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2. Incorporation of bevacizumab in first-line treatment of advanced ovarian cancer: results and indications Ursula Matulonis, M.D. Associate Professor of Medicine, Harvard Medical School Director/Program Leader, Medical Gynecologic Oncology Dana-Farber Cancer Institute Boston MA Email: Umatulonis@partners.org

3. Agenda State of the art of treatment for newly diagnosed ovarian cancer Upfront bevacizumab trials Ongoing studies using bevacizumab and other anti-angiogenic agents

4. Basic principles of management Surgery ideally performed by a gynecologic oncologist 1 Staging: involves: --histologic diagnosis --establishes stage --removal of bulk tumor (debulking) --careful inspection of all peritoneal surfaces --inspection/palpation of retroperitoneal nodes +/- removal Extent of debulking is what is left behind after surgery. >1 cm of residual tumor is termed “suboptimal” debulking ≤1 cm is termed “optimal” debulk These distinctions are important for prognosis and treatment planning For neoadjuvant treatment: histological diagnosis should be made by FNA or core biopsy of a solid mass; 3 cycles of platinum/taxane chemotherapy, interval cytoreduction, then completion of 6 cycles total of treatment. 1 Elit et al, Gynecologic Oncology 87(3):260-7, 2002.

5. Standard of Care for pts with advanced epithelial ovarian cancer: 2012 1 If optimally cytoreduced (i.e. ≤ 1cm tumor remaining), options are: *Placement of an IP port and IP/IV tx 2, *IV carboplatin/paclitaxel (q21d or weekly paclitaxel) *Clinical trial. If suboptimally cytoreduced, options are: *IV carboplatin/paclitaxel (q21d or weekly paclitaxel) *clinical trial Neoadjuvant chemotherapy 3 has demonstrated equivalent results to upfront cytoreduction → chemotherapy IV carboplatin and paclitaxel dosing is: Carboplatin AUC 6 via Cockgroft Gault and Paclitaxel 175 mg/m 2 1 NCCN ovarian cancer guidelines, nccn.org (2012 version) 2 Armstrong DK, et al, N Engl J Med 354(1):34-43, 2006. 3 Vergote I et al. N Engl J Med. 2010 Sep 2;363(10):943-53.

6. Clique para editar o título mestre StudyStudy ArmsMedian PFSMedian OS GOG 111 1 (all IV) Cisplatin/cyclophosphamide13.3 mos24.8 mos Cisplatin/paclitaxel18 mos36.9 mos Improvements in OS achieved with paclitaxel, weekly paclitaxel and IP chemotherapy 1 McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 2006 3 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.

7. Clique para editar o título mestre StudyStudy ArmsMedian PFSMedian OS GOG 111 1 (all IV) Cisplatin/cyclophosphamide13.3 mos24.8 mos Cisplatin/paclitaxel18 mos36.9 mos GOG 172 2 IV cisplatin/paclitaxel18.3 mos49.7 mos IP cis/paclitaxel and IV paclitaxel23.8 mos65.6 mos Improvements in OS achieved with paclitaxel, weekly paclitaxel and IP chemotherapy 1 McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 2006 3 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.

8. Clique para editar o título mestre StudyStudy ArmsