown BMI / BSA not available if no chemo started ECOG PS, Eastern Cooperative Oncology Group Performance Status; BMI, Body Mass Index; BSA, Body Surface Area Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC 55994 Kenter G et al., ASCO 2019, abstract 5503 (oral presentation)

Treatment compliance NACT + Sy CTRTx
Of the 314 patients, 74 (24%) received no surgery Main reasons: Chemotherapy toxicity: 25 (34%) Progression: 18 (24%) Insufficient response: 12 (16%) Patient refusal: 10 (14%) Protocol violation: 6 (8%) Other: 3 (4%) Of the 314 patients, 240 (76%) received surgery Type of surgery was: Piver-Rutledge III: 86% Piver-Rutledge IV: 4% Piver-Rutledge V: 6% Other 5% Chemotherapy Cisplatin mono: 46% Cisplatin + PT: 20% Cisplatin + PT + Ifos: 19% Cisplatin + Other 15% Of the 312 patients, 20 (6%) received no CTRT Main reasons: Patient refusal: 11 (55%) Protocol violation: 5 (25%) Withdrawal of consent: 2 (10%) Physician decision Of the 312 patients, 292 (94%) received CTRT Median dose: 46 Gy (pelvic) External boost: 123 (42%) Brachy: 280 (97%) Chemotherapy Cisplatin mono: 87% Cisplatin + Taxol 13% CTRT, Chemoradiation Therapy; NACT +Sy, Neoadjuvant Chemotherapy followed by Radical Hysterectomy Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC 55994 Kenter G et al., ASCO 2019, abstract 5503 (oral presentation)

Pathological evaluation / Response
Pathological evaluation NACT + Sy arm* Pathological response NACT + Sy Response n % Complete response 54 23% Optimal response 35 15% Suboptimal 124 52% Other 27 11% Complete Optimal Sub-opt Other Cisplatin alone 19% 13% 52% 16% n=119 Cisplatin + Paclitaxel (+/- other) 28% 17% 3% n=94 Cisplatin + other 22% 15% 48% n=27 n=55 n=35 n=124 n=26 n=240 32% 45% 37% Complete = no microscopic residual disease Optimal = carcinoma in situ or stomal invasion <3 mm Suboptimal = neither complete nor optimal Other = not assessable, missing, unknown Cisplatin alone has the lowest response rate with 32% (38/119) reporting either complete or optimal response, however this difference is not statistically significant. * Pathological evaluation available for 240 patients who underwent protocol surgery; NACT +Sy, Neoadjuvant Chemotherapy followed by Radical Hysterectomy Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC 55994 Kenter G et al., ASCO 2019, abstract 5503 (oral presentation)

Adverse events Treatment period: CTC grade 3/4
Follow up period: Chassagne Score1 grade 3/4 N (%) Treatment Total (N=591) NACT + Sy (N=299) CTRTx (N=292) 122 (40.8%) 66 (22.6%) 188 (31.8%) Gastrointestinal 34 (11.4) 20 (6.8) 54 (9.1) Blood/Bone Marrow 36 (12.0) 15 (5.1) 51 (8.6) Infection 25 (8.4) 8 (2.7) 33 (5.6) Cardiovascular 10 (3.3) 11 (3.8) 21 (3.6) Renal/genitourinary 16 (5.4) 4 (1.4) 20 (3.4) Hemorrhage 15 (5.0) 2 (0.7) 17 (2.9) Constitutional 7 (2.3) 15 (2.5) Dermatology 14 (4.7) 1 (0.3) Metabolic 5 (1.7) 13 (2.2) Neurolgy 9 (3.0) 11 (1.9) Pain 3 (1.0) 7 (2.4) 10 (1.7) N (%) Treatment Total (N=583) NACT + Sy (N=293) CTRTx (N=202) Bladder and urethra 13 (4.4) 11 (3.8) 24 (4.1) Ureter 12 (4.1) 23 (3.9) Uterus-vagina-vulva 6 (2.0) 20 (3.4) Colon (non sigmoid) 5 (1.7) 8 (2.8) 13 (2.2) Pelvic soft tissues 11 (1.9) Rectum 4 (1.4) 9 (1.5) Sigmoid colon 1 (0.3) 6 (1.0) Bone 2 (0.7) Peripheral nerves 3 (1.0) Hemopoietic tissue 4 (0.7) Non specific abdominal 2 (0.3) Vesicular Stomach and duodenum 0 (0.0) 1 (0.2) Cutaneous Two patients in CTRTx arm died due to complications: Chronic small bowel obstruction + malabsorption eventually death Infection following surgery for rectal stricture CTC, common toxicity criteria; CTRT, Chemoradiation Therapy; NACT +Sy, Neoadjuvant Chemotherapy followed by Radical Hysterectomy 1.Chassagne D et al. Radiother Oncol Mar;26(3): Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC 55994 Kenter G et al., ASCO 2019, abstract 5503 (oral presentation)

Results Overall survival (OS) − ITT population
OS of patients who completed treatment 100 100 90 90 80 80 No statistically significant difference at year 5 Δ = 4% (-3% - 12%); p=0.297 70 70 Difference at year 5 Δ = 0% (-9% - 9%) 60 60 50 50 40 Treatment Patients (n) Events (o) % at 5 Year (s) NACT + Sy 314 104 71.7 (66.2, 76.5) CTRTx 312 94 75.5 (70.2, 80.0) Similar results in eligible and per protocol population 40 Treatment Patients (n) Events (o) % at 5 Year (s) NACT + Sy 217 61 77.8 (71.4, 82.9) CTRTx 230 67 77.5 (71.4, 82.5) 30 30 20 20 Overall Score test: p=0.253 10 10 (years) (years) 2 4 6 8 10 12 2 4 6 8 10 12 Treatment NACT + Sy CTRTx Treatment NACT + Sy CTRTx O N 104 314 94 312 Number of patients at risk: O N 61 217 67 230 Number of patients at risk: 244 212 156 116 78 262 228 162 119 84 179 158 117 84 58 201 174 121 89 63 Subgroups with more CTRTx benefits: age > 50 years low body weight (BMI) larger tumors (FIGO IIB) CTRT, Chemoradiation Therapy; ITT, Intention-to-Treat; NACT +Sy, Neoadjuvant Chemotherapy followed by Radical Hysterectomy Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC 55994 Kenter G et al., ASCO 2019, abstract 5503 (oral presentation)

