1. Advances in Treatment and Management of Ovarian Cancer: Emerging Concepts and Practical Guidance
Bradley J. Monk, MD, FACS, FACOG
Professor, Division of Gynecologic Oncology Arizona Oncology (US Oncology Network) University of Arizona College of Medicine--Phoenix Creighton University School of Medicine at St Joseph’s Hospital Phoenix, Arizona

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3. Faculty Bradley J. Monk, MD, FACS, FACOG
Professor, Division of Gynecologic Oncology Arizona Oncology (US Oncology Network) University of Arizona College of Medicine--Phoenix Creighton University School of Medicine at St Joseph's Hospital Phoenix, Arizona
Bradley J. Monk, MD, FACS, FACOG, has disclosed that he has received consulting fees from Advaxis, Amgen, AstraZeneca, Biodesix, Clovis, Gradalis, ImmunoGen, Insys, Mateon, Merck, Perthera, Pfizer, Precision Oncology, Roche/Genentech, and Tesaro; fees for non-CME/CE services from AstraZeneca, Clovis, Janssen/Johnson & Johnson, Roche/Genentech, and Tesaro; and funds for research support from Amgen, Array, Genentech, Janssen/Johnson & Johnson, Morphotek, Lilly, and Tesaro.

4. Initial Surgical Management of Ovarian Cancer

5. Newly Diagnosed Advanced Ovarian Cancer

6. Adequate Surgery Is Vital in Treating Ovarian Cancer
Maximal effort at primary cytoreduction
Goal is R0 (complete resection = optimal)
Imaging and perhaps laparoscopy to assess feasibility
Decision requires gynecologic oncology input
Role of lymphadenectomy controversial
3 cycles of neoadjuvant chemotherapy and interval debulking in unique circumstances
Infirm and elderly unlikely to tolerate extensive surgery
Carcinomatosis where R0 is unlikely
Slide credit: clinicaloptions.com
Wright AA, et al. J Clin Oncol. 2016;34:

7. LION (Lymphadenectomy In Ovarian Neoplasms): Study Design
A prospective, randomized phase III AGO study group led Gynecologic Cancer Intergroup trial (AGO OVAR OP3/ENGOT-ov31)
All centers required to demonstrate surgical skill prior to participation; pts enrolled at least 1 day prior to surgery
Primary endpoint: OS
Secondary endpoints: PFS, QoL, number of resected LN
Stratified by center, age, ECOG PS
Pts with FIGO stage IIB-IV epithelial ovarian cancer, macroscopic complete resection,
ECOG PS 0/1, and clinically/radiologically negative pelvic and para-aortic LN;
no prior CT or LN dissection (N = 647)
Lymphadenectomy
(n = 323)
No lymphadenectomy
(n = 324)
CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; LN, lymph node; PS, performance status; QoL, quality of life.
Slide credit: clinicaloptions.com
Harter P, et al. ASCO Abstract 5500.

8. LION: Characteristics of Surgery
Characteristic, n (%)
LNE (n = 323)
No LNE (n = 324)
P Value
Bilateral salpingo-oophorectomy*
319 (98.8)
320 (98.8)
.99
Hysterectomy*
321 (99.4)
322 (99.4)
Omentectomy
.41
(Partial) peritonectomy
Pelvis
Paracolic
Diaphragm
291 (90.1)
276 (85.5)
193 (59.8)
173 (53.6)
291 (89.8)
278 (85.8)
208 (64.2)
196 (60.5)
GI tract resection/stoma
169 (52.3)/34 (10.5)
167 (51.5)/24 (7.4)
.84/.17
Splenectomy
62 (19.2)
56 (17.3)
.53
Porta hepatis/lesser omentum
61 (18.9)
69 (21.3)
.44
Partial pancreatectomy
7 (2.1)
Partial hepatectomy
27 (8.4)
28 (8.6)
.90
Pleurectomy
20 (6.2)
24 (7.4)
.54
Complete resection
GI, gastrointestinal; LNE, lymphadenectomy
Harter P, et al. ASCO Abstract 5500.
*Includes procedures performed earlier.

9. LION: Intraoperative Outcomes
LNE
(n = 323)
No LNE
(n = 324)
Difference
P Value
Study procedure per randomization, n (%)
320 (99.1)
313 (96.6)
Median total resected LN (IQR)
Para-aortic
Pelvic
57 (45-73)
22 (16-33)
35 (26-43)
LN metastases, n (%)
180 (55.7)
Median surgery duration, min (IQR)
340 ( )
280 ( )
+1 hr
< .001
Median blood loss, mL (IQR)
650 ( )
500 ( )
+150 mL
Transfusions, n (%)
Massive (> 10 RBC/24 hrs)
205 (63.7)
7 (2.2)
181 (56.0)
2 (0.6)
+8%
.005
.09
Fresh-frozen plasma, n (%)
117 (36.3)
96 (29.7)
+7%
.07
Intermediate/intensive care unit, n (%)
250 (77.6)
223 (69.4)
.01
IQR, interquartile range; LN, lymph node; LNE, lymphadenectomy; RBC, red blood cell.
Slide credit: clinicaloptions.com
Harter P, et al. ASCO Abstract 5500.

10. LION: Postoperative Outcomes
Outcome With Significant Difference Between Arms, n (%)
LNE (n = 323)
No LNE (n = 324)
P Value
Infections requiring antibiotics
83 (25.8)
60 (18.6)
.03
Asymptomatic lymph cysts
14 (4.4)
1 (0.3)
< .001
Symptomatic lymph cysts
10 (3.1)
.001
Readmission
40 (12.4)
27 (8.3)
.09
Relaparotomy for complications
21 (6.5)
.01
60-day post-op mortality
3 (0.9)
.049
Platinum/taxane chemotherapy
257 (79.6)
274 (84.6)
LNE, lymphadenectomy.
No statistically significant difference between arms in rates of fever, sepsis, thrombosis, pulmonary embolism, secondary wound healing, prolonged ileus, peripheral sensory/motor neurologic events, fistula
Slide credit: clinicaloptions.com
Harter P, et al. ASCO Abstract 5500.

11. LION: PFS and OS of All Pts
100
100 80 80 60 60
PFS (%)
OS (%) 40 40 20
N = 647, 429 events Median PFS: 25.5 mos (95% Cl: )
N = 647, 274 events
Median OS: 67.2 mos (95% Cl: ) 20 6 12 18 24 30 36 42 48 54 60 66 72 78 6 12 18 24 30 36 42 48 54 60 66 72 78
Mos
Mos
Pts at Risk, n
Pts at Risk, n
Pts with advanced ovarian cancer and complete resection have median PFS of 25.5 mos and median OS of 67.2 mos (5-yr OS rate: 55.9%)
Slide credit: clinicaloptions.com
Harter P, et al. ASCO Abstract 5500.

12. LION: PFS and OS (Primary Endpoint)
100
100
Events, n Median PFS, Mos
LNE
No LNE 80 80 60 60
PFS (%)
OS (%)
HR: ( ;
P = .65) 40 40 20
Events Median OS, Mos
LNE
No LNE 20
LNE, lymphadenectomy.
HR: (95% CI: ) 6 12 18 24 30 36 42 48 54 60 66 72 78 6 12 18 24 30 36 42 48 54 60 66 72 78
Mos
Mos
LNE
No LNE
LNE
No LNE
Slide credit: clinicaloptions.com
Harter P, et al. ASCO Abstract 5500.

13. Systemic Treatment Options for Newly Diagnosed Advanced Epithelial Ovarian Cancer

14. What Is the Standard Systemic Tx for Newly Diagnosed Advanced Epithelial Ovarian Cancer?
Depends on many factors
Fitness of the pt
Histologic subtype
Volume of disease (stage and ascites)
Setting (neoadjuvant)
Reimbursement and guidelines
Tx, treatment.

15. What Is the Standard Systemic Tx for Newly Diagnosed Advanced Epithelial Ovarian Cancer?
For stage IV or large volume residual disease (suboptimal): carboplatin/paclitaxel Q3W + bevacizumab is preferred[1]
Based on GOG 218,[2] ICON7[3]
Ascites, angiogenesis phenotype (MVD/CD31 and tumor VEGF-A) predicts treatment benefit of bevacizumab[4,5]
Reimbursement and cost effectiveness are challenges
Alternative treatment is weekly chemotherapy
Dose-dense paclitaxel in fittest pts (JGOG 3016: GOG 262)[6,7]
Fractionated paclitaxel in infirm and weak pts (MITO-7)[8]
Tx, treatment.
1. Ledermann JA, et al. Ann Oncol. 2013;24(suppl 6):vi24-vi Burger RA, et al N Engl J Med. 2011;365: Oza A, et al. Lancet Oncol. 2015;16: Ferriss JS, et al. Gynecol Oncol. 2015;139: Bais C, et al. J Natl Cancer Inst. 2017;109:djx Katsumata N, et al. Lancet Oncol. 2013;14: Chan JK, et al. N Engl J Med. 2016;374: Pignata S, et al Lancet Oncol. 2014;15:
Slide credit: clinicaloptions.com

