Targeted therapy in frontline treatment of ovarian cancer The GOG 218 trial showed that adding bevacizumab to carboplatin and paclitaxel chemotherapy followed by bevacizumab maintenance therapy significantly improved progression-free survival compared to chemotherapy alone in patients with newly diagnosed advanced ovarian cancer. Updated results found an overall survival benefit as well. The ICON7 trial found no significant improvement in overall survival with the addition of bevacizumab to chemotherapy, though there was a progression-free survival benefit seen in the high-risk subgroup. Ongoing research continues to evaluate additional targeted agents in the frontline setting to improve outcomes for patients with ovarian cancer.

1. Targeted therapy in frontline treatment
of ovarian cancer
Dr. Rajib Bhattacharjee
Consultant Oncologist
Chittaranjan National Cancer Institute

2. Ongoing phase III first-line
trials in ovarian cancer with
targeted agents
J A Ledermann; Front-line therapy of advanced ovarian cancer: new
approaches, Annals of Oncology, Volume 28, Issue suppl_8, 1
November 2017, Pages viii46–viii50,

3. 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 (0.63-0.82)
ICON7[2] Bevacizumab Front line/maintenance 0.81 (0.70-0.94)
AGO-OVAR12[3] Nintedanib Front line/maintenance 0.84 (0.72-0.98)
AGO-OVAR16[4] Pazopanib Primary maintenance 0.77 (0.64-0.91)
AURELIA[5] Bevacizumab Recurrence, platinum resistant, 1-2 priors 0.48 (0.38-0.60)
TRINOVA-1[6] Trebananib Recurrence, platinum resistant/sensitive, 1-3 priors 0.66 (0.57-0.77)
OCEANS[7] Bevacizumab Recurrent, platinum sensitive, 1 prior 0.53 (0.41-0.70)
ICON6[8] Cediranib Recurrent, platinum sensitive, 1 prior 0.57 (0.44-0.74)
GOG-213[9] Bevacizumab Recurrent, platinum sensitive, 1 prior 0.63 (0.53-0.74)
1. Burger RA, et al. N Engl J Med. 2011;365:2473-2483. 2. Perren TJ, et al. N Engl J Med. 2011;365:2484-2496. 3. du Bois A, et al. Lancet Oncol.
2016;17:78-89. 4. du Bois A, et al. ASCO 2013. LBA5503. 5. Pujade-Lauraine E, et al. J Clin Oncol. 2014;32:1302-1308. 6. Monk BJ, et al.
Lancet Oncol. 2014;15:799-808. 7. Aghajanian C, et al. J Clin Oncol. 2012;30:2039-2045. 8. Ledermann JA, et al. Eur J Cancer.
2013;49(suppl):LBA10. 9. Coleman RL, et al. Lancet Oncol. 2017;18:779-791.

4. Ovarian Carcinoma: Clinical Course
Symptoms
Diagnosis
Chemotherapy #1
Staging
Primary cytoreduction
Interval
Cytoreduction
Progression
Chemo #2 Chemo #3+
Supportive
Care
Death
Consolidation/
Maintenance
Cure
Secondary
CytoreductionSecond-Look

5. Historical Perspective on Current Systemic Treatment of Ovarian
Cancer
IV Cisplatin + IV Paclitaxel
vs.
IV Cisplatin + IV
Cyclophosphamide
PACLITAXEL regimen:
Superior PFS and OS
(N Engl J Med 1996; 334:1; J
Natl Cancer Inst 2000;
93:699)
IV Carboplatin + IV Paclitaxel
vs.
IV Cisplatin + IV Paclitaxel
Equivalent PFS and OS
CARBOPLATIN regimen: More
favorable toxicity profile
(J Clin Oncol 2003; 21:3194)
IV Carboplatin + IV Paclitaxel
vs.
IV Carboplatin + IV Docetaxel
Equivalent PFS and OS
Different toxicity profiles
(J Natl Cancer Inst 2004;
96:1682)

6. Hanahan D, Weinberg R. Hallmarks of Cancer: The Next Generation. Cell. 2011;144(5):646-674.
Sustained Angiogenesis is one of the hallmark feature of solid tumors
Inhibitors of
VEGF signaling

8. Bevacizumab – Mechanism of Action
ABEVMY

10. Bevacizumab – Adverse Effects
Thromboembolism
Hemorrhage
Hypertension
Proteinuria
GI perforation
Delayed Wound healing
Financial toxicity