Results PFS − ITT population PFS of patients who completed treatment D
100 100 D 90 90 80 80 70 Statistically significant difference at year 5 Δ = 9% (2% - 18%); p=0.021 70 Difference at year 5 Δ = 7% (-17% - 3%) 60 60 50 50 40 Treatment Patients (n) Events (o) % at 5 Year (s) NACT + Sy 314 144 56.9 (51.1, 62.3) CTRTx 312 119 65.6 (59.9, 70.7) Similar results in eligible and per protocol population 40 Treatment Patients (n) Events (o) % at 5 Year (s) NACT + Sy 217 90 61.8 (54.8, 68.0) CTRTx 230 84 67.7 (61.2, 73.4) p=0.154 30 30 20 20 10 Overall Score test: p=0.011 10 (years) (years) 2 4 6 8 10 12 2 4 6 8 10 12 Treatment NACT + Sy CTRTx Treatment NACT + Sy CTRTx O N 144 314 119 312 Number of patients at risk: O N 90 217 84 230 Number of patients at risk: 202 169 122 93 64 230 145 105 75 155 129 90 66 48 178 154 110 80 57 CTRT, Chemoradiation Therapy; ITT, Intention-to-Treat; NACT +Sy, Neoadjuvant Chemotherapy followed by Radical Hysterectomy Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC 55994 Kenter G et al., ASCO 2019, abstract 5503 (oral presentation)

SUMMARY & CONCLUSIONS These preliminary results of the EORTC study revealed no significant difference in 5-year OS between stage Ib2-IIb cervical cancer patients (n=626) treated with neoadjuvant chemotherapy followed by surgery (NACT+Sy) and those treated with standard concomitant chemoradiotherapy (CCRTx) - OS 72% in NACT+Sy arm and 76% in CTRTx arm (median follow-up 8 years) PFS difference in the ITT population was significant in favor of CTRTx vs NACT+Sy (66% vs 57%), but this difference disappeared for patients completing total treatment Only 76% of the patients randomized in the NACT arm eventually received surgery Further results: Trend towards better results in NACT+Sy arm for stage Ib2 Trend towards better results for CTRTx arm 2 for stage IIb, BMI<25 and age> 50 yr Trend towards better results in NACT+ Sy arm for combination chemo Short term gr 3 and 4 toxicity higher in NACT+Sy arm (41 vs 22 %) Long term toxicity higher in CTRTx arm (15 vs 21%) Results from neoadjuvant chemotherapy followed by surgery compared to chemoradiation for stage Ib2-IIb cervical cancer, EORTC 55994 Kenter G et al., ASCO 2019, abstract 5503 (oral presentation)

Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi-institutional analysis of 700 cases (oral abstract 5504) Shitanshu Uppal, Paola Gehrig, Monica Hagan Vetter, Brittany Anne Davidson, Brittany F Lees, Laurie Leigh Brunette, Katherine Tucker, Koji Matsuo, Kristin Leigh Bixel, Allison Stuart Staley, Walter H. Gotlieb, Robert W. Holloway, Kathleen N. Moore, Stephen L. Rose Abstract 5504: Background: Compare outcomes between open and minimally invasive radical hysterectomy. Methods: Retrospective multi-institutional review of patients undergoing radical hysterectomy for stage IA1, IA2 and IB1 squamous, adeno- or adeno-squamous carcinoma between 01/01/ /31/2017. Results: From 704 cases that met the inclusion criteria, 185 (26.3%) underwent open and 519 (73.7%) underwent minimally invasive surgery (MIS). Women treated with open surgery were older, had larger tumors on preoperative assessment as well as on final pathology assessment, had higher proportion of patients with IB1 stage and adjuvant therapy. Patients undergoing open surgery had longer median follow-up compared to MIS (44 vs months, p < 0.001). The two groups were similar in regard to race distribution, body mass index, comorbidities and preoperative histology. There were 13/185 (7%) recurrences and 10/185 (5.4%) deaths in the open compared to 42/519 (8.1%) recurrences and 26/519 (5%) deaths in MIS (p = n.s for both). However, on multivariate analysis, after controlling for race, comorbidities, preoperative tumor size, histology, grade and smoking status, MIS had higher odds of recurrence (OR 2.24, 95% CI , p = 0.04). On a second model, in addition to prior mentioned factors, we included lymphovascular space invasion, receipt of adjuvant therapy and vaginal margin status. Undergoing MIS remained associated with higher odds of recurrence (OR 2.37, 95% CI , p = 0.031). On sub-group analysis of cases with preoperative tumor size less than equal to 2 cm, there were 5/121 (4.1%) recurrence in open and 25/415 (6%) recurrences in MIS group (p = 0.34). Multivariate analysis did not show a higher rate of recurrence in MIS arm in this subgroup. In 26 cases of MIS where no vaginal manipulator was used, no recurrences were noted. In comparison 19/270 (7%) recurrences were noted in intra-uterine manipulator (V-care/Zumi/Rumi) and 22/210 (11%) in vaginal manipulators (EEA sizer/Colpo Probe) groups (p = 0.119). Conclusions: In this large retrospective analysis, patients undergoing MIS for early stage cervical cancer had higher odds of recurrence. In patients with 2 cm or less tumor on preoperative assessment, recurrence rates were similar between the two groups. Role of manipulator in increasing recurrence should be further studied in this patient population.