16. Angiogenesis as a Target: 9 Positive Phase III Ovarian Cancer Studies
Study
Agent
Setting
PFS HR
(95% CI)
GOG 218[1]
Bevacizumab
Front line/maintenance
0.72 ( )
ICON7[2]
0.81 ( )
AGO-OVAR12[3]
Nintedanib
0.84 ( )
AGO-OVAR16[4]
Pazopanib
Primary maintenance
0.77 ( )
AURELIA[5]
Recurrence, platinum resistant, 1-2 priors
0.48 ( )
TRINOVA-1[6]
Trebananib
Recurrence, platinum resistant/sensitive, 1-3 priors
0.66 ( )
OCEANS[7]
Recurrent, platinum sensitive, 1 prior
0.53 ( )
ICON6[8]
Cediranib
0.57 ( )
GOG-213[9]
0.63 ( )
1. Burger RA, et al. N Engl J Med. 2011;365: Perren TJ, et al. N Engl J Med. 2011;365: du Bois A, et al. Lancet Oncol. 2016;17: du Bois A, et al. ASCO LBA Pujade-Lauraine E, et al. J Clin Oncol. 2014;32: Monk BJ, et al. Lancet Oncol. 2014;15: Aghajanian C, et al. J Clin Oncol. 2012;30: Ledermann JA, et al. Eur J Cancer. 2013;49(suppl):LBA Coleman RL, et al. Lancet Oncol. 2017;18:

17. Phase III GOG 218: Addition of Bevacizumab for Primary Therapy in Stage III/IV Ovarian Cancer
Paclitaxel 175 mg/m2/3 hrs + Carboplatin AUC 6 Q21D x 6 Placebo Day 1 x 5 begin cycle 2
(n = 625)
Placebo Q21D x 15 mos
Pts with newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer; stage III optimal (macroscopic), stage III suboptimal, stage IV
(N = 1873)
Paclitaxel 175 mg/m2/3 hrs + Carboplatin AUC 6 Q21D x 6 Bevacizumab* Day 1 x 5 begin cycle 2
(n = 625)
Placebo Q21D x 15 mos
AUC, area under the curve.
Paclitaxel 175 mg/m2/3 hrs + Carboplatin AUC 6 Q21D x 6 Bevacizumab* Day 1 x 5 begin cycle 2
(n = 623)
Bevacizumab* Q21D x 15 mos
*Bevacizumab 15 mg/kg IV.
Slide credit: clinicaloptions.com
Burger RA, et al. N Engl J Med. 2011;365:

18. GOG 218: Investigator-Assessed PFS30 20 10
100 90 80 70 60 50 40
PFS (%) 12 24 36
Events, n (%)
Median PFS,
Mos
Stratified HR (95% CI)
P Value CP
423 (67.7)
10.3 ‒
CP + Bev
418 (66.9)
11.2
0.908
( )
.16
CP + Bev  Bev
360 (57.8)
14.1
0.717
( )
< .001
Bev, bevacizumab; C, carboplatin; P, paclitaxel.
Mos Since Randomization
Slide credit: clinicaloptions.com
Burger RA, et al. N Engl J Med. 2011;365:

19. GOG 218: Impact of Using CA-125 as a Determinant of PFS
Outcome
Protocol-Defined Analysis
CA-125–Censored Analysis
Median PFS, mos
CP (Arm 1)
10.3
12.0
CP + Bev  Bev (Arm 3)
14.1
18.0
Absolute difference in median PFS, mos
3.8
6.0 HR
0.717
0.645
1-sided log-rank P value
< .0001
Pts censored for CA-125, % 20 19
Bev, bevacizumab; C, carboplatin; P, paclitaxel.
Slide credit: clinicaloptions.com
Burger RA, et al. ASCO Abstract LBA1.

20. GOG 218: OS at Time of Primary PFS Analysis
100 90 80 70 60
OS (%) 50 40
Events, n (%)
Median, Mos
HR* (95% CI)
P Value CP
156 (25.0)
39.3 ‒
CP + Bev
150 (24.0)
38.7
1.036 ( )
0.76
CP + Bev  Bev
138 (22.2)
39.7
0.915 ( )
0.45 30
Bev, bevacizumab; C, carboplatin; P, paclitaxel. 20 10 12 24 36 48
Mos
Pts at Risk, n
625/625/623
442/432/437
173/162/171
46/39/40
*Stratified analysis.
Slide credit: clinicaloptions.com
Burger RA, et al. N Engl J Med. 2011;365:

21. GOG 218: Select Adverse Events
Adverse Event, n (%)
CP (n = 601)
CP + Bev (n = 607)
CP + Bev  Bev (n = 608)
GI events*†
7 (1.2)
17 (2.8)
16 (2.6)
Hypertension†
43 (7.2)
100 (16.5)‡
139 (22.9)‡
Proteinuria§
4 (0.7)
10 (1.6)
Pain†
250 (41.6)
252 (41.5)
286 (47.0)
Neutropenia׀׀
347 (57.7)
384 (63.3)
385 (63.3)
Febrile neutropenia¶
21 (3.5)
30 (4.9)
26 (4.3)
Venous thromboembolic event¶
35 (5.8)
32 (5.3)
41 (6.7)
Arterial thromboembolic event¶
5 (0.8)
Wound disruption
22 (3.6)
18 (3.0)
CNS bleeding¶
2 (0.3)
Non-CNS bleeding§
8 (1.3)
13 (2.1)
RPLS¶
1 (0.2)
Bev, bevacizumab; C, carboplatin; CNS, central nervous system; GI, gastrointestinal; P, paclitaxel; RPLS, reversible posterior leukoencephalopathy syndrome.
Onset between cycle 2 and 30 days after date of last treatment;
*Perforation/fistula/necrosis/anastomotic leak. †Grade ≥ 2. ‡P < .05. §Grade ≥ 3. ׀׀Grade ≥ 4. ¶All grades.
Footnotes in slidenotes. Burger RA, et al. N Engl J Med. 2011;365:
Slide credit: clinicaloptions.com

22. GOG 218: Ascites Predict Treatment Benefit of Bevacizumab
PFS in Pts With Ascites
OS in Pts With Ascites
100
100
Median PFS, Mos
10.4
15.2
P < .001
Median OS, Mos
39.9
43.3
P = .035 80 CP
CP + Bev  Bev 80 CP
CP + Bev  Bev 60 60
PFS (%)
OS (%) 40 40 20 20
Bev, bevacizumab; C, carboplatin; P, paclitaxel. 12 24 36 48 60 72 84 96
108
120 12 24 36 48 60 72 84 96
108
120
Mos
Mos
Arm 1 (chemo)
Arm 3 (ext. bev)
Arm 1 (chemo)
Arm 3 (ext. bev)
80% had ascites (defined as peritoneal fluid > 50 cm3)
Slide credit: clinicaloptions.com
Ferriss JS, et al. Gynecol Oncol. 2015;139:17-22.

23. Angiogenesis Phenotype (Microvessel Density, Tumor VEGF-A) and PFS Benefit
100
CP + Bev  Bev high microvessel density 80
CP + Bev  Bev low microvessel density
CP high microvessel density 60
CP low microvessel density
PFS (%) 40 20
Bev, bevacizumab; C, carboplatin; P, paclitaxel.
P interaction = .003 6 12 18 24 30 36 42
Mos
CP + Bev  Bev high microvessel density
CP + Bev  Bev low microvessel density
CP high microvessel density
CP low microvessel density
Slide credit: clinicaloptions.com
Bais C, et al. J Natl Cancer Inst. 2017;109:djx066

24. Phase III ICON7: Carboplatin/Paclitaxel ± Bev in Newly Diagnosed Ovarian Cancer
Stratified by HR status, nodal status
Control (n = 764)
Pts with epithelial ovarian, fallopian tube, or primary peritoneal cancer;
stage I-IIA (grade 3 or clear cell) or stage IIB-IV (all grades/histologic types); surgically debulked histologically confirmed ovarian cancer
(N = 1528)
Carboplatin AUC 5 or 6
Paclitaxel 175 mg/m2
Treatment (CPB7.5+) (n = 764)
Bevacizumab 7.5 mg/kg
AUC, area under the curve; Bev, bevacizumab; PD, progressive disease.
Bevacizumab concurrently Q3W x 5 or 6 cycles, followed by 12 additional cycles or until PD. Bevacizumab omitted in cycle 1 to avoid delayed wound healing if chemotherapy was started within 4 wks of surgery
Slide credit: clinicaloptions.com
Oza AM, et al. Lancet Oncol. 2015;16:

25. ICON7: PFS PFS (%) 17.5 19.9 Mos 100 CP CP + Bev Events, n (%)
526 (69)
554 (73)
Restricted mean, mos
27.7
29.2
Median PFS, mos
17.5
19.9
Log-rank test
P = .25
HR (95% CI)
0.93 ( )
PFS (%) 75 50 25
Bev, bevacizumab; C, carboplatin; P, paclitaxel.
17.5
19.9 6 12 18 24 30 36 42 48 54 60
Mos
Pts at Risk , n CP CP + Bev
764
484
604
294
314
239
226
198
182 66 54
Slide credit: clinicaloptions.com
Oza AM, et al. Lancet Oncol. 2015;16:

26. ICON7: Final OS OS (%) Mos 100 75 50 CP CP + Bev Total Deaths, n 352
362
714 (47)
Restricted mean OS, mos
44.6
45.5
+0.9
Median OS, mos
58.6
58.0
-0.6
Log-rank test
P = .85
HR (95% CI)
0.99 ( ) 25
Bev, bevacizumab; C, carboplatin; P, paclitaxel. 6 12 18 24 30 36 42 48 54 60
Mos
Pts at Risk, n CP CP + Bev
764
676
707
578
618
476
502
397
401
117
124
Slide credit: clinicaloptions.com
Oza AM, et al. Lancet Oncol. 2015;16:

