Presentation on theme: "Ana Oaknin, MD Medical Oncology Department. Gyneacological Cancer Unit Vall d´Hebron University Hospital. Vall d’Hebron Institute of Oncology Barcelona,"— Presentation transcript:
Ana Oaknin, MD Medical Oncology Department. Gyneacological Cancer Unit Vall d´Hebron University Hospital. Vall d’Hebron Institute of Oncology Barcelona, Spain Avances Terapéuticos en el Tratamiento de los Tumores Ginecológicos: Papel de la Angiogénesis
Gynecologic Tumors(GYNT): Epidemiology GYNT comprises 19% of new cancer cases each year. Endometrial cancer is the GYNT most common. Cervical Cancer is the second most common cancer in women after breast cancer. Ovarian cancer is the fifth cause of cancer death and the most lethal GYNT Source: American Cancer Society. Cancer Facts&Figures 2013.
Bergers, et al. Nature 2002 The angiogenic switch in tumour development Tumour Vasculature effect Small tumour (1–2mm) Avascular Dormant Larger tumour Vascular Metastatic potential Bergers G. et al. Nature Reviews Cancer 2003;3:401–10.
Therapeutic Targeting of Angiogenesis One of the most prolific arenas of drug development More than 360 agents in various phases of development –Compounds: modeled for direct and/or indirect AA properties –Approaches: ligand, receptor, signal, and regulators –Targets: endothelial cells, tumor cells, pericytes Approved: 9 (2 others with indirect effects) –Most recent Everolimus (3/30/09) in RCC
Key Signaling Pathways Involved in Ovarian Cancer Angiogenesis Yap TA, et al. Nat Cancer Rev 2009; 9:2583; J Clin Oncol, Vol 30, Nº 4, 2012;
VEGF and Angiopoetin-2 Levels Markers of Poor Prognosis in Ovarian Cancer Duncan et al; Clin Cancer Res 2008; 14: ; Sallinen et al; Int Journal Gyn Oncol; 20; p=0.04
Targeting the VEGF Pathway Strategies Bevacizumab Soluble VEGF receptors- aflibercept Antibodies to VEGF VEGFR tyrosine kinase inhibitors: Pazopanib BIBF1120 Cediranib Ribozymes VEGFR2 VEGF Migration, permeability, DNA synthesis, survival
Angiogenesis as a Target in Ovarian Cancer: Anti-VEGF-VEGFR Pathway Anti-vascular endothelial growth factor (VEGF) therapy improves progression-free survival (PFS) GOG 218* Front-line: Bevacizumab HR = 0.72; 95% CI, 0.63– ICON 7* Front-line: Bevacizumab HR = 0.81; 95% CI, 0.70– AGO-OVAR12 Front-line: Nintedanib HR = 0.84; 95% CI, 0.72, AGO-OVAR16 Maintenance: Pazopanib HR = 0.77; 95% CI, 0.64– AURELIA** Platinum-resistant, recurrent / 1 or 2 prior regimens: Bevacizumab HR = 0.48; 95% CI, 0.38– OCEANS* Platinum-sensitive, recurrent / 1 prior regimen: Bevacizumab HR = 0.48; 95% CI, 0.41– ICON6 Platinum-sensitive, recurrent / 1 prior regimen: Cediranib HR = 0.57; 95% CI, 0.44– HR = hazard ratio; 95% CI = confidence interval 1.Burger RA et al. N Engl J Med. 2011;365:2473 ‒ Perren TJ et al. N Engl J Med. 2011;365:2484 ‒ du Bois A et al. J Clin Oncol. 2013;31(18suppl):LBA du Bois A et al. LBA ESGO 2013 Liverpool, UK 5.Pujade-Lauraine E et al. J Clin Oncol. 2012;30(18suppl):LBA Aghajanian C et al. J Clin Oncol. 2012;30:2039 ‒ Ledermann JA et al. Eur J Cancer. 2013;49(suppl):LBA *EMA Approved *FDA Approved
1. Cannistra SA, et al. J Clin Oncol. 2007;25: Burger RA, et al. J Clin Oncol. 2007;25: Parameter, % Cannistra et al.  (N = 44) Garcia et al. 2] (N = 70) Burger et al.  (N = 62) GOG#170 Prior regimens o platinum DFI < 6 mos, % Dose/schedule 15 mg/kg every 21 days 10mg/kg plus Ciclophosphamide 50mg/day 15 mg/kg every 21 days RR, n (%)7 (16%)17(24%)13(21%) ≥ G3 Proteinuria (%)0<161 ≥ G3 HTA(%)14<1610 Gastrointestinal perforations (%) 1160 Single- Agent BEVACIZUMAB in Ovarian Cancer: Phase II Efficacy Results 2.Garcia AA, et al. J Clin Oncol. 2008;26:76-82.