The phase III LACC trial found that minimally invasive surgery (MIS) / radical hysterectomy was inferior to open radical hysterectomy (ORH) with reduced disease-free survival (86% vs 96.5%) and a higher disease-specific death rate (DSDR) (4.4% v 0.6%) in patients with early-stage cervical cancer (CC)1 A multi-institutional analysis investigated recurrence rates in 700 cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy (MIS) Comparison of outcomes between open and minimally invasive radical hysterectomy Retrospective multi-institutional review Cervical cancer patients underwent radical hysterectomy for stage IA1, IA2 and IB1 squamous, adeno- or adeno-squamous carcinoma between Jan Dez (see study scheme on next slide) Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi-institutional analysis of 700 cases Uppal S et al., ASCO 2019, abstract 5504 (oral presentation)

Converted to OPEN from MIS (n=7)
Study Scheme Patient flow chart Seven high volume hospitals participated in this analysis Total n=704 Similar to LACC criteria Total n=662 Exclude = 42 Stage I A1 with negative LVSI n=5 Preoperative imaging with metastasis =17 26.9% − (OPEN) (n=178) 73.1% − (MIS) (n=484) Planned OPEN (n=172) Converted to OPEN from MIS (n=7) 9% − Laparoscopic (n=46) 91% − Robotic (n=473) LVSI, Lymphovascular Space Invasion; MIS, Minimally Invasive Radical Hysterectomy Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi-institutional analysis of 700 cases Uppal S et al., ASCO 2019, abstract 5504 (oral presentation)

Baseline cohort demographics (i)
No difference in age groups Higher proportion of African American patients in MIS arm No difference in Median BMI Comorbidity scores OPEN (N=178) MIS (N=484) p-value N=178 N=484 STAGE 1a1 0 (0.0%) 7 (1.4%) 0.18 1a2 12 (6.7%) 43 (8.9%) 1b1 166 (93.3%) 434 (89.7%) PREOP TUMOR SIZE No visible tumor 61 (34.3%) 175 (36.2%) 0.030 ≤ 2 cm 56 (31.5%) 129 (26.7%) > 2 cm 98 (20.2%) Missing 82 (16.9%) Higher 1b1 stage in Open One site did not collect ‘preop’ tumor size BMI, Body Mass Index; MIS, Minimally Invasive Radical Hysterectomy Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi-institutional analysis of 700 cases Uppal S et al., ASCO 2019, abstract 5504 (oral presentation)

Baseline cohort demographics (iI)
OPEN (N=178) MIS (N=484) p-value N=178 N=484 Pre-operating imaging obtained Yes 102 (57.3%) 314 (64.9%) 0.074 GRADE 1-Grade 1 40 (22.5%) 90 (18.6%) 0.011 2-Grade 2 86 (48.3%) 204 (42.1%) 3-Grade 3 42 (23.6%) 118 (24.4%) Unknown 10 (5.6%) 72 (14.9%) Histology Squamous 107 (60.1%) 270 (55.8%) 0.45 Adenocarcinoma 62 (34.8%) 194 (40.1%) Adeno-squamous 9 (5.1%) 20 (4.1%) OPEN (N=178) MIS (N=484) p-value Final tumor size (Centimeters) 2 (.7-3.5) 1.3 (0-2.8) <0.001 Follow up Duration (Months) 44.7 ( ) 30.2 ( ) LVSI No 121 (65.4%) 320 (61.7%) 0.81 Yes 63 (34.1%) 174 (33.5%) Missing 1 (0.5%) 25 (4.8%) Nodes Positive 164 (88.6%) 449 (86.5%) 0.60 21 (11.4%) 66 (12.7%) 0 (0.0%) 4 (0.8%) Parametria Positive 173 (93.5%) 486 (93.6%) 0.74 12 (6.5%) 30 (5.8%) 3 (0.6%) No difference in proportion undergoing preoperative imaging More ‘Unknown’ grade in MIS No difference in histology Open cases had larger tumors Longer duration of follow-up Similar rates of LVSI, node positive and parametria positive disease LVSI, Lymphovascular Space Invasion Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi-institutional analysis of 700 cases Uppal S et al., ASCO 2019, abstract 5504 (oral presentation)

Baseline cohort demographics (iII)
OPEN MIS p-value Vaginal Margins Positive No 174 (94.1%) 502 (96.7%) 0.083 Yes 11 (5.9%) 16 (3.1%) Missing 0 (0.0%) 1 (0.2%) Margin Distance, median (mm) 7 (3-12) 8 (4-12) 0.34 Adjuvant Treatment 110 (59.5%) 344 (66.3%) 0.050 75 (40.5%) 166 (32.0%) 9 (1.7%) Open cases had: Higher positive vaginal margins Similar margin distance in case with negative margins More adjuvant treatment MIS, Minimally Invasive Radical Hysterectomy Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi-institutional analysis of 700 cases Uppal S et al., ASCO 2019, abstract 5504 (oral presentation)

Recurrence rates / Recurrence free survival*
Recurrence-free survival (unadjusted) OPEN (n=178) MIS (n=484) p-value No recurrence 167 (93.8%) 464 (91.1%) 0.3 Total recurrences 11 (6.2%) 43 (8.9%) Locoregional only 4 (2.2%) 13 (2.7%) Distal only 1 (0.6%) 14 (2.9%) Both local & distal 6 (3.4%) Unspecific 0 (0.0%) 3 (0.6%) Compared to open radical hysterectomy, minimally invasive hysterectomy has an increased risk of recurrence − HR 2.06 (95% CI, ) * Results in the unadjusted cohort Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi-institutional analysis of 700 cases Uppal S et al., ASCO 2019, abstract 5504 (oral presentation)

Recurrence rates / Recurrence free survival*
Recurrence rates − propensity matched cohort Recurrence-free survival − prop. matched c. OPEN (n=120) MIS (n=117) p-value No recurrence 114 (95%) 102 (87.2%) 0.034 Total recurrences 6 (5%) 15 (12.8%) Locoregional only 3 (2.5%) 3 (2.6%) Distal only 0 (0.6%) 5 (4.3%) Both local & distal 6 (5.1%) Unspecific 0 (0.0%) 1 (0.9%) Propensity matched cohort – unadjusted Kaplan-Meier survival estimates Propensity matched cohort – adjusted for adjuvant therapy HR 6.8 (95% CI ) Compared to open radical hysterectomy, minimally invasive hysterectomy has an increased risk of recurrence * Results in the adjusted cohort Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi-institutional analysis of 700 cases Uppal S et al., ASCO 2019, abstract 5504 (oral presentation)

SUMMARY & CONCLUSIONS In this large retrospective analysis, patients (n=662) undergoing minimally invasive radical hysterectomy (MIS) for early stage cervical cancer (IA1, IA2 and IB1) had higher odds of recurrence vs patients undergoing open surgery This analysis is in line with previous findings (LACC study) and provides confirmative data for the inferiority of minimally invasive surgery (MIS) vs open surgery in early stage cervical cancer In addition this analysis suggests an advantage of open surgery also for tumors ≤ 2 cm Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi-institutional analysis of 700 cases Uppal S et al., ASCO 2019, abstract 5504 (oral presentation)