27. ICON7: MRC Final OS Subgroup Analyses
Median OS, Mos HR
(95% CI) n CP
CP + Bev
All pts
44.6
45.5
58.6
58.0
0.99 ( )
1528
Stage I, II, III (0 cm)
52.3
51.9 NR
1.23 ( )
725
Stage III >0, ≤1 cm
42.6
41.9
45.7
44.2
0.95 ( )
301
Stage III >1 cm
36.1
40.2
32.1
39.7
0.84 ( )
290
Stage IV
33.5
38.9
29.4
39.6
0.76 ( )
182
Non-operable
24.9
34.5
20.8
40.4
0.52 ( ) 30
Nonhigh risk
49.7
48.4
67.2
1.14 ( )
1026
High risk
39.3
30.3
0.78 ( )
502
Restricted Mean OS, mos
CP + Bev
Better CP
Better
Disease Stage
Trend
P = .004
Bev, bevacizumab; C, carboplatin; P, paclitaxel.
Risk Status
Interaction
P = .01
HR (95% CI)
Oza AM, et al. European Cancer Congress Abstract LBA 6. Oza AM, et al. Lancet Oncol. 2015;16:
Slide credit: clinicaloptions.com

28. ICON7: Final PFS in High-Risk Subgroup
100 CP
CP + Bev
Events, n (%)
228 (90)
223 (90)
Restricted mean PFS, mos
15.9
20.0
Median PFS, mos
10.5
16.0
Log-rank test
P = .001
HR (95% CI)
0.73 ( )
PFS (%) 75 50
High-risk subgroup: stage III suboptimally debulked, stage IV, or no debulking surgery, n = 502 25
Nonproportionality test: P < .0001
Bev, bevacizumab; C, carboplatin; P, paclitaxel. 6 12 18 24 30 36 42 48 54 60
Mos
Pts at Risk, % CP CP + Bev
254
248
109
175 43 53 24 32 18 23 6 5
Slide credit: clinicaloptions.com
Oza AM, et al. Lancet Oncol. 2015;16:

29. ICON7: Final OS in High-Risk SubgroupCP
CP + Bev
Deaths, n (%)
174 (69)
158 (64)
Restricted mean OS, mos
34.5
39.3
Median OS, mos
30.3
39.7
Log-rank test
P = .03
HR (95% CI)
0.78 ( )
100 75
OS (%) 50
Nonproportionality test: P = .0072
High-risk subgroup: stage III suboptimally debulked, stage IV, or no debulking surgery,
n = 502 25
Bev, bevacizumab; C, carboplatin; P, paclitaxel.
9.4 6 12 18 24 30 36 42 48 54 60
Mos
Pts at Risk, n CP CP + Bev
254
248
208
224
156
180
101
135 82 95 21 27
Slide credit: clinicaloptions.com
Oza AM, et al. Lancet Oncol. 2015;16:

30. ICON7: AEs of Specific Interest (All Grades)
CP (n = 753) CP + Bev (n = 745)
All Grades
Grade ≥ 3
Pts (%)
Pts (%)
AE, adverse event; ATE, arterial thromboembolism; Bev, bevacizumab; C, carboplatin; CHF, congestive heart failure; GI, gastrointestinal; P, paclitaxel; RPLS, reversible posterior leukoencephalopathy syndrome; VTE, venous thromboembolism.
Slide credit: clinicaloptions.com
Perren TJ, et al. N Engl J Med. 2011;365:

31. What Is the Standard Systemic Tx for Newly Diagnosed Advanced Epithelial Ovarian Cancer?
Intraperitoneal is an option in the adjuvant setting when the volume of residual disease is < 1cm
Advanced stage: 60% to 70%
No symptoms because of large peritoneal cavity
Peritoneal dissemination
Not curative by surgery or radiation therapy
Importance of chemotherapy delivery
Infusing a high concentration of anticancer drugs appears to be a reasonable approach
Tx, treatment.
Slide credit: clinicaloptions.com

32. Historical Large IP Trials
Study
IP Regimen
IV Control
PFS
(IP vs IV) OS
Critique
SWOG 8501
(N = 546)[1]
Cisplatin IP 100 mg/m2
Cyclophosphamide IV 600 mg/m2
Cisplatin IV 100 mg/m2
Cyclophosphamide IV 600 mg/m2
Not reported
49 vs 41 mos
P = .02
No paclitaxel
0-2 cm residual disease
GOG 114
(N = 462)[2]
Carboplatin IV AUC 9 x 2 
Paclitaxel IV 135 mg/m2 (24 hrs) D1
Cisplatin IP 100 mg/m2 D2
Paclitaxel IV 135 mg/m2 (24 hrs) D1
Cisplatin IV 75 mg/m2 D2
28 vs 22 mos
63 vs 52 mos
P = .05
High-dose carboplatin
One-tail P value for OS
GOG 172
(N = 415)[3]
Paclitaxel IP 60 mg/m2 D8
Paclitaxel IV 135 mg/m2 (24 hrs) D1
Cisplatin IV 75 mg/m2 D2
24 vs 18 mos
HR: 0.80
66 vs 50 mos
HR: 0.75
P = .03
D8 paclitaxel confounds
AUC, area under the curve.
1. Alberts DS, et al. N Engl J Med. 2006;335:
2. Markman M, et al. J Clin Oncol. 2001;19:
3. Armstrong D, et al. N Engl J Med. 2006;354:34-43.
Slide credit: clinicaloptions.com

33. IP Regimen Better IV Regimen Better
NCI Clinical Announcement: Preferred Treatment Methods for Advanced Ovarian Cancer (2006)
Treatment HRs for OS IP vs IV therapy
HR Var (In(HR))
IP Regimen Better IV Regimen Better
SWOG/GOG 104 (1996)
GONO (2000)
GOG 114/SWOG (2001)
Taiwan (2001)
EORTC (2003)
GOG 172 (2006)
Pooled estimate
0.79
HR, hazard ratio; NCI, National Cancer Institute; Rel, relative.
0.33
0.50
0.67
1.00
1.50
2.00
3.00
Relative Hazard
Slide credit: clinicaloptions.com
National Cancer Institute

34. Long-term Survival and Prognostic Factors Associated With IP Chemo in Advanced Ovarian Cancer
876 pts from GOG 114 and 172 with median follow-up of 10.7 yrs
1.0
1.0
GOG 172 IP, 6
GOG 172 IP, 3-5 to IV
GOG 172 IP, < 3 to IV
GOG 172 IV, 6
Median OS, Mos
0.8
0.8 IP IV
0.6
0.6
Probability of OS
Probability of OS
0.4
0.4
0.2
0.2
Adjusted HR: 0.77 (95% CI: )
P = .002 30 60 90
120 30 60 90
120
Mos
Mos
Pts at Risk, n
GOG 172 IP, 6
GOG 172 IP, 3-5 to IV
GOG 172 IP, < 3 to IV
GOG 172 IV, 6 78 26 61
182 73 19 46
133 50 14 30 79 31 8 18 47 4 7 25
Pts at Risk, n IV IP
436
440
303
337
184
217
110
140 68 85
Slide credit: clinicaloptions.com
Tewari D, et al. J Clin Oncol. 2015;33:

35. Phase III GOG 252: IV vs IP Chemotherapy + Bevacizumab in Stage II/III Ovarian Cancer
Cycles 1-6
Cycles 7-22
Carboplatin AUC 6 IV
Paclitaxel 80 mg/m2 IV (1 hr) D1, 8, 15
Bevacizumab 15 mg/kg IV D1, C2-6
Bevacizumab D1, C7-22
Pts with stage II/III epithelial ovarian, fallopian tube, or primary peritoneal carcinoma and no prior therapy; R0 (N = 1560)
Carboplatin AUC 6 IP
Paclitaxel 80 mg/m2 IV (1 hr) D1, 8, 15 Bevacizumab 15 mg/kg IV D1, C2-6
Bevacizumab D1, C7-22
Paclitaxel 135 mg/m2 IV (3 hrs) D1
Cisplatin 75 mg/m2 IP D2
Paclitaxel 60 mg/m2 IP D8
Bevacizumab 15 mg/kg IV D1, C2-6
AUC, area under the curve; R0, complete resection.
Bevacizumab D1, C7-22
Walker JL, et al. SGO Abstract LBA7. ClinicalTrials.gov. NCT
Slide credit: clinicaloptions.com 35

36. GOG 252: Completion of Assigned Treatment
Arm
Bev Cycles Completed, n
Completed ≥ 6 Cycles of Platinum, %
Completed ≥ 6 Cycles of Taxane, %
IV Carboplatin 20 90 87
IP Carboplatin 19 88
IP Cisplatin 17 84
Twice as many pts stopped protocol-directed bevacizumab
prior to completion of cycle 6 on Arm 3 (IP cisplatin; 30% vs 15%)
Bev, bevacizumab.
Slide credit: clinicaloptions.com
Walker JL, et al. SGO Abstract LBA7.

37. GOG 252: PFS by Treatment Group
PFS in Stage II or Stage III Optimally Debulked (< 1 cm)
PFS in Stage III With No Gross Residual Disease (R0)
100
100
Treatment
Median, Mos
26.8
28.7
27.8
1: IV Carbo (n = 239)
2: IP Carbo (n = 239)
3: IP Cis (n = 239)
Treatment
Median, Mos
31.3
31.8
33.8
1: IV Carbo (n = 461)
2: IP Carbo (n = 464)
3: IP Cis (n = 456) 80 80 60 60
PFS (%)
PFS (%) 40 40 20
HR IV Carbo vs IP Carbo: 0.95 (95% CI: ; P = .416) 20
HR IV Carbo vs IP Cis: 1.01 (95% CI: ; P = .727)
Carbo, carboplatin; Cis, cisplatin. 12 24 36 48 60 72 12 24 36 48 60 72
Mos on Study
Mos on Study
Estimated HR, log-rank tests adjusted for stage of disease and size of residual disease (micro vs < 1 cm)
CT required every 6 mos for surveillance (not required in GOG 114/172)
Slide credit: clinicaloptions.com
Walker JL, et al. SGO Abstract LBA7.