11. Burger RA, et al. N Engl J Med. 2011;365:2473-2483.
Phase III GOG 218: Addition of Bevacizumab for Primary Therapy in
Stage III/IV Ovarian Cancer
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)
Paclitaxel 175 mg/m2/3 hrs +
Carboplatin AUC 6 Q21D x 6
Placebo Day 1 x 5 begin cycle 2
(n = 625)
Paclitaxel 175 mg/m2/3 hrs +
Carboplatin AUC 6 Q21D x 6
Bevacizumab* Day 1 x 5 begin cycle 2
(n = 623)
Placebo
Q21D
x 15 mos
Placebo
Q21D
x 15 mos
Bevacizumab*
Q21D
x 15 mos
*Bevacizumab 15 mg/kg IV.
Bevacizumab dose – 15mg/kg

12. Patient characteristics
The median age was 60 years and 28% of patients
were >65 years of age.
Approximately 50% of patients had a GOG PS of 0 at
baseline, and 43% score of 1.
Serous adenocarcinoma was the most common
histologic type
Overall, approximately 34% of patients had
resected FIGO Stage III with residual disease < 1cm,
40% had resected Stage III with residual disease >1
cm, and 26% had resected Stage IV disease

13. GOG 218: Investigator-Assessed PFS at
primary analysis
Mos Since Randomization
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
(0.795-1.040)
.16
CP + Bev  Bev 360 (57.8) 14.1
0.717
(0.625-0.824)
< .001
Burger RA, et al. N Engl J Med. 2011;365:2473-2483.
30
20
10
0
100
90
80
70
60
50
40
PFS(%)
0 12 24 36

14. 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 < .0001
Pts censored for CA-125, %
 CP (Arm 1) 0 20
 CP + Bev  Bev (Arm 3) 0 19
Burger RA, et al. ASCO 2010. Abstract LBA1.

15. 30
20
10
0
100
90
80
70
60
50
40
OS(%)
Mos
120 3624 48
625/625/623 442/432/437 173/162/171 46/39/40
Pts at Risk, n
Burger RA, et al. N Engl J Med. 2011;365:2473-2483.
GOG 218: OS at Time of Primary PFS Analysis
primary analysis
Events, n (%) Median, Mos HR* (95% CI) P Value
CP 156 (25.0) 39.3 ‒ ‒
CP + Bev 150 (24.0) 38.7 1.036 (0.827-1.297) 0.76
CP + Bev  Bev 138 (22.2) 39.7 0.915 (0.727-1.152) 0.45
*Stratified analysis.

16. GOG 218: Ascites Predict Treatment Benefit of Bevacizumab
PFS in Pts With Ascites OS in Pts With Ascites
80% had ascites (defined as peritoneal fluid > 50 cm3)
Median OS, Mos
39.9
43.3
P = .035
Ferriss JS, et al. Gynecol Oncol. 2015;139:17-22.
Median PFS, Mos
10.4
15.2
P < .001
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96 108 120
CP
CP + Bev  Bev
PFS(%)
Mos
450 188 78 46 36 28 17 5 1 Arm 1 (chemo)
436 276 109 49 38 31 21 7 2 Arm 3 (ext. bev)
OS(%)
Mos
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96 108 120
450 403 320 237 166 105 56 18 3 Arm 1 (chemo)
436 396 328 249 186 129 62 19 6 Arm 3 (ext. bev)
CP
CP + Bev  Bev

17. Updated final analysis GOG – 218 results
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125085s323lbl.pdf

18. Updated final analysis -PFS
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125085s323lbl.pdf

19. Selected
adverse events

20. Authorspeak…
“Our study shows that bevacizumab plus carboplatin and
paclitaxel, followed by bevacizumab, could be considered a
front-line treatment option for patients with advanced
ovarian cancer….”

21. 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)
Phase III ICON7: Carboplatin/Paclitaxel ± Bev in Newly
Diagnosed Ovarian Cancer
Stratified by HR status, nodal status
Treatment (CPB7.5+) (n = 764)
Control (n = 764)
Bevacizumab 7.5 mg/kg
Carboplatin AUC 5 or 6
Paclitaxel 175 mg/m2
Oza AM, et al. Lancet Oncol. 2015;16:928-936.
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

22. ICON7: PFS
100
75
50
25
17.5 19.9
0
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 (0.83-1.05)
0 6 12 18 30 36 42 48 54 60
MosPts at Risk , n
CP
CP + Bev
764
764
484
604
294
314
239
226
198
182
66
54
24
PFS(%)
Oza AM, et al. Lancet Oncol. 2015;16:928-936.