Recurrence and survival after robotic-assisted radical hysterectomy (RRH) for early-stage cervical cancer: Experience may matter (poster abstract 5535) Christine K. Fitzsimmons, Amanda J. Stephens, Jessica A. Kennard, Madhavi Manyam, Julie W. Pepe, Kayla M. DeCoff, Sarfraz Ahmad, Nathalie Dauphin McKenzie, James Erasmus Kendrick, Robert W. Holloway Abstract 5535: Background: The phase III LACC Trial found that minimally invasive surgery (MIS) / radical hysterectomy was inferior to open radical hysterectomy (ORH) with reduced disease-free survival (86% v 96.5%) and a higher disease-specific death rate (DSDR) (4.4% v 0.6%). We evaluated our experience with attention to the learning curve. Methods: Patients (pts) with early-stage CC (4/ /2017) who underwent RRH with a uterine manipulator were evaluated in a contemporaneously maintained database. First 10 learning curve cases per surgeon (Group A) were compared to all subsequent cases (Group B). Inclusion criteria mirrored the LACC trial: > one-year follow-up, adenocarcinoma, adenosquamous, or squamous carcinoma, stage IA2 or IB1 using FIGO 2014 guidelines, and pathologic tumor size (TS) of 4 cm or less. Atypical histologies and lesions > 4 cm were excluded. Study parameters assessed included recurrence free survival (RFS), DSDR, and pattern of recurrence. Results: 144 RRH pts were identified and 90 met inclusion criteria with mean age of 45.6±14.3 years. Exclusions included stage 1A1 without LVSI (n = 13), atypical histology (n = 10), lost to follow-up (n = 13), and occult stage 1B2 (n = 18). 40 pts met Group A and 50 met Group B criteria. Median follow-up was 61±34.3 months (A = 71.5, B = 52.5). The 5-year RFS was 92% (95 CI ±4%) and the DSDR 5.5% (n = 5). There were 7 (7.8%) recurrences with median time to recurrence of 12±8.3 mos. Recurrence in Group A (n = 6, 15%) exceeded Group B (n = 1, 2%), p= DSDR was 10% Group A v 2% B (p= 0.184). The 4.5 yr RFS was 84.8% (95 CI ±7%) in Group A v 98% (95 CI ±3%) in Group B. There were no differences in risk factors for recurrence between A & B (TS > 2 cm, LN (+), adjuvant therapy (AT), and LVSI p> 0.05), except (+) vaginal margin status (A = 10% v B = 0%, p= 0.034). Three recurrences involved carcinomatosis, which may be insufflation related. All recurrent cases had TS > 2 cm and 5 received AT. Conclusions: In this study, recurrence of disease in early-stage CC clustered in the first 10 cases per surgeon and occurred in TS > 2 cm. This data suggests a possible learning curve effect and argues against a uterine manipulator cause. Carcinomatosis may be insufflation related, unique to MIS, and deserves further study.

The phase III LACC trial found that minimally invasive surgery (MIS) / radical hysterectomy was inferior to open radical hysterectomy (ORH) with reduced disease-free survival (86% vs 96.5%) and a higher disease-specific death rate (DSDR) (4.4% v 0.6%) in patients with early-stage cervical cancer (CC)1 The present study evaluated surgeon experience with attention to the learning curve * treated between 04/ /2017 Patients* with early-stage CC who underwent RRH with a uterine manipulator were evaluated in a contemporaneously maintained database: First 10 learning curve cases per surgeon (Group A) were compared to all subsequent cases (Group B), see next slide Inclusion criteria mirrored the LACC trial:1 > one-year follow-up, adenocarcinoma, adenosquamous, or squamous carcinoma, stage IA2 or IB1 using FIGO 2014 guidelines, and pathologic tumor size (TS) of 4 cm or less. Atypical histologies and lesions > 4 cm were excluded Study parameters assessed included recurrence free survival (RFS), DSDR, and pattern of recurrence RRH, robotic-assisted radical hysterectomy 1. Ramirez PT et al. N Engl J Med Nov 15;379(20): Recurrence and survival after robotic-assisted radical hysterectomy (RRH) for early-stage cervical cancer (CC): Experience may matter Fitzsimmons CK et al., ASCO 2019, abstract 5535 (poster presentation)

Results Disease-free survival (DFS) and disease-specific death rate (DSDR) 100 ◼︎ Group A ◼︎ Group B ◼︎ Total ◼︎ LACC Trial MIS ◼︎ LACC Trial Open 90 80 70 First 10 learning curve cases per surgeon (Group A) were compared to all subsequent cases (Group B) 60 Percentage (%) 50 40 The 4.5 year DFS was 84.8% (95 CI ±7%) in Group A vs 98% (95 CI ±3%) in Group B. 30 20 10 4.5 DFS DSDR DFS, disease-free survival; DSDR, disease-specific death rate; MIS, minimally invasive surgery; Open; open radical hysterectomy Recurrence and survival after robotic-assisted radical hysterectomy (RRH) for early-stage cervical cancer (CC): Experience may matter Fitzsimmons CK et al., ASCO 2019, abstract 5535 (poster presentation)

Results Group A Group B Histology: Adenocarcinoma vs Squamous
20 (50%) 20 (40%) vs 30 (60%) Median tumor size cm 1.5±1.5 2±1.2 Tumor size ≥ 2 cm 17 (42.5%) 25 (50%) LVSI 19 (51.3%) (+) Vaginal Margins 4 (10%) (+) Pelvic Nodes 7 (17.5%) 9 (18%) Adjuvant Therapy 15 (38.5%) 17 (34%) Recurrences 6 (15%) 1 (2%) LVSI, Lymphovascular Space Invasion Recurrence and survival after robotic-assisted radical hysterectomy (RRH) for early-stage cervical cancer (CC): Experience may matter Fitzsimmons CK et al., ASCO 2019, abstract 5535 (poster presentation)