38. GOG 252: Toxicity AE, % IV Carboplatin IP Carboplatin IP Cisplatin
Grade 2
Grade ≥ 3
Febrile neutropenia
2.5
2.6
3.3
Neutropenia 71 68 64
Platelets
17.6
15.1
6.1
Hypertension
11.9
13.8
20.5
Thrombocytopenia
6.3
8.4
9.0
Nausea/vomiting
5.1
4.7
11.2
Fistula
5.3
3.7
4.3
Urine protein
2.7
3.1
1.6
Sensory neuropathy
24.1
5.7
22.6
4.5
21.3
5.5
AE, adverse event.
Slide credit: clinicaloptions.com
Walker JL, et al. SGO Abstract LBA7.

39. Did Inclusion of Bevacizumab Compromise PFS in GOG 252?
Lessons learned from GOG 262
With bevacizumab, dose-dense weekly chemotherapy does not prolong PFS
Without bevacizumab, dose-dense weekly chemotherapy prolongs PFS
Median
PFS, Mos
Median
PFS, Mos
Events, n
Events, n
Weekly paclitaxel (n = 346)
Q3W paclitaxel (n = 346)
Weekly paclitaxel (n = 55)
Q3W paclitaxel (n = 57) 20 40 60 80
100 12 24 36
Mos
PFS (%)
HR: 0.89 (95% Cl: ;
P = .18) 20 40 60 80
100 12 24 36
PFS (%)
HR: 0.62 (95% Cl: ;
P = .03)
Mos
bev, bevacizumab.
PFS without bev
PFS with bev
Slide credit: clinicaloptions.com
Chan JK, et al. N Engl J Med. 2016;374:

40. Did Inclusion of Bevacizumab Compromise PFS in GOG 252?
Adding bevacizumab should have exaggerated any difference between the treatments rather than mitigating any IP benefit
No difference between the treatment arms in GOG 252, even with the inclusion of bevacizumab, shows that IP chemotherapy does not improve PFS
Median
PFS, Mos
Median
PFS, Mos
Events, n
Events, n
Weekly paclitaxel (n = 346)
Q3W paclitaxel (n = 346)
Weekly paclitaxel (n = 55)
Q3W paclitaxel (n = 57) 20 40 60 80
100 12 24 36
Mos
PFS (%) 20 40 60 80
100 12 24 36
PFS (%)
Mos
HR: 0.89 (95% Cl: ;
P = .18)
HR: 0.62 (95% Cl: ;
P = .03)
bev, bevacizumab.
PFS without bev
PFS with bev
Slide credit: clinicaloptions.com
Chan JK, et al. N Engl J Med. 2016;374:

41. Phase II/III iPocc Trial: IV vs IP Paclitaxel/ Carboplatin in Stage II-IV Ovarian Cancer
Paclitaxel 80 mg/m2/1h IV, weekly, Cycles 1-6
Carboplatin AUC 6 IV, Day 1, Cycles 1-6
Pts with stage II-IV
ovarian, primary peritoneal, or fallopian tube cancer;
suboptimal cases included (Planned N = 654)
Paclitaxel 80 mg/m2/1h IV, weekly, Cycles 1-6
Carboplatin AUC 6 IP, Day 1, Cycles 1-6
AUC, area under the curve; QoL, quality of life.
Primary endpoint: PFS
Secondary endpoints: OS, toxicity, QoL, cost/benefit
Slide credit: clinicaloptions.com
ClinicalTrials.gov. NCT

42. Considerations for Genetic Mutations in Patients With Ovarian Cancer

43. BRCA Mutations: Basic Concepts
Germline BRCA mutations
Germline non-BRCA mutations in HR pathway proteins
Sporadic (somatic) BRCA mutations
Sporadic non-BRCA mutations in HR pathway proteins
Mutations in HR pathway ↓
HR deficiency
HR, homologous recombination
Slide credit: clinicaloptions.com

44. Overview of BRCA1 and BRCA2
Risk of Developing Ovarian Cancer
MUTATED BRCA1
39%
MUTATED BRCA2
11% to 17%
NORMAL BRCA
1.4%
Enzymes that repair double- stranded DNA breaks
Mutations in BRCA1 or BRCA2
Increased risk of breast and ovarian cancer
Prognostic marker
Predictive biomarker for PARP inhibitor activity
Slide credit: clinicaloptions.com

45. Homologous Recombination Repair
DNA DSB
MRN-mediated sensing of the DSB → ATM activation
MRN-mediated 5’ to 3’ end resection
End processing via BRCA1 & 2-containing complex → binds directly to RAD 51
Displacement of RPA and assembly of RAD51 onto ssDNA via BRCA2
Strand invasion into undamaged homologous DNA leading to repaired DNA
HR is a complex process involving many gene products
Cells with disruptive BRCA mutations are deficient in HR
Other mediators of the HR pathway include MRE11, RAD50, NBS1, ATM, CtIP, PALB2, BRCA2, RAD51, RPA
Disruptive mutations in other HR pathway genes can also result in HR deficiency
HR, homologous recombination.
Slide credit: clinicaloptions.com
Hosoya N, et al. Cancer Sci. 2014;105:370–388.

46. Germline vs Somatic Mutations
Germline mutation
Somatic mutation
Parental gametes
Parental gametes
Embryo
Embryo
Entire organism carries mutation
Mutation only in affected area
©Medscape, LLC
©Medscape, LLC
Half of gametes carry mutation
No gametes carry mutation
Organism
Organism
Offspring gametes
Offspring gametes
Germline mutations are inherited and found in all cells
Somatic mutations are not inherited and are found within the tumor
Slide credit: clinicaloptions.com

47. Single-Gene vs Multigene (Panel) Testing
Single-Gene Testing
Tests for mutation-specific gene
PCR and direct sequencing
Traditionally used when personal or FH suggests single inherited cancer syndrome
Panel Testing
Tests mutation status of multiple genes with one sample
Most commonly using NGS
Can be used in place of single-gene testing; should be considered when negative for single-gene test but FH suggests an inherited susceptibility
FH, family history; NGS, next-generation sequencing.
Slide credit: clinicaloptions.com

48. Genetic Testing: Timing Recommendations
Germline panel testing at diagnosis in all women with ovarian, peritoneal and fallopian tube cancer
Somatic testing at recurrence
BRCA, HRD, MSI, etc
HRD, homologous recombination deficiency; MSI, microsatellite instability.
Slide credit: clinicaloptions.com

49. Management Options for Patients With Recurrent Ovarian Cancer

50. Bevacizumab for Recurrent Ovarian Cancer: Clinical Data Summary
Trial
Treatment
ORR, %
PFS, Mos
PFS HR
P Value
OS, Mos
OS HR
Platinum-sensitive recurrent ovarian cancer
GOG 213[1]
(N = 673)
Paclitaxel/carboplatin 59
10.4
0.628
P < .0001
37.3
0.829
P = .056
+ bevacizumab 78
13.8
42.2
OCEANS[2,3]
(N = 484)
Gem/carboplatin 57
8.4
0.48
32.9
0.952
P = .65
Gem/carboplatin + bevacizumab 79
12.4
33.6
Platinum-resistant recurrent ovarian cancer
AURELIA[4]
(N = 361)
Single-agent chemotherapy 13
3.4
P < .001
13.3
0.85
P < .174
Single-agent chemotherapy + bevacizumab 31
6.7
16.6
Gem, gemcitabine.
1. Coleman RL, et al. Lancet Oncol. 2017;18: Aghajanian C, et al. J Clin Oncol. 2012;30: Aghajanian C, et al. Gynecol Oncol. 2015;139: Pujade-Lauraine E, et al. J Clin Oncol. 2014;32:
Slide credit: clinicaloptions.com

51. Phase III OCEANS Study: Second-line Gem/Carbo ± Bevacizumab in Recurrent Ovarian Cancer
Stratified by platinum-free interval (6-12 mos vs > 12 mos), cytoreductive surgery for recurrent disease (yes vs no)
Pts with platinum-sensitive, recurrent ovarian cancer, progression on first-line chemotherapy, no prior bevacizumab, ECOG PS 0/1
(N = 484)
Carboplatin AUC 4 Day 1 Gemcitabine 1000 mg/m2 Days 1, 8
Bevacizumab 15 mg/kg Day 1 21-day cycles
Carboplatin AUC 4 Gemcitabine 1000 mg/m2 Days 1 ,8
Placebo Day 1 21-day cycles
AE, adverse event; Carbo, carboplatin; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; Gem, gemcitabine; GI, gastrointestinal; PS, performance status
Primary endpoint: PFS
Secondary endpoints: ORR, DoR, OS, % of pts with GI perforation, AEs
Slide credit: clinicaloptions.com
Aghajanian C, et al. Gynecol Oncol. 2015;139:10-16.

52. OCEANS: PFS, ORR, and DoR Investigator-Assessed PFS 100
Outcome
GC + Pbo
(n = 242)
GC + Bev
PFS by investigator
Median PFS, mos
8.4
12.4
Stratified HR
(95% CI)
0.484
( )
Log-rank P value
< .0001
ORR and DoR by investigator
ORR, % 57 79
Median DoR, mos
7.4
10.4
HR (95% CI)
0.53 ( )
100
GC + placebo (n = 242)
GC + bev (n = 242) 80 60
PFS (%) 40
Bev, bevacizumab; C, carboplatin; DoR, duration of response; G, gemcitabine; Pbo, placebo. 20
Data cutoff date:
September 17, 2010 6 12 18 24 30
Mos
Slide credit: clinicaloptions.com
Aghajanian C, et al. J Clin Oncol. 2012;30:

53. OCEANS: Final OS Analysis
100
Median OS, Mos
GC + placebo 32.9
GC + bev 33.6 80 60
OS (%)
HR: (95% CI: ;
log-rank P = .6479) 40 20
Bev, bevacizumab; C, carboplatin; G, gemcitabine.
Data cutoff date: July 19, 2013; median follow-up: 56.4 mos in placebo arm and mos in bev arm, with 353 deaths (72.9% of pts) 6 12 18 24 30 36 42 48 54 60 66 72 78
Mos
Pts at Risk, n
GC + placebo
242
235
222
191
160
128
104 87 64 41 20 7 1
GC + bev
242
239
226
201
172
138
105 87 68 47 25 7 1
Slide credit: clinicaloptions.com
Aghajanian C, et al. Gynecol Oncol. 2015;139:10-16.