23. ICON7: Final OS
100
75
50
25
OS(%)
0
0 6 12 18 24 30 36 42 48
MosPts at Risk, n
CP
CP + Bev
764
764
676
707
578
618
476
502
397
401
117
124
54 60
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 (0.85-1.14)
Oza AM, et al. Lancet Oncol. 2015;16:928-936.

24. ICON7: MRC Final OS Subgroup Analyses
Subgroup
Median OS, Mos
HR
(95% CI) nCP CP + Bev CP CP + Bev
All pts 44.6 45.5 58.6 58.0 0.99 (0.85-1.14) 1528
Stage I, II, III (0 cm) 52.3 51.9 NR NR 1.23 (0.93-1.62) 725
Stage III >0, ≤1 cm 42.6 41.9 45.7 44.2 0.95 (0.71-1.26) 301
Stage III >1 cm 36.1 40.2 32.1 39.7 0.84 (0.63-1.11) 290
Stage IV 33.5 38.9 29.4 39.6 0.76 (0.53-1.10) 182
Non-operable 24.9 34.5 20.8 40.4 0.52 (0.21-1.27) 30
Nonhigh risk 49.7 48.4 NR 67.2 1.14 (0.93-1.40) 1026
High risk 34.5 39.3 30.3 39.7 0.78 (0.63-0.97) 502
0.2 0.5 1 2 5
HR (95% CI)
Risk Status
Interaction
P = .01
Disease
Stage
Trend
P = .004
Oza AM, et al. European Cancer Congress 2013. Abstract LBA 6.
Oza AM, et al. Lancet Oncol. 2015;16:928-936.
CP + Bev
Better
CP
Better
Restricted Mean OS, mos

25. ICON7: Final PFS in High-Risk Subgroup
100
75
50
PFS(%)
0
0 6 12 18 24 30 36 42 48 54 60
MosPts at Risk, %
CP
CP + Bev
254
248
109
175
43
53
24
32
18
23
6
5
Nonproportionality test: P < .0001
25
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 (0.61-0.88)
High-risk subgroup: stage III suboptimally debulked, stage IV, or no
debulking surgery, n = 502
Oza AM, et al. Lancet Oncol. 2015;16:928-936.

26. High-risk subgroup: stage III
suboptimally debulked, stage IV,
or no debulking surgery,
n = 502
ICON7: Final OS in High-Risk Subgroup
100
OS(%)
50
9.4
Nonproportionality test: P = .0072
0
0 6 12 18 24 30 36 42 48 54 60
MosPts at Risk, n
CP
CP + Bev
254
248
208
224
156
180
101
135
82
95
21
27
75
25
CP 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 (0.63-0.97)
Oza AM, et al. Lancet Oncol. 2015;16:928-936.

27. Authorspeak…
“The apparently greater effect of bevacizumab in patients with a poor
prognosis is encouraging..”

29. Median PFS – 28.2 v 17.5 mo
HR – 0.76 P-0.0037
Median OS – 100.5 v 62.2 mo
HR – 0.79 P – 0.039

33. Bevacizumab, in combination with carboplatin and paclitaxel
is indicated for the front-line treatment of adult patients
with advanced (International Federation of Gynecology and
Obstetrics (FIGO) stages III B, III C and IV) epithelial ovarian,
fallopian tube, or primary peritoneal cancer

34. Bevacizumab in combination with paclitaxel and
carboplatin is not recommended for first-line treatment of
advanced ovarian cancer (International Federation of
Gynaecology and Obstetrics [FIGO] stages IIIB, IIIC and IV
epithelial ovarian, fallopian tube or primary peritoneal
cancer).

36. • On June 13, 2018, the Food and Drug Administration approved
bevacizumab (Avastin, Genentech, Inc.) for patients with epithelial
ovarian, fallopian tube, or primary peritoneal cancer in combination
with carboplatin and paclitaxel, followed by single-agent
bevacizumab, for stage III or IV disease after initial surgical resection.

37. PARTING QUESTIONS
• Does using Bevacizumab upfront a better strategy or should we save
it for later?
• What would be the dosage schedule – 15mg/kg or 7.5mg/kg?
• Can dose dense chemo replace Bevacizumab?
• Can we use Bevacizumab in neoadjuvant setting?
• Is Bevacizumab cost effective in Indian scenario?

38. Thank You