SUMMARY & CONCLUSIONS In this study, recurrence of disease in early stage cervical cancer clustered in the first 10 robotic radical hysterectomies performed by a surgeon All recurrences occurred in lesions > 2 cm Although many surgeons utilize the robot in other procedures, radical hysterectomies are technically more challenging This data suggests a learning curve effect as a cause for the higher recurrence rates seen with MIS Clustering of recurrences within the early experience of a surgeon argues against a uterine manipulator cause of higher recurrences rates Recurrences with carcinomatosis may be related to insufflation, and is unique to MIS MIS, Minimally Invasive Surgery Recurrence and survival after robotic-assisted radical hysterectomy (RRH) for early-stage cervical cancer (CC): Experience may matter Fitzsimmons CK et al., ASCO 2019, abstract 5535 (poster presentation)

Surveillance in stage I MOGCTs (malignant ovarian germ cell tumors): A MITO prospective study (multicenter Italian trials in ovarian cancer) (poster discussion abstract 5516) Alice Bergamini, Giorgio Giorda, Gabriella Ferrandina, Gennaro Cormio, Domenica Lorusso, Chiara Cassani, Francesco Raspagliesi, Marco Marinaccio, Elena Bertone, Luigi Frigerio, Giovanna Scarfone, Myriam Perrone, Luca Bocciolone, Antonella Savarese, Sandro Pignata, Giorgia Mangili Abstract 5516: Background: The standard of treatment of stage I MOGCTs is surgery followed by BEP (bleomycin + etoposide + cisplatin) chemotherapy, except for stage IA dysgerminoma (D) and IAG1 immature teratoma (IT). Surveillance has emerged as a possible option to avoid adjuvant chemotherapy in IB-C1 D, IA-C G2 – G3 IT, and in stage IA mixed and yolk sac tumors (YST), after comprehensive surgical staging (CSS) with negative postoperative markers. The aim of this study was to analyze oncological outcome of stage I MOGCT patients included in the MITO9 study. Methods: MITO9 was a prospective observational study analyzing data collected between 2013 and patients with stage I conservatively treated MOGCTs were included. Three groups were identified: group A. IA D and IAG1 IT candidate to surveillance according to guidelines; group B. stages IB-C1 D, stage IA-C G2-G3 IT, stage IA mixed and YST were consulted about the option of close surveillance vs adjuvant chemotherapy in case of CSS; group C. all other patients receiving BEP. Results: Median age was 25.6 years (range 14-40). Median follow up was 36,4 months. Group A included 12 patients, 5 IA G1 IT and 7 IA D. Group B included 24 patients. Of these, 2 out of 5 patients (40%) were positive at restaging and were excluded from surveillance protocol. Seven of the 22 remaining patients (31.8%) received chemotherapy, while 15 (68.1%) were enrolled in the surveillance protocol. Out of these 15 patients, 4 were stage IC D (one IC1, one IC2 and two IC3), 2 were mixed stage IA with YST tumor, 9 were G3 IT (four IA, three IC2, one IC3 and one IB). The 7 patients receiving chemotherapy were: 1 dysgerminoma IC2, 2 YST IA, 3 IT G3 (one IA and one IC2) and 1 mixed IA tumour. Group C included 5 patients, three IC YST and two mixed IC2 with YST. Survival of these patients was 100%, while disease free survival was 97.5%. Only one patient in C Group, a stage IA G3 IT treated with adjuvant BEP, relapsed as mature teratoma. None of the patients in the surveillance protocol experienced relapse. Conclusions: These data suggest that close surveillance could be an alternative option to avoid adjuvant chemotherapy in properly staged IB-C1 D, stage IA G2 – G3 IT, stage IA mixed and YST. These findings deserve further confirmation in an international cooperative setting.

Standard treatment of stage I malignant ovarian germ cell tumors (MOGCTs) is surgery followed by BEP (bleomycin + etoposide + cisplatin) chemotherapy (CT), with the exception of stage IA dysgerminoma (D) and IAG1 immature teratoma (IT) Surveillance is a possible option to avoid adjuvant CT in IB-C1 D, IA-C G2 – G3 IT, and in stage IA mixed and yolk sac tumors (YST), after comprehensive surgical staging (CSS) with negative postoperative markers Aim of this study was to analyze outcome of stage I MOGCT patients included in the MITO9 study MITO9 was a prospective observational study analyzing data collected from 41 patients with stage I conservatively treated MOGCTs were included Three groups were identified: - Group A: IA-D and IA-G1 IT candidate for surveillance according to guidelines - Group B: stages IB-C1 D, stage IA-C G2-G3 IT, stage IA mixed and YST were counselled about the option of close surveillance vs adjuvant chemotherapy in case of CSS - Group C: all other patients receiving BEP Surveillance in stage I MOGCTs (malignant ovarian germ cell tumors): A MITO prospective study (multicenter Italian trials in ovarian cancer) Bergamini A et al., ASCO 2019, abstract 5516 (poster discussion presentation)

Background About malignant ovarian GC tumors
CT treatment-related toxicities Germ cell (GC) tumors account for 1-2% of ovarian malignancies More common at younger ages but may be present at any age Standard treatment of BEP results in toxicities that may be lifelong Pulmonary fibrosis Raynaud‘s disease Hearing loss Hypertension Kidney damage Secondary malignancies (leukemia) The number of occurrences of potentially chronic chemotherapy treatment-related toxicities Potentially chronic toxicity Number Kidney injury 2 Cardiac failure 1 Tinnitus/hearing loss 9 Bleomycin lung 4 Peripheral neuropathy 11 Died of ALL Total 27 ALL, acute lymphoblastic leukemia. BEP, Bleomycin + Etoposide + Cisplatin Surveillance in stage I MOGCTs (malignant ovarian germ cell tumors): A MITO prospective study (multicenter Italian trials in ovarian cancer) Bergamini A et al., ASCO 2019, abstract 5516 (poster discussion presentation)

outcomes IA dysgerminomas IAG1 immature teratomas Surveillance N=12
Group A IA dysgerminomas IAG1 immature teratomas Surveillance N=12 7 IA dysgermonomas 5 IA G1 immature teratomas Group B IB-C1 dysgerminomas IA-IC G2-G3 immature teratomas Stage IA mixed MOGCTs Stage IA yolk sac tumor After CSS Close surveillance vs adjuvant chemotherapy N=22 (24) 2/5 (40%) re-staged patients excluded due to positive restaging 15 received surveillance (68.1%) 4 were Stage IC D 2 were mixed stage IA with YST tumor 9 were G3 IT 7 received adjuvant chemotherapy (31.8%) 1 was D IC2 2 were YST IA 3 were IT G3 1 mixed IA tumor Group C All other stage I MOGCTs Adjuvant chemotherapy N=5 3 IC yolk sac tumors 2 IC2 mixed MOGCTS (with yolk sac) Median age was 25.6 years (14-40); median follow-up was 36.4 months 5-year overall survival was 100%, and 5-year disease-free survival was 97.5% Only one patient (group B) with stage IA G3 immature teratoma treated with adjuvant BEP relapsed as mature teratoma None of the patients in the surveillance protocol experienced relapse Surveillance in stage I MOGCTs (malignant ovarian germ cell tumors): A MITO prospective study (multicenter Italian trials in ovarian cancer) Bergamini A et al., ASCO 2019, abstract 5516 (poster discussion presentation)