54. OCEANS: AEs of Special Interest
AEs, n (%)
GC + Placebo (n = 233)
GC + Bev (n = 247)
Arterial thromboembolic event (all grades)
1 (0.4)
6 (2.4)
Venous thromboembolic event (grades ≥ 3)
6 (2.6)
11 (4.5)
Bleeding (CNS) (all grades)
2 (0.9)
2 (0.8)
Congestive heart failure (grades ≥ 3)
Febrile neutropenia (all grades)
4 (1.7)
4 (1.6)
Neutropenia (grades ≥ 4)
51 (21.9)
52 (21.1)
Fistula/abscess (all grades)*
Gastrointestinal perforation (all grades)*
Reversible posterior leukoencephalopathy syndrome (all grades)
Wound-healing complication (grades ≥ 3)
Proteinuria (grades ≥ 3)
27 (10.9)
Bleeding (non-CNS) (grades ≥ 3), mostly epistaxis
14 (5.7)
Hypertension (grades ≥3)
45 (18.2)
AE, adverse event; Bev, bevacizumab; C, carboplatin; CNS, central nervous system; G, gemcitabine.
*Due to coding changes to using the gastrointestinal perforation (GIP) standardized medical query, this is different than the primary analysis, where no GI perforations were reported and fistula/abscess were reported in 1 patient in the GC + placebo arm and 4 patients in the GC + Bev arm. GIPs were reported in 2 additional patients outside the safety reporting window.
Footnote in slidenotes.
Aghajanian C, et al. Gynecol Oncol. 2015;139:10-16.
Slide credit: clinicaloptions.com

55. Phase III GOG 213: Carbo/Pac ± Bevacizumab in Recurrent Ovarian Cancer
Surgical
candidate
Regimen I
Carboplatin AUC 5
Paclitaxel 175 mg/m2
21-day cycles R A N D O M I Z E
Surgery
Pts with recurrent ovarian, peritoneal primary, or fallopian tube cancer and a treatment-free interval ≥ 6 mos (N = 674)
Yes
No Surgery
No surgery
Regimen II
Carboplatin AUC 5
Paclitaxel 175 mg/m2
Bevacizumab 15 mg/kg 21-day cycles
Maintenance
Bevacizumab
15 mg/kg Q21D No
Primary objectives: OS with addition of bevacizumab, OS with addition of secondary cytoreductive surgery
Secondary objectives: PFS, carboplatin/paclitaxel hypersensitivity, HRQoL
AUC, area under the curve; Carbo, carboplatin; HRQoL, health-related quality of life; Pac, paclitaxel.
Slide credit: clinicaloptions.com
Coleman RL, et al. Lancet Oncol. 2017;18:

56. GOG 213: PFS Adjusted HR: 0.628 (95% CI: 0.534-0.739; P < .0001)
100
Events, n
Median PFS, Mos
PC (n = 337)
304
10.4 80
PC + bev (n = 337)
296
13.8
Adjusted HR: (95% CI: ;
P < .0001) 60
PFS (%) 40 20
Bev, bevacizumab; C, carboplatin; P, paclitaxel. 12 24 36 48 60
Mos on Study
Pts at Risk, n PC
337
125 40 20 12 5
PC + bev
337
201 84 46 16 9
Slide credit: clinicaloptions.com
Coleman RL, et al. Lancet Oncol. 2017;18:

57. GOG 213: OS Adjusted HR: 0.829 (95% CI: 0.683-1.005; P = .056)
Events, n
Median OS, Mos
PC (n = 337)
214
37.3
100
PC + bev (n = 337)
201
42.2 80 60
OS (%) 40 20
Bev, bevacizumab; C, carboplatin; P, paclitaxel.
Adjusted HR: (95% CI: ;
P = .056) 12 24 36 48 60
Pts at Risk, n
Mos on Study PC
337
303
234
152 69 18
PC + bev
337
306
253
183 75 28
Slide credit: clinicaloptions.com
Coleman RL, et al. Lancet Oncol. 2017;18:

58. GOG 213: Select AEs Related to Bevacizumab Tx
 AEs (All Grades Unless Otherwise Stated), %
PC (n = 327)
PC + Bev (n = 330)
Any AE 23 72
Grade ≥ 3 8 30
Serious 6 15
Bleeding (CNS) 1
< 1
Bleeding (non-CNS) 11 42
CHF
Grade 3/4 fistula/abscess (nongastrointestinal)
Gastrointestinal perforations 2
Hypertension (any grade/grade ≥ 3)
3/1
41/12
Neutropenia and complications (any grade/grade ≥ 3)
8/4
12/7
Posterior reversible encephalopathy syndrome
Proteinuria 17
Thromboembolic event, arterial 7
Thromboembolic event, venous
Wound healing complication 3
Secondary primary malignancy
Bev, bevacizumab; C, carboplatin; CHF, congestive heart failure; CNS, central nervous system; P, paclitaxel; Tx, treatment.
*Medical review of embolism events in AdEERS reports and comments recorded in CRFs revealed that all 5 of the Grade 4 emboli were pulmonary emboli. Therefore, the pulmonary emboli were recategorized as VTEs. Medical review of 9 cases of deep vein thrombosis and pulmonary embolism initially classified under the ATE category were reclassified as Grade ≥3 VTEs.
Slide credit: clinicaloptions.com
Coleman RL, et al. Lancet Oncol. 2017;18:

59. AURELIA: Randomized Phase III Trial of Bev + CT for Platinum-Resistant Recurrent Ovarian Cancer
Stratified by selected chemotherapy, prior antiangiogenic therapy, platinum-free interval (< 3 vs 3-6 mos)
Pts with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer, ≤ 2 prior regimens, no bowel obstruction, GI perforation, or rectosigmoid involvement, ECOG PS 0/1
(N = 484)
Chemotherapy
(n = 182)
Treat to PD or unacceptable toxicity
Bevacizumab monotherapy permitted on clear evidence of progression
Chemotherapy + Bevacizumab 10 mg/kg Q2W or 15 mg/kg Q3W
(n = 179)
Bev, bevacizumab; ECOG, Eastern Cooperative Oncology Group; CT, chemotherapy; GI, gastrointestinal; PD, progressive disease; PS, performance status; QoL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors.
Investigators first selected chemotherapy, then pts were randomized to bevacizumab or no bevacizumab
Chemotherapy (physician’s choice):
Paclitaxel 80 mg/m2 Days 1, 8, 15, 22 Q4W
Topotecan 4 mg/m2 Days 1, 8, 15 Q4W (or 1.25 mg/m2 Days 1-5 Q3W)
Pegylated liposomal doxorubicin 40 mg/m2 Day 1 Q4W
Primary endpoint: PFS (RECIST v1.0)
Secondary endpoints: ORR, OS, QoL, safety
Slide credit: clinicaloptions.com
Pujade-Lauraine E, et al. J Clin Oncol. 2014;32: 59

60. AURELIA: PFS (ITT Population) and Secondary Outcomes
Median
PFS, Mos
Median
OS, Mos
ORR, %
100
Bev + CT (n = 179) 80
CT alone (n = 182) 60
PFS HR: 0.48 (95% CI: ;
log-rank P < .001)
PFS (%) 40
OS HR: 0.85 (95% CI: ) 20
Bev, bevacizumab; CT, chemotherapy; ITT, intent to treat. 3 6 9 12 15 18 21 24
Pts at Risk, n
Mos
CT alone
182 92 35 18 9 1 1
Bev + CT
179
144 91 51 19 6 4 1
Slide credit: clinicaloptions.com
Pujade-Lauraine E, et al. J Clin Oncol. 2014;32:

61. AURELIA: Cohorts Treated With Paclitaxel— PFS and OS
Median OS, Mos
100
100
Median PFS, Mos
CT (n = 55)
CT (n = 55)
Bev + CT (n = 60) 22.4 80
Bev + CT (n = 60) 10.4 75 60
PFS (%)
OS (%) 50 40 25
Bev, bevacizumab; CT, chemotherapy. 20
HR: 0.46
(95% CI: )
HR: 0.65 (95% CI: ) 3 6 9 12 15 18 21 24 6 12 18 24 30 36 42
Mos
Mos
Slide credit: clinicaloptions.com
Poveda AM, et al. J Clin Oncol. 2015;33:

62. AURELIA: Cohorts Treated With Topotecan— PFS and OS
Median OS, Mos
100
Median PFS, Mos
100
CT (n = 63)
CT (n = 63)
Bev + CT (n = 57) 13.8
Bev + CT (n = 57) 6.2 75 75
50%
OS (%) 50
PFS (%) 50
HR: 0.24 (95% CI: ) 25 25
Bev, bevacizumab; CT, chemotherapy. 8%
13%
HR: 1.09 (95% CI: ) 3 6 9 12 15 18 21 24 6 12 18 24 30 36 42
Mos
Mos
1. Poveda AM, et al ESMO Congress. Abstract LBA26.
2. Witteveen P, et al European Cancer Congress. Abstract LBA 5.
Slide credit: clinicaloptions.com