N Engl J Med 2011;365: , Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV N=1873 Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV N=1873 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE 1:1:1 15 months Paclitaxel (P) 175 mg/m 2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Maintenance (16 cycles) (CP) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo BEV 15 mg/kg II (CP + BEV) BEV 15 mg/kg Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 III (CP + BEV BEV) GOG#218: Schema 1ºEnd-Point: PFS PFS HR 0.77 M. PFS shift: 14.0 m 18.2M
CP (Arm I) Arm I CP (n=625) Patients with event, n (%) 423 (67.7) Median PFS, months10.3 Stratified analysis HR (95% CI) One-sided p-value (log rank) GOG-0218: PFS RECIST, global clinical deterioration, or CA BEV (Arm II) a p-value boundary = BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization Arm III CP + BEV BEV (n=623) 360 (57.8) (0.625–0.824) < a Arm II CP + BEV (n=625) 418 (66.9) (0.759–1.040) a N Engl J Med 2011;365:
Overall survival at time of final PFS analysis Arm I CP + PLA → PLA (n=625) Arm II CP + BEV → PLA (n=625) Arm III CP + BEV BEV (n=623) Patients with events, n (%) 156 (25) 150 (24) 138 (22) Median (months) HR (stratified) (95% CI) (0.827–1.297) (0.727–1.152) One-sided p-value year OS rate, % Proportion alive Months since randomization No. at risk N Engl J Med 2011;365: ,
ICON7: Study design Paclitaxel 175 mg/m 2 (P) Carboplatin AUC 6* (C) Carboplatin AUC 6* Paclitaxel 175 mg/m 2 (P) Stratification variables: Stage I–III debulked ≤1 cm vs stage I–III debulked >1 cm vs stage IV and inoperable stage III Intent to start treatment ≤/> 4 weeks after surgery 1º End- Point: PFS only determined by RECIST Criteria 12 months R 1:1 Bevacizumab 7.5 mg/kg q3w Epithelial ovarian, primary peritoneal or fallopian tube cancer ● High-risk stage I–IIA (grade 3 or clear cell) ● Stage IIB–IV n=1528 Perren TJ et al. N Engl J Med. 2011;365:2484‒2496. HIGH RISK GROUP( 31% ) : FIGO III>1cm/FIGO IV Debulking
Summary of Updated Results Perren T et al N Engl J Med Dec 29;365(26): HR = 0.81 (95% CI 0.70–0.94) HR 0.68 (95% CI ) Median 10.5 vs 15.9mo HR 0.64 (95% CI ) Median 36.6 vs 28.8mo HR = 0.81 (95% CI 0.63–1.04) High risk: FIGO IV or III with >1cm RD
GOG-0218 and ICON7: Efficacy Across the Trials GOG-0218 (Arm I vs III ) ICON7 Results of primary analysis n PFS (HR) Median PFS, months PFS ∆, months p value 1, vs < , vs Results based on RECIST only (regulatory analysis*) n PFS (HR) Median PFS, months PFS ∆, months p value 1, vs < , vs Subgroup of advanced disease only (operated FIGO IV/IIIC 1cm+ residuals) N PFS (HR) Median PFS, months PFS ∆, months p value vs <0.001 *Censoring CA 125
A1-2: What are the appropriate endpoints for different trials: (maintenance, upfront chemotherapy trials including molecular drugs) The recommended primary endpoints for future front line/maintenance clinical trials in ovarian cancer are: Phase II Screening for activity PFS, PFS at defined time point, or Response Phase III Early ovarian cancer - Recurrence free survival (note: recurrence = recurrent disease + deaths from any cause) Advanced ovarian cancer - Both PFS and OS are important endpoints to understand the full impact of any new treatment. Although overall survival is an important endpoint, progression free survival is most often the preferred primary endpoint for trials because of the confounding effect of the post-recurrence/progression therapy on overall survival. Each protocol should specify if PFS or OS is the preferred endpoint. Regardless of which is selected, the study should be designed and powered for both PFS and OS when feasible. Maintenance trials: These criteria should be applied to trials that include maintenance therapy. Int J Gynecol Cancer 2011: 21; th Ovarian Cancer Consensus Conference. June 25 – 27, 2010 UBC Life Sciences Institute, Vancouver, BC Is the PFS a valid primary end-point?