SUMMARY & CONCLUSIONS The findings of the prospective observational MITO9 study suggest that close surveillance could be an alternative option to avoid adjuvant chemotherapy in properly staged patients with malignant ovarian germ cell tumors in the following scenarios: stage IB-C1 dysgerminoma stage IA-C G2-G3 immature teratoma stage IA mixed and yolk sac tumors These data should be replicated and confirmed in an international cooperative setting Surveillance in stage I MOGCTs (malignant ovarian germ cell tumors): A MITO prospective study (multicenter Italian trials in ovarian cancer) Bergamini A et al., ASCO 2019, abstract 5516 (poster discussion presentation)

Mismatch repair deficiency as a predictor of adjuvant radiotherapy response in endometrioid endometrial carcinoma (poster abstract 5586) Stefan Kommoss, Casper Reijnen, Heidi V.N. Küsters-Vandevelde, Clemens Prinsen, Massuger Leon, Marc P.M.L. Snijders, Sara Brucker, Diethelm Wallwiener, Janice S Kwon, Jessica N. McAlpine, Johanna M.A. Pijnenborg Abstract 5586: Background: Adjuvant radiotherapy improves progression-free survival in intermediate and high-risk endometrial cancer. However, so far there is no evidence of improved overall or disease-specific survival after adjuvant radiotherapy. There is accumulating evidence that MMR proteins are involved in DNA repair following radiotherapy. We investigated the predictive value of MMR status in terms of survival benefit after adjuvant radiotherapy in patients with stage IB/II, grade 3 endometrioid endometrial cancer (EEC). Methods: A retrospective multicenter cohort study was performed to compare patients with histopathologically confirmed stage IB/II grade 3 EEC with and without adjuvant radiotherapy. Patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifying ECs as either MMR-deficient, POLE, p53abn or p53wt. Multivariable Cox regression analysis explored associations between patient characteristics, adjuvant treatment and outcome. Results: A total of 128 patients were analyzed, including 57 patients (43.0%) with MMR-deficient EECs. Baseline characteristics were comparable, except a higher proportion of MMR-deficient EECs were stage II (36.8% vs. 15.5%, p = 0.006). Eighty-two patients (64.1%) received adjuvant radiotherapy (external beam [n = 55], vaginal brachytherapy [n = 27]). In multivariate analysis, adjuvant radiotherapy was independently associated with improved disease-specific survival in patients with MMR-deficient EECs (hazard ratio 0.19, 95%-CI ), but not in patients with MMR-proficient EECs (hazard ratio 0.92, 95%-CI ). Conclusions: Adjuvant radiotherapy improved disease-specific survival in patients with MMR-deficient EECs, but not in those with MMR-proficient EECs. This study demonstrates the predictive ability of MMR IHC to identify women who likely have increased benefit from radiotherapy.

In intermediate and high-risk endometrial cancer (EC), adjuvant radiotherapy (RT) improves PFS. However, there is no evidence of improved overall or disease-specific survival after adjuvant RT so far Accumulating evidence suggests that mismatch repair (MMR) proteins are involved in DNA repair following RT This study investigated the predictive value of MMR status in terms of survival benefit after adjuvant RT in patients with stage IB/II, grade 3 endometrioid endometrial cancer (EEC) PFS, progression-free survival A retrospective multicenter cohort study comparing patients with histopathologically confirmed stage IB/II grade 3 EEC with and without adjuvant RT Patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifying ECs as either MMR-deficient, POLE, p53abn or p53wt Multivariable Cox regression analysis explored associations between patient characteristics, adjuvant treatment and outcome Mismatch repair deficiency as a predictor of adjuvant radiotherapy response in endometrioid endometrial carcinoma Kommoss S et al., ASCO 2019, abstract 5586 (poster presentation)

Methods AND Results Proactive molecular risk classifier for EC
Baseline characteristics MMR IHC missing n=128 unclassified MMR-p, RT- (n=25) MMR-p, RT+ (n=46) MMR-d, RT- (n=21) MMR-d, RT+ (n=36) Age (y) 70 (44 – 96) 68 (52 – 90) 70 (55 – 89) 64 (48 – 86) Follow-up (months) 55 (4 – 163) 37 (2 – 271) 26 (2 – 171) 35 (10 – 182) FIGO IB FIGO II 21 (35.0) 4 (36.4) 39 (65.0) 7 (63.6) 16 (44.4) 5 (23.8) 20 (55.6) 16 (76.2) LVSI yes LVSI no 7 (21.9) 13 (44.8) 25 (78.1) 16 (55.2) 11 (39.3) 8 (32.0) 17 (60.7) 17 (68.0) MMR deficient MMR proficient POLE status missing MMRD hypermutated (n=57) n=71 unclassified POLE mutation POLE wild type p53 IHC missing POLE ultramutated (n=11) n=60 unclassified p53 mutation p53 wild type p53 abnormal (n=21) p53 wild type (n=39) IHC, Immunohistochemistry; MMR, Mismatch Repair, POLE, exonuclease domain of DNA Polymerase Epsilon Mismatch repair deficiency as a predictor of adjuvant radiotherapy response in endometrioid endometrial carcinoma Kommoss S et al., ASCO 2019, abstract 5586 (poster presentation)