63. AURELIA: Cohorts Treated With PLD— PFS and OS
Median OS, Mos
100
Median PFS, Mos
100
CT (n = 64)
CT (n = 64)
Bev + CT (n = 62) 13.7
Bev + CT (n = 62) 5.1 75 75
OS (%) 50
PFS (%) 50
41%
HR: 0.47 (95% CI: ) 25
Bev, bevacizumab; CT, chemotherapy; PLD, pegylated liposomal doxorubicin. 25
14%
23% 4%
HR: 0.91 (95% CI: ) 3 6 9 12 15 18 21 24 6 12 18 24 30 36 42
Mos
Mos
1. Poveda AM, et al ESMO Congress. Abstract LBA26.
2. Witteveen P, et al European Cancer Congress. Abstract LBA 5.
Slide credit: clinicaloptions.com

64. AURELIA: Summary of Grade ≥ 3 (and Selected Grade ≥ 2) AEs of Special Interest
Grade ≥ 3 AE of Special Interest, %
Bev + CT (n = 179)
CT Alone (n = 181)
Hypertension (grade 2)
7 (20)
1 (7)
Proteinuria 2
GI perforation (grade 2)
2 (2)
Fistula/abscess (grade 2)
1 (2)
Bleeding 1
Arterial/venous thromboembolic event
2/3
0/4
Wound healing complication
RPLS
CHF
Cardiac disorders
AE, adverse event; Bev, bevacizumab; CHF, congestive heart failure; CT, chemotherapy; GI, gastrointestinal; PD, progressive disease; RPLS, reversible posterior leukoencephalopathy syndrome.
In each arm, 5 deaths occurred that were not considered to be caused primarily by PD
Slide credit: clinicaloptions.com
Pujade-Lauraine E, et al. J Clin Oncol. 2014;32:
REFERENCE:
Bevacizumab® (bevacizumab) [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2014.

65. PARP Inhibitor Summary: Current Indications
Olaparib[1]
Niraparib[2]
Rucaparib[3]
Approval date
December 2014, August 2017
March 2017
December 2016
Current indication
Maintenance tx for recurrent disease in CR or PR to platinum tx
gBRCA+ pts with ≥ 3 lines of tx
Somatic or gBRCA+ pts with ≥ 2 lines of tx
Dose and schedule
300 mg (two 150-mg tablets)
PO BID
300 mg (three 100-mg capsules) PO QD
600 mg (two 300-mg tablets) PO BID
Safety
MDS/AML confirmed in 2%
Pneumonitis, including fatal cases, occurred in < 1% 
Thrombocytopenia
(61%; 29% grade ≥ 3)
Neutropenia
(30%; 20% grade ≥ 3)
Hypertension
(20%; 9% grade ≥ 3)
Elevated AST/ALT
(75%; 5%-13% grade ≥ 3)
Dysgeusia (39%)
Most common tx-related AEs include fatigue (60% to 80%); GI symptoms: nausea (65% to 75%), vomiting (35% to 45%), diarrhea (20% to 35%), pain (30% to 40%); and anemia (35% to 50%)
AE, adverse event; ALT, alanine aminotransferase; AML, acute myeloid leukemia; AST, aspartate aminotransferase; GI, gastrointestinal; MDS, myelodysplastic syndromes; Tx, treatment.
1. Olaparib [package insert] Niraparib [package insert]
3. Rucaparib [package insert]
Slide credit: clinicaloptions.com

66. Treatment until PD with no crossover allowed
Phase III NOVA: Niraparib Maintenance in Platinum-Sensitive Ovarian Cancer
Niraparib 300 mg QD
(n = 136)
Platinum-sensitive, recurrent ovarian, fallopian tube, or primary peritoneal cancer; ≥ 2 prior platinum-based regimens with CR/PR and progression
> 6 mos after most recent platinum-based therapy
(N = 553)
Germline BRCA mutation cohort
(n = 203)
Placebo QD
(n = 65)
Treatment until PD with no crossover allowed
Niraparib 300 mg QD
(n = 231)
No germline BRCA mutation cohort
(n = 350)
Placebo QD
(n = 114)
PD, progressive disease.
Primary endpoint: PFS
Secondary endpoints: chemotherapy-free interval, time to first subsequent therapy, PFS2, time to second subsequent therapy, OS
Maintenance therapy initiated within 8 wks of last dose of platinum chemotherapy
Slide credit: clinicaloptions.com
Mahner S, et al. SGO Abstract 8084.

67. NOVA: PFS Results in Pt Subgroups
gBRCAmut (n = 203)
Non-gBRCAmut Overall (n = 350)
100 2 4 6 8 10 12 14 16 18 20 24 22
100 75 50 25
Median PFS, Mos
Median PFS, Mos
Pbo 75
Nira
Pbo 3.9
PFS (%) 50
PFS (%)
Nira 9.3 25
HR: 0.27 (P < .001)
HR: 0.45 (P < .001) 2 4 6 8 10 12 14 16 18 20 22 24
Mos
Mos
Non-gBRCAmut, HRD+ (n = 162)
HRD Negative (n = 134) 2 4 6 8 10 12 14 16 18 20 24 22
100 75 50 25 2 4 6 8 10 12 14 16 18 20 24 22
100 75 50 25
Median PFS, Mos
Median PFS, Mos
HRD, homologous recombination deficiency; Nira, niraparib; Pbo, placebo.
Pbo
Pbo 3.8
PFS (%)
Nira
PFS (%)
Nira 6.9
HR: 0.38 (P < .001)
HR: 0.58 (P = .02)
Mos
Mos
Slide credit: clinicaloptions.com
Mahner S, et al. SGO Abstract Mirza MR, et al. N Engl J Med. 2016;375:

68. NOVA: Chemotherapy-Free Interval
Non-gBRCAmut Overall (n = 350)
100
Median CFI, Mos
Pbo 75
Nira
gBRCAmut (n = 203)
PFS (%) 50
Median CFI, Mos
100
Pbo 25
HR: 0.5 (P < .0001)
Nira 75 2 4 6 8 10 12 14 16 18 20 22 24
PFS (%) 50
Non-gBRCAmut, HRD+ (n = 162)
100
Median CFI, Mos 25
Pbo
CFI, chemotherapy-free interval; HRD, homologous recombination deficiency; Nira, niraparib; Pbo, placebo. 75
HR: 0.26 (P < .0001)
Nira 2 4 6 8 10 12 14 16 18 20 22 24
PFS (%) 50
Mos 25
HR: 0.31 (P < .0001)
Mahner S, et al. SGO Abstract Mirza MR, et al. N Engl J Med. 2016;375: 2 4 6 8 10 12 14 16 18
Slide credit: clinicaloptions.com 20 22 24
Mos

69. NOVA: Impact on Efficacy of Next-Line Therapy
(PFS2 - PFS1) in the Pooled gBRCAmut and Non-gBRCAmut Cohorts
Randomization
Progression
100
Progression
Niraparib
Placebo
Platinum
Chemo
Chemo 75
PFS1
PFS2-PFS1
PFS2
Estimated Survival Function 50
Niraparib
Placebo 25
HR: 1.02 (95% CI: ) 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Mos Since Randomization
Slide credit: clinicaloptions.com
Mahner S, et al. SGO Abstract 8084.

70. Mos Since Randomization Mos Since Randomization
Niraparib in Pts With Recurrent Ovarian Cancer With PR to Last Platinum-Based Chemotherapy
gBRCAmut
Non-gBRCAmut
100
Niraparib/all
Niraparib/PR
Placebo/all
Placebo/PR
100
Niraparib/all
Niraparib/PR
Placebo/all
Placebo/PR 80 80 60 60
PFS (%)
PFS (%) 40 40 20 20 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24
Mos Since Randomization
Mos Since Randomization
Nira/all
Nira/PR
Pbo/all
Pbo/PR
138 67 65 32
125 62 52 22
107 50 34 14 98 45 21 9 89 41 12 3 79 37 8 3 63 27 6 1 44 19 2 28 10 2 26 9 2 16 5 1 3 1 1
Nira/all
Nira/PR
Pbo/all
Pbo/PR
234
117
116 56
188 90 88 40
145 66 52 13
113 54 33 5 88 39 23 2 75 31 19 2 57 26 10 2 41 16 8 1 23 8 4 1 21 7 4 1 16 6 3 1 7 2 1 3 1
Slide credit: clinicaloptions.com
Mirza M, et al. ASCO Abstract 5517.