Magnitude of Clinical Benefit: Is PFS a valid End-Point? Advanced ovarian cancer has a long survival post-progression and subsequent interventions can impact on the OS result, especially the crossover. -In GOG 218, 39% of patients received any anti-angiogenic therapy at relapse 1. -In ICON-7 less than 5% of cross-over could explain the OS When SPP is long enough( >12 months), the chance of expecting a statistically significant prolongation of PFS translating into an OS benefit is extremely low and the number of patients required for demonstrating a survival benefit is extremely large( >2000) 2. For clinical trials with a PFS benefit, a lack of statistical significance in OS does not mean a lack of improvement in OS. 1. Chan, et al. SGO 2013: Abstract 292; 2. Broglio et al: J Natl Cancer Inst Dec 2;101(23):1642-9
Bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of advanced (FIGO stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer Bevacizumab is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Bevacizumab as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier The recommended dose of Bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion
GOG 252: Stage II/III Disease: Small Volume Residual Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m 2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days Cisplatin 75 mg/m 2 (IP d2) Paclitaxel 135 mg/m 2 (d1, 3h) Paclitaxel 60 mg/m 2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed:30 Nov 2011 Accrual:1100 Study Chair: J Walker I III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT
Du Bois A. et al ; Journal Clin Oncol ; AGO-OVAR 16: Study Design N=940
Du Bois A. et al ; Journal Clin Oncol ; HR= 0.77; (95% CI, 0.64 to 0.91) HR=1.08; 95% CI, 0.87 to 1.33; P m 12.3m
Du Bois A. et al ; Journal Clin Oncol ;
Recommended Guidelines of Systemic therapy in Relapsed Ovarian Cancer / Cediranib/ AMG386
28 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Platinum-sensitive recurrent OC a Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) Aghajanian et al. J Clin Oncol; Vol 30;17;2012 G 1000 mg/m 2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m 2, d1 & 8 CG + BV CG + PL (n=242) CG + BV (n=242) Events, n (%)187 (77)151 (62) Median PFS, months (95% CI) 8.4 (8.3–9.7) 12.4 (11.4–12.7) Stratified analysis HR (95% CI) Log-rank p-value (0.388–0.605) <0.0001
AURELIA trial design & PFS Results Platinum-resistant OC a ≤2 prior anticancer regimens No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvement Treat to PD/toxicity Investigator’s choice (without BEV) Optional BEV monotherapy c BEV 15 mg/kg q3w b + chemotherapy Chemotherapy R 1:1
Cediranib: Tirosin Kinase Inhbitor of VEGFR1,2,3 6 Cycles platinum-based Chemotherapy Carboplatin/paclitaxel Carboplatin/Gemcitabine Single agent platinum Maintenance phase ICON 6 Cediranib with Platinum-based Chemotherapy in platinum- sensitive relapsed ovarian cancer Treatment continued to 18 months or until progression (>18 for patients continuing to benefit Continue placebo Switch to placebo Maintenance cediranib Chemotherapy + cediranibChemotherapy + placebo Arm A (Chemo only) Arm B (Concurrent)Arm C (Maintenance) Chemotherapy + cediranib Relapse > 6 months after completion of first line platinum-based chemotherapy Randomise 2 : 3 : 3 Ledermann et al ECCO2013 N=456 pts
Chemo.Maint. OS events, n (%)63 (53.3)75 (45.7) Median, months Log-rank testp=0.042 HR (95% CI)0.70 (0.51 – 0.99) Test for non-proportionality p= Restricted means, months Restricted mean survival time increases by 2.7 months with maintenance treatment (over two years) Overall survival Chemo. Maint. Chemotherapy Maintenance Ledermann et al ECCO2013
Stratification factors Platinum-free interval (PFI) (≤ 6 vs. > 6 months) Measurable disease (Yes/No) Region (North America, Western Europe/Australia, Rest of World) Recurrent EOC ≤ 3 prior anticancer regimens Evaluable or measurable disease GOG Performance Status of 0 or 1 PFI < 12 months Treat to PD/toxicity Weekly Paclitaxel + Trebananib Weekly Paclitaxel + Placebo R 1:1 46% of patients w ILP>6Months 25% 3 previous lines of therapy. Lancet Oncol, 2014 Jul;15(8),