Duration of follow up (months)
Results Distribution according to molecular subtype Disease specific survival by ProMisE subgroup Disease specific survival 1.0 FIGO IB/II – Grade 3! 0.8 0.6 30.2% 44.5% Cumulative survival 0.4 ProMisE MMR-D POLE p53abn p53wt 0.2 16.3% 8.5% 0.0 10 20 30 40 50 60 Duration of follow up (months) Mismatch repair deficiency as a predictor of adjuvant radiotherapy response in endometrioid endometrial carcinoma Kommoss S et al., ASCO 2019, abstract 5586 (poster presentation)

RESULTS Kaplan Meier curves (DSS) in MMR deficient and MMR proficient ECs Disease-specific survival (MMR-deficient) Disease-specific survival (MMR-proficient) 1.0 1.0 0.8 0.8 0.6 0.6 Cumulative survival Cumulative survival HR: 0.19 (95% CI: ) HR: 0.92 (95% CI: ) 0.4 0.4 Radiotherapy No Yes Radiotherapy No Yes 0.2 0.2 0.0 Log-rank: p= 0.034 Benefit only in patients with MMR-deficiency! 0.0 Log-rank: p= 0.476 10 20 30 40 50 60 10 20 30 40 50 60 Duration of follow up (months) Duration of follow up (months) Cox regression analysis Disease-specific survival HRa 95%-CI HRb MMR-deficient Radiotherapy 0.31 0.10 – 0.97 0.19 0.05 – 0.77 MMR-proficient Radiotherapy 0.73 0.30 – 1.76 0.92 0.37 – 2.31 HR; Hazard Ratio, aunivariable, bmultivariable DSS, Disease specific Survival; MMR, Mismatch Repair Mismatch repair deficiency as a predictor of adjuvant radiotherapy response in endometrioid endometrial carcinoma Kommos S et al., ASCO 2019, abstract 5586 (poster presentation)

SUMMARY & CONCLUSIONS In patients with endometrioid endometrial carcinoma (EEC), molecular classification of mismatch repair status identified a subgroup of patients with excellent prognosis despite FIGO > Ia and Grade 3 Adjuvant radiotherapy significantly improved survival in the subgroup of ECC patients with a mismatch repair-deficiency (MMRD) Hence, MMR status may be used as a predictive biomarker to select patients that benefit most from adjuvant radiotherapy Mismatch repair deficiency as a predictor of adjuvant radiotherapy response in endometrioid endometrial carcinoma Kommoss S et al., ASCO 2019, abstract 5586 (poster presentation)

p53 and p16 expression profiles reveal three prognostically relevant subgroups in vulvar cancer: A TMA based study by the AGO-CaRE-translational study group (poster abstract 5592) Linn Lena Woelber, Katharina Prieske, Christine Eulenburg, Nikolaus de Gregorio, Rüdiger Klapdor, Matthias Kalder, Elena Ioana Braicu, Sophie Fuerst, Maximillian Klar, Hans-Georg Strauss, Grit Mehlhorn, Werner Meier, Atanas Ignatov, Alexander Mustea, Julia Kathrin Jueckstock, Georg Schmidt, Dirk Bauerschlag, Martin Hellriegel, Sven Mahner, Eike Burandt Abstract 5592: Background: Currently, there are two major pathways for tumorigenesis of vulvar squamous cell carcinoma (VSCC) – an HPV-dependent with p16 overexpression as a surrogate for HPV-associated transformation and an HPV-independent route linked to lichen sclerosus, characterized by p53 mutation. A possible correlation of HPV dependency with a favourable prognosis has been proposed. Methods: The AGO CaRE-1 study is a retrospective survey of pts with primary VSCC FIGO stage ≥1B (UICC-TNM version 6) treated at 29 gynecologic cancer centers in Germany (n = 1,618). For this CaRE-translational sub-study available FFPE tissue was collected centrally (n = 648). A tissue micro array (TMA) was constructed; p16 and p53 expression was determined by immunohistochemistry (IHC). HPV status and subtype were analyzed by PCR. Results: p16 IHC was interpretable in 550 TMA spots and considered positive in 166/550 (30.2%). HPV DNA was detected in 78.4% of the p16+ tumors, with HPV 16 being the most common subtype (88.3%). Pts with p16+ tumors were younger at diagnosis (63 vs. 70 yrs for p16- tumors; p = 0 < 0.01) and showed lower rates of lymph-node involvement (29.0% vs. 39.7%; p = 0.021). p53 IHC was interpretable in 597 spots, 187/597 (31.3%) were considered positive. Pts with p53+ tumors were older at first diagnosis (71 vs. 66 yrs; p = for p53- tumors) and showed lymph-node involvement more often (43.3% vs. 31.1%; p = 0.007). There was a relevant number of tumors with neither p16 nor p53 overexpression (221/535); while co-expression of p53 and p16 was rare (12/535). For survival analyses, three groups were defined: p53+ (n = 163), p16+/p53- (n = 151) and p16-/p53- (n = 221). 2-y-disease-free (DFS) and overall survival (OS) rates were significantly different between the groups: DFS: p %; p16-/p53- 53% and p16+/p % (p < 0.001); OS: 70.4%, 72.6% and 82.7% (p = 0.003), respectively. Adjustment for age and nodal status showed consistent p16 and p53 effects regarding DFS. Conclusions: p16 overexpression is associated with an improved prognosis in VSCC while p53 positivity is linked to an adverse outcome. Our data provide evidence of a clinically relevant third subgroup of VSCC with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.

Study background and methods
Two major pathways are currently known for the tumorigenesis of vulvar squamous cell carcinoma (VSCC): an HPV-dependent route with p16 overexpression as a surrogate for HPV-associated transformation HPV-independent route linked to lichen sclerosus, characterized by p53 mutation A possible correlation of HPV dependency with a favourable prognosis has been proposed HPV, human papillomavirus This study (AGO CaRE-1) is a retrospective survey of patients with primary VSCC FIGO stage ≥1B (UICC-TNM version 6) treated at 29 German gynecologic cancer centers between 1998 and 2008 (n=1,618) For the translational sub-study presented here, available FFPE tissue was collected centrally (n=648) A tissue micro array (TMA) was constructed; expression of p16 and p53 was determined by immunohistochemistry (IHC); HPV status and subtype were analyzed by PCR FFPE, formalin fixed paraffin embedded p53 and p16 expression profiles reveal three prognostically relevant subgroups in vulvar cancer: A TMA based study by the AGO-CaRE-translational study group Woelber LL et al., ASCO 2019, abstract 5592 (poster presentation)