71. NOVA: Summary of AEs
AE, n (%)
Niraparib
(n = 367)
Placebo
(n = 179)
Any TEAE
367 (100)
171 (95.5)
Any related TEAE
358 (97.5)
127 (70.9)
Any CTCAE grade ≥ 3 TEAE
272 (74.1)
41 (22.9)
Any related CTCAE grade ≥ 3 TEAE
237 (64.6)
8 (4.5)
Thrombocytopenia
124 (33.8)
1 (0.6)
Anemia
93 (25.3)
Neutropenia
72 (19.6)
3 (1.7)
Fatigue
30 (8.2)
Hypertension
4 (2.2)
Any serious TEAE
110 (30.0)
27 (15.1)
Any related serious TEAE
62 (16.9)
2 (1.1)
Any TEAE leading to treatment interruption
253 (68.9)
9 (5.0)
Any TEAE leading to dose reduction
244 (66.5)
26 (14.5)
Any TEAE leading to treatment discontinuation
54 (14.7)
Any TEAE leading to death
MDS/AML occurred in 5 of 367 pts (1.4%) who received niraparib and 2 of 179 pts (1.1%) who received placebo
No grade 3/4 bleeding AEs were associated with thrombocytopenia
No grade 5 events occurred
AE, adverse event; AML, acute myeloid leukemia; CTCAE, Common Terminology Criteria for Adverse Events; MDS, myelodysplastic syndromes; TEAE, treatment-emergent adverse event
Grade 1-4 cardiac palpitations 10 2
Slide credit: clinicaloptions.com
Mahner S, et al. SGO Abstract Mirza MR, et al. N Engl J Med. 2016;375:

72. NOVA: Pt-Reported Outcomes
gBRCAmut: FOSI
gBRCAmut: EQ-5D-5L 30
1.0
Measured using FOSI and the EQ-5D-5L
PRO surveys were collected at
Screening visit
Every other cycle through cycle 14
Postprogression
Compliance rates high and similar between the 2 treatment arms
Niraparib: FOSI completion rate ranged from 75.0% to 97.1%
Placebo: FOSI completion rate ranged from 79.6% to 97.4%
PROs were similar for niraparib compared with placebo 25
0.8 20
0.6
FOSI (Adjusted Means) ± SE
EQ-5D-5L (Adjusted Means) ± SE 15
0.4 10
0.2
Screening C2 C4 C6 C8
C10
C12
C14
Post-
Prog
Screening C2 C4 C6 C8
C10
C12
C14
Post-
Prog
Non-gBRCAmut: FOSI
Non-gBRCAmut: EQ-5D-5L 30
1.0 25
0.8
EQ-5D-5L, EuroQol five dimension questionnaire; FOSI, Functional Assessment of Cancer Therapy—Ovarian Symptom Index; PRO, patient-reported outcome; SE, standard error. 20
0.6
FOSI (Adjusted Means) ± SE
EQ-5D-5L (Adjusted Means) ± SE 15
0.4 10
0.2
Screening C2 C4 C6 C8
C10
C12
C14
Post-
Prog
Screening C2 C4 C6 C8
C10
C12
C14
Post-
Prog
Niraparib
Placebo
Mahner S, et al. SGO Abstract Mirza MR, et al. N Engl J Med. 2016;375:
Slide credit: clinicaloptions.com

73. Accelerated Approval for Olaparib: December 2014
Administration: 400 mg BID (capsules)
Approval based on multicenter phase II trial in pts with a germline BRCA1/2 mutation and recurrent ovarian cancer after ≥ 3 lines of treatment (N = 137)
DoR, duration of response.
Slide credit: clinicaloptions.com
Domchek SM, et al. Gynecol Oncol. 2016;140:

74. Number of Prior Lines of Therapy
Number of Prior Lines of Chemotherapy Predicts ORR With Olaparib in mBRCA+ Ovarian Cancer
100 90 80 70 60 50 40 30 20 10 3 4 5
6-14
Sensitive (n = 18)
Resistant (n = 24)
Number of Prior Lines of Therapy
ORR (95% Cl)
Slide credit: clinicaloptions.com
Domchek SM, et al. Gynecol Oncol. 2016;140:

75. SOLO-2: Study Design
International, randomized, double-blind phase III trial[1]
Pts with recurrent serous OC and germline BRCA1/2 mutation, ≥ 2 prior lines of platinum-based therapy and responded to most recent platinum, CR or PR on most recent therapy
(N = 295)
Olaparib 300 mg BID
(n = 196*)
RECIST assessment Q12W ± 7 days up to 72 wks, then ~ Q24W until PD or unacceptable toxicity
Placebo
(n = 99)
*n = 195 received treatment.
Primary endpoint: investigator-assessed PFS
Key secondary endpoints: safety/tolerability, PFS2, TFST, TSST, OS, HRQoL
EQ-5D-5L, EuroQol five dimension questionnaire; FACT-O, Functional Assessment of Cancer Therapy-Ovarian; HRQoL, health-related quality of life; OC, ovarian cancer; PD, progressive disease; QAPFS, quality-adjusted PFS; RECIST, Response Evaluation Criteria in Solid Tumors; TFST, time to first subsequent therapy or death; TOI, trial outcome index; TSST, time to second subsequent therapy or death; TWiST, time without symptoms of disease or toxicity.
HRQoL analyses:
Primary: change in FACT-O TOI
Secondary pt-centered benefits: QAPFS (PFS + EQ-5D-5L); TWiST (mean PFS - mean toxicity)
1. Pujade-Lauraine E, et al. SGO Abstract LBA2. 2. Ledermann JA, et al. ASCO Abstract Friedlander M, et al. ASCO Abstract 5507.
Slide credit: clinicaloptions.com

76. SOLO-2: PFS by Investigator Assessment
100
Median PFS, Mos 90
Placebo 5.5 80
Olaparib 19.1 70 60
HR: 0.30 (95% CI: ;
log-rank P < .0001)
PFS (%) 50 40 30 20 10
Median follow-up: 22.1 mos in the olaparib group, 22.2 mos for placebo 3 6 9 12 15 18 21 24 27 30
Pts at Risk, n
Mos Since Randomization
Olaparib
196
182
156
134
118
104 89 82 32 29 3
Placebo 99 70 37 22 18 17 14 12 7 6
Slide credit: clinicaloptions.com
Pujade-Lauraine E, et al. SGO Abstract LBA2.

77. SOLO-2: PFS Sensitivity Analysis Using BICR
100
Median PFS, Mos 90
Placebo 5.5 80
Olaparib 30.2 70
HR: 0.25 (95% CI: ;
log-rank P < .0001) 60
PFS (%) 50 40 30 20 10
BICR, blinded independent central review. 3 6 9 12 15 18 21 24 27 30 33
Pts at Risk, n
Mos Since Randomization
Olaparib
196
176
148
128
112
103 88 82 30 28 3 1
Placebo 99 62 26 18 16 14 14 11 6 5
Slide credit: clinicaloptions.com
Pujade-Lauraine E, et al. SGO Abstract LBA2.

78. SOLO-2: Secondary Endpoints (TFST, PFS2, TSST)
HR: 0.28
(95% CI: ;
P < .0001)
27.9
TFST
7.1
Olaparib
Placebo
Median not reached
HR: 0.50
(95% CI: ;
P = .0002)
PFS2
18.4
HR: 0.37
(95% CI: ;
P < .0001)
Median not reached
TSST
TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death.
18.2 10 20 30
Mos
Slide credit: clinicaloptions.com
Pujade-Lauraine E, et al. SGO Abstract LBA2.

79. SOLO-2: Most Common AEs
AEs, %
Olaparib (n = 195)
Placebo (n = 99)
All Grades
Grade ≥ 3
Any
98.5
36.9
94.9
18.2
Nausea
75.9
2.6
33.3
Fatigue/asthenia
65.6
4.1
39.4
2.0
Anemia
43.6
19.5
8.1
Vomiting
37.4
19.2
1.0
Diarrhea
32.8
20.2
Dysgeusia
26.7
7.1
Headache
25.1
0.5
13.1
Abdominal pain
24.1
31.3
3.0
Decreased appetite
22.1
11.1
Constipation
20.5
23.2
AE, adverse events; AML, acute myeloid leukemia; MDS, myelodysplastic syndromes.
MDS/AML occurred in 4 pts receiving olaparib (2.1%) and 4 cases in placebo group (4.0%)
Friedlander M, et al. ASCO Abstract Ledermann JA, et al. ASCO Abstract Pujade-Lauraine E, et al. SGO Abstract LBA2.
Slide credit: clinicaloptions.com

80. SOLO-2: QAPFS Using Health-Related Quality of Life
Significantly longer QAPFS with olaparib vs placebo
Olaparib
1.0
Olaparib quality adjusted
Placebo
Outcome
Olaparib (n = 185)
Placebo (n = 94)
Difference (95% CI)
P Value
Mean PFS, mos
17.55
8.94
8.61 (6.47 to 10.87)
< .0001
Mean utility (mixed model)
0.80
0.81
(-0.05 to 0.02)
.284
QAPFS, mos
13.96
7.28
6.68 (4.98 to 8.54)
0.8
Placebo quality adjusted
0.6
Probability
0.4
QAPFD, quality-adjusted PFS.
0.2 3 6 9 12 15 18 21 24 27
Mos From Randomization
Slide credit: clinicaloptions.com
Friedlander M, et al. ASCO Abstract 5507.

81. Mos From Randomization Mos From Randomization
SOLO-2: TWiST
TWiST duration = mean PFS – mean toxicity
Olaparib, Mos (n = 185)
Placebo, Mos (n = 94)
Difference (95% CI)
P Value
TWiST
13.5
7.21
(2.95 to 8.58)
< .0001
Toxicity
3.69
0.71
(1.52 to 4.68)
.0002
1.0
1.0
Olaparib
0.8
0.8
0.6
0.6
Probability
Probability
Placebo
0.4
0.4
TWiST
TWiST
0.2
TWiST, time without symptoms of disease or toxicity.
0.2
Toxicity
Toxicity 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 27
Mos From Randomization
Mos From Randomization
Slide credit: clinicaloptions.com
Friedlander M, et al. ASCO Abstract 5507.

82. Accelerated Approval Cohort for Rucaparib, December 2016
Dose: 600 mg BID
Pt population: N = 106 (from phase II ARIEL2 and a phase I/II trial)
Recurrent ovarian cancer
2+ prior lines of treatment
Germline or somatic BRCA mutations
ORR: 54%
Slide credit: clinicaloptions.com
fda.gov/drugs/informationondrugs/approveddrugs/ucm htm

83. ARIEL2 Analysis: Pts With Mutated Germline or Somatic BRCA
ARIEL2 (n = 493)
Germline/Somatic BRCAmut
or BRCA WT
ARIEL2: This Analysis (n = 134)
Germline/Somatic BRCAmut
Part 1 (n = 206)
≥ 1 prior platinum-based therapy
Platinum as their last treatment
Platinum sensitive
Part 1 (n = 41)
≥ 1 prior platinum-based therapy
Platinum as their last treatment
Platinum sensitive
WT, wild type.
Part 2 (n = 287)
3 or 4 prior chemotherapies
Platinum sensitive, platinum resistant, or platinum refractory
Part 2 (n = 93)
3 or 4 prior chemotherapies
Platinum sensitive, platinum resistant, or platinum refractory
Slide credit: clinicaloptions.com
Konecny GE, et al. SGO Abstract 1.