Angiogenesis In Cervical Cancer CD31 – Intratumoral microvessel density Atypical vessels on colposcopy Tewari KS, Monk BJ. Invasive Cervical Cancer. In: Clinical Gynecologic Oncology, 8 th ed. DiSaia PJ, Creasman WT (eds). Mosby, Accumulating evidence supports the concept that angiogenesis plays a central role in cervical carcinogenesis and disease progression
GOG #227-C: Bevacizumab in the treatment of Recurrent/Metastatic Cervical Cancer Monk BJ et al Gynecol Oncol 2008;108:21S abstr 45 Warrant phase III: GOG#240
Activated: 4/6/09 Closed to accrual: 1/3/12 RANDOMIZERANDOMIZE Carcinoma of the cervix Primary stage IVB Recurrent/persistent Measureable disease GOG PS 0–1 No prior chemotherapy for recurrence (N=452) Stratification factors: Stage IVB vs recurrent/persistent disease Performance status Prior cisplatin Rx as radiation-sensitizer 1:1:1:1 I Paclitaxel 135 or 175 mg/m 2 IV Cisplatin 50 mg/m 2 IV III Paclitaxel 175 mg/m 2 IV Topotecan 0.75 mg/m 2 d1-3 Chemo alone II Paclitaxel 135 or 175 mg/m 2 IV Cisplatin 50 mg/m 2 IV Bevacizumab 15 mg/kg IV IV Paclitaxel 175 mg/m 2 IV Topotecan 0.75 mg/m 2 d1-3 Bevacizumab 15 mg/kg IV Q21d Rx to PD, toxicity, CR Chemo + Bev Identifier: NCT GOG #240 : Incorporation of Bevacizumab in the treatment of Recurrent and Metastatic Cervical Cancer Schema 1º End-Points: If adding BEV to Chemo improves OS If a non-platinum doublet improves OS
Chemotherapy (n=225) Events, n (%) 140 (62) Median OS, mos 13.3 Chemotherapy + Bev (n=227) 131 (58) 17.0 HR=0.71 (97% CI, ) P= GOG #240: OS for Chemo vs Chemo + Bev Tewari KS, et al. N Engl J Med 2014;370: Proportion Surviving Months on Study Median follow-up 20.8 mos
Chemotherapy + Bev (n=227) 183 (81) 8.2 HR=0.67 (95% CI, ) 2-sided P= GOG #240: PFS for Chemo vs Chemo + Bev Proportion Progression-Free Months on Study Chemotherapy (n=225) Events, n (%)184 (82) Median PFS, mos5.9 RR, %36 (CR, n=14)48 (CR, n=28) 2-sided P= Tewari KS, et al. N Engl J Med 2014;370:734-43
Median Overall Survival in Months 7.0 vs. 7.1 CIS 50 vs.CIS vs. 8.3 CIS vs.CIS/IFO 6.5 vs. 9.4 CIS vs.CIS/TOP 10.3 vs CIS/TOP vs.CIS/PAC 13.3 vs CTX vs. CTX BEV * * p< 0.05 Months Phase III Studies Courtesy of: Gottfried Konecny MD GOG 240: Chemotherapy in Advanced Cervical Cancer *
FDA News : For Immediate Release August 14, 2014 FDA approves Bevacizumab to treat patients with aggressive and late-stage cervical cancer First targeted agent licensed for gynecologic malignancy in the USA
Arm 1: Paclitaxel 175 mg/m2 IV over 3 hours day 1 Carboplatin AUC = 6 IV day 1 Bevacizumab 15mg/kg IV day 1 Maintenance regimen - Bevacizumab 15mg/kg IV every 21 days until disease progression or prohibition of further therapy. Arm 2: Paclitaxel 175 mg/m2 IV over 3 hours day 1 Carboplatin AUC = 5 IV day 1 Temsirolimus 25 mg IV days 1 and 8 Maintenance regimen – Temsirolimus 25 mg IV weekly. Days 1,8 and 15 until disease progression or prohibition of further therapy. Arm 3: Ixabepilone 30 mg/m2 IV over 1 hour day 1 Carboplatin AUC = 6 IV day 1 Bevacizumab 15mg/kg IV day Maintenance regimen - Bevacizumab 15mg/kg IV every 21 days until disease progression or prohibition of further therapy. Eligibility: Stage III or IVA EC measurable disease Stage IVB or Recurrent EC (whether there is measurable disease or not) No prior Chemotherapy GOG#0086P PI: Carol Aghajanian, M.D. From: 9/14/2009 to 9/9/2014 ClinicalTrials.gov Identifier:NCT Phase II Randomized 1º End-Point: PFS N= 349 Endometrial Cancer
Anti-Angiogenic Therapy in GYNT: Conclusions There is a strong rationale. Four clinical trials incorporating BEV in first line and recurrence : Level 1 evidence( EMA Approved) Meaningful differences in PFS OS benefit in ICON-7 High-Risk group Pazopanib Trial has a poor therapeutic index( benefit/toxicity) Trinova- 1 trial met its 1º End-Point: PFS Results from GOG240 have led to a new standard of care in Metastatic/ Recurrent Cervical Cancer Antiangiogenic Therapy is here to stay.