Results Compared to the other groups, patients with p16+/p53- tumors were younger at diagnosis and showed lower rates of lymph- node involvement Total n=535 p16+/p53-(n=151, 28.2%) p53+ (n=163, 30.5%) p16-/p53- (n=221,41.3%) p-value n % Age, years (mean, SD) 67.8+/-14.4 63.1+/-16.1 71.6+/-12.1 68.1+/-13.9 0.003a Tumor stage pT1b 149 50 33.1 39 23.9 60 27.2 0.183b pT2 274 66 43.7 90 55.2 118 53.4 pT3/4 62 23 15.2 15 9.2 24 10.9 unknown 12 8.0 19 11.7 8.6 Nodal status pN0 315 100 66.2 80 49.1 135 61.1 0.029b pN1 178 40 26.5 69 42.3 31.2 hrHPV neg. 234 18 11.9 94 57.7 122 <0.001c 70 20 13.2 14.1 27 12.2 positive 231 113 74.8 46 28.2 72 32.6 Type 16 200 101 66.9 37 22.7 28.1 Type 33 10 6.6 2 1.2 3 1.4 Type 18 8 0.0 4 2.4 1.8 Type 45 6 1 0.7 other 0.6 Tumor diameter mm, (mean, SD), n=423 35.6 +/- 29.3 38.1 +/-39.5 34.8 +/-21.8 34.6 +/-26.0 0.570a Depth of invasion mm, (mean, SD), n=312 8.6 +/- 11.0 6.9 +/-5.4 9.7 +/-10.8 9.4 +/- 13.3 0.185a Grading G1 57 9 5.9 16 9.8 32 14.5 0.173b G2 304 88 58.3 95 121 54.7 G3 124 42 27.8 36 22.1 20.8 7.9 22 9.6 p53 and p16 expression profiles reveal three prognostically relevant subgroups in vulvar cancer: A TMA based study by the AGO-CaRE-translational study group Woelber LL et al., ASCO 2019, abstract 5592 (poster presentation)

Results DFS with regard to expression profile
OS with regard to expression profile 1 1 logrank p<0.001 logrank p<0.005 .75 .75 Disease free survival Overall survival .5 .5 .25 .25 24 48 72 96 120 144 168 24 48 72 96 120 144 168 months months p16=0, p53=0 p16=1, p53=0 p53=1 p16=0, p53=0 p16=1, p53=0 p53=1 Number at risk 139 57 35 17 12 4 1 149 48 23 10 5 203 77 44 20 11 Number at risk 139 71 46 23 14 4 1 149 58 35 18 12 2 203 94 50 28 8 p16+/p53- n=151 p53+ n=163 p16-/p53- n=221 2-year DFS 65.5% 47.0% 53.0% 2-year OS 82.7% 70.4% 72.6% 2-y-disease-free (DFS) and overall survival (OS) rates were significantly different between the groups: DFS: p %; p16-/p % and p16+/p % (p<0.001); OS: 70.4%, 72.6% and 82.7% (p=0.003), respectively p53 and p16 expression profiles reveal three prognostically relevant subgroups in vulvar cancer: A TMA based study by the AGO-CaRE-translational study group Woelber LL et al., ASCO 2019, abstract 5592 (poster presentation)

SUMMARY & CONCLUSIONS In women with vulvar squamous cell carcinoma (VSCC), p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome These data provide evidence of a clinically relevant third subgroup of VSCC with a p53-/p16- phenotype showing an intermediate prognosis that needs further characterization p53 and p16 expression profiles reveal three prognostically relevant subgroups in vulvar cancer: A TMA based study by the AGO-CaRE-translational study group Woelber LL et al., ASCO 2019, abstract 5592 (poster presentation)

Endometrial, cervical & rare gynaegological cancer
ASCO 2019 Fazit Oral Abstract 5500 Carboplatin/Paclitaxel wurde als bislang inoffizieller Standard beim uterinen oder ovariellen Karzinosarkom nun auch in einer Phase III-Studie bestätigt. Oral Abstracts 5501 & 5502 Immun-Checkpoint-Inibitoren zeigen beim dMMR-Endometriumkarzinom moderate Aktivität, die weiterverfolgt werden sollte. Außerhalb dieser Gruppe machen sie als Monotherapie aktuell keinen Sinn. Oral Abstract 5503 Die primäre RCTX sollte beim Zervixkarzinom, bei dem die alleinige primäre Operation keine Option ist, weiterhin der Standard bleiben. Die neoadjuvante Chemotherapie kann allerdings in Ausnahmefällen (z.B. zum Fertilitätserhalt) eingesetzt werden. Oral Abstract 5504 Die Level I-Evidenz der LACC-Studie1 wird hier wieder einmal bestätigt, so dass die offene radikale Hysterektomie der Standard beim frühen Zervixkarzinom ist. dMMR, deficient mismatch repair; RCTX, Radiochemotherapie; 1. Ramirez PT et al. N Engl J Med Nov 15;379(20):

Endometrial, cervical & rare gynaegological cancer
ASCO 2019 Fazit Poster Discussion Abstract 5516 Bei Patientinnen mit ovariellen Keimzelltumoren kann der Verzicht einer CTX eine Option sein. Poster Abstract 5586 Die molekulare Subtypisierung des endometrioiden Endometriumkarzinoms scheint in Zukunft eine Therapie- stratifizierung auch in Bezug auf die Strahlentherapie zu ermöglichen. Hier muss eine Validierung erfolgen. Poster Abstract 5592 Die Klassifizierung des Vulvakarzinoms aufgrund der p53- und p16-Expressionen ermöglicht die Identifizierung prognostischer Subgruppen, die auch im Hinblick auf mögliche Therapiestratifizierungen weiter untersucht werden sollten.

Imprint Legal Disclaimer
This slide-kit is intended for healthcare professionals only The authors of this report were supported by TESARO Bio Germany GmbH, their participation at the ASCO 2019 was in agreement with legal and ethical guidelines The content presented here corresponds to opinions and impressions of the authors and does not necessarily reflect the views of TESARO Bio Germany GmbH TESARO BIO Germany GmbH is not responsible for the content of this report Herausgeberin: TESARO Bio Germany GmbH Leopoldstraße 37 A 80802 München

NEw developments IN gynecological Oncology

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