84. ARIEL2: PFS by Platinum Sensitivity
Median PFS, Mos
95% CI
Pt-sensitive, last treatment pt-based; PFI ≥ 6 mos (n = 57)
12.7
Pt-sensitive, last treatment non-pt-based (n = 14)
7.4
Platinum resistant (n = 49)
7.3
Platinum refractory (n = 14)
5.0
100 80 60
PFS (%) 40
PFI, progression-free interval. 20 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Mos
Slide credit: clinicaloptions.com
Konecny GE, et al. SGO Abstract 1.

85. ARIEL2: PFS by Degree of Platinum Sensitivity (PFI)
95% CI
PFI ≥ 18 mos (n = 9)
25.1
5.5-NR
PFI ≥ 12 mos (n = 21)
16.9
PFI ≥ 6 mos (n = 57)
12.7
Last tx non-pt based (n = 14)
7.4
Median PFS, Mos
100 80 60
PFS (%) 40
NR, not reached; PFI, progression-free interval; tx, treatment. 20 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Mos
Slide credit: clinicaloptions.com
Konecny GE, et al. SGO Abstract 1.

86. ARIEL2: PFS in Platinum-Sensitive Pts by Germline vs Somatic BRCA Mutation
100 80 60 40 20 30 28 26 24 22 18 16 14 12 10 8 6 4 2
PFS (%)
Mos
Median PFS, Mos
95% CI
Germline BRCAmut (n = 32)
12.8
Somatic BRCAmut (n = 19)
12.7
Indeterminate BRCAmut (n = 6)
7.1
5.5-NR
Slide credit: clinicaloptions.com
Konecny GE, et al. SGO Abstract 1.

87. ARIEL2: Treatment-Emergent AEs in ≥ 20% of Pts With BRCAmut HGOC (N = 134)
All Grades
Grade 3/4
Nausea 78 5
Asthenia/fatigue 10
Vomiting 49
Anemia 48 29
Dysgeusia 40
ALT/AST increased 39
Decreased appetite 3
Abdominal pain 38 2
Constipation 35
<1
Diarrhea 34
Thrombocytopenia 25 7
Blood creatinine increased 23
Dyspnea
Urinary tract infection 20 4
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HGOC, high-grade ovarian cancer.
Slide credit: clinicaloptions.com
Konecny GE, et al. SGO Abstract 1.

88. Phase III ARIEL3: Rucaparib Maintenance in Platinum-Sensitive Ovarian Cancer
Stratified by HRD classification, response to platinum regimen, PFI after penultimate platinum
Pts with high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer after ≥ 2 prior platinum regimens, sensitive to penultimate platinum regimen, response to most recent platinum regimen, CA-125 ≤ ULN, ECOG PS 0-1, no prior PARP inhibitor
(Planned N = 540)
Rucaparib
600 mg BID
Placebo BID
ECOG, Eastern Cooperative Oncology Group; HRD, homologous recombination deficiency; PFI, progression-free interval; PS, performance status; ULN, upper limit of normal.
Primary endpoint: PFS in molecularly defined subgroups
Secondary endpoints: OS
PFS by independent radiology
Pt-reported outcomes
Safety
Slide credit: clinicaloptions.com
Clinicaltrials.gov. NCT

89. ARIEL3: Primary Efficacy Analyses
Analysis Population
PFS by Investigator Review
(Primary Endpoint)
PFS by BICR
(Key Secondary Endpoint) HR
Median PFS, Mos
Rucaparib vs Pbo
Primary Analyses
tBRCAmut (n = 196)
0.23; P < .0001
16.6 vs 5.4
0.20; P < .0001
26.8 vs 5.4
HRD positive (n = 354)
0.32; P < .0001
13.6 vs 5.4
0.34; P < .0001
22.9 vs 5.5
Intent to treat (n = 564)
0.36; P < .0001
10.8 vs 5.4
0.35; P < .0001
13.7 vs 5.4
Exploratory Analyses
BRCAwt/HRD positive
(n = 158)
0.44; P < .0001
9.7 vs 5.4
0.55; P = .0135
11.1 vs 5.6
BRCAwt/HRD negative
(n = 161)
0.58; P = .0049
6.7 vs 5.4
0.47; P = .0003
8.2 vs 5.3
BICR, blinded independent central review; HRD, homologous recombination deficiency; Pbo, placebo.
Press release, June An expanded description of the ARIEL3 results will be presented in a scientific session at a medical meeting in late 2017.
Slide credit: clinicaloptions.com

90. Future Directions

91. Relationship Between MSI and Tumor-Associated Inflammatory Response
Robust tumor-associated inflammatory response
Hypermutation
(10x to 100x increase in mutational load vs MMR-proficient tumors)
Many neoantigens expressed on tumor cells
MSI-H
High PD-1 and/or PD-L1 on tumor-infiltrating inflammatory cells
High PD-L1 on tumor cells
MMR, mismatch repair; MSI, microsatellite instability; MSI-H, microsatellite instability high.
Slide credit: clinicaloptions.com
Le DT, et al. N Engl J Med. 2015;372:

92. MSI Analysis Using Microsatellite Markers
175
189
203
217
231
245
330
Normal
Amount of DNA
220
110
175
189
203
217
231
245
600
Tumor
Amount of DNA
400
MSI, microsatellite instability.
200
Size of DNA Fragments (bp)
Allelic shift in tumor demonstrated by presence of new peaks vs control normal tissue
Slide credit: clinicaloptions.com

93. New Approval: Pembrolizumab
In May 2017, pembrolizumab received accelerated approval from FDA
For MSI-H or MMR-deficient CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
For ALL unresectable or metastatic MSI-H or MMR-deficient SOLID TUMORS (pediatric and adult) that have progressed on prior treatment and with no satisfactory alternative treatment options
CRC, colorectal cancer; MMR, mismatch repair; MSI-H, microsatellite instability high.

94. Pembrolizumab in Pts With Metastatic MSI-High or dMMR Tumors After PD on Prior Tx
Included data from KEYNOTE-016, -164, -012, -028, and -158 for total of 149 pts
MMR testing using standard PCR-based assay for detection of MSI
Additional pts not listed in table included 2 each of breast and prostate cancer; 1 each of bladder, esophageal, sarcoma, thyroid, retroperitoneal adenocarcinoma, SCLC, and RCC with 6 pts achieving CR or PR
Tumor Type n
ORR, % (95% CI)
DoR Range, Mos
CRC 90
36 (26-46)
1.6+ to 22.7+
Non-CRC 59
46 (33-59)
1.9+, 22.1+
Endometrial cancer 14
36(13-65)
4.2+ to 17.3+
Biliary cancer 11
27 (6-61)
11.6+ to 19.6+
Gastric or GEJ cancer 9
56 (21-86)
5.8+ to 22.1+
Pancreatic cancer 6
83 (36-100)
2.6+ to 9.2+
Small intestinal cancer 8
38 (9-76)
1.9+ to 9.1+)
CRC, colorectal cancer; dMMR, mismatch repair deficiency; DoR, duration of response; GEJ, gastroesophageal junction; MMR, mismatch repair; MSI, microsatellite instability; PD, progressive disease; RCC, renal cell carcinoma; SCLC, small-cell lung cancer; Tx, treatment.
Slide credit: clinicaloptions.com
Pembrolizumab [package insert]

95. MSI-High and dMMR in Ovarian Cancer
MSI-H in Unselected Ovarian Cancers
Histologic
Subtype
HNPCC
MSI-High
dMMR
Pooled
Proportion
(95% CI)
Serous
0.42
( )
0.36
( )
0.32
( )
Nonserous
0.57
( )
0.063
( )
0.95
( )
0.68
( )
Mucinous
0.16
( )
0.22
( )
0.26
( )
0.19
( )
 Endometrioid
0.25
( )
( )
0.34
( )
0.29
( )
 Clear cell
0.17
( )
0.10
( )
0.35
( )
0.18
( )
Undifferentiated
1 study
0.24
( )
Allen et al 2000
Alvi et al 2001
Buller et al 2001
Codegoni et al 1999
Dallas et al 2004
Fujita et al 1995
Geisler et al 2001
Gras et al 2001
Han et al 1993
Iwabuchi et al 1995
King et al 1995
Kobayashi et al 1995
Krajinovic et al 1998
Osborne et al 1994
Shih et al 1998
Sood et al 1996
Sood et al 2001
Tangir et al 1996
Combined
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
dMMR, mismatch repair deficiency; HNPCC, hereditary nonpolyposis colorectal cancer; MSI, microsatellite instability.
0.2
0.4
0.6
Proportion (95% CI)
Slide credit: clinicaloptions.com
Pal T, et al. Clin Cancer Res. 2008;14:

96. Conclusions Cytotoxic chemotherapy still has a role in ovarian cancer
Differences in dose and schedule may be important
Role of IP therapy becoming clearer
Angiogenesis is an established target
Bevacizumab now FDA approved
PARP inhibitors are emerging as important therapy
Olaparib, rucaparib, and niraparib now FDA approved
Labels are expanding based on recently reported positive trials
Role of immunotherapy promising in ovarian cancer
Slide credit: clinicaloptions.com

97. Go Online for More CCO Coverage of Ovarian Cancer!
CME-certified text module with key data and expert perspective on managing ovarian cancer ClinicalThoughtTM Commentaries on ovarian cancer with expert discussion and insights
clinicaloptions.com/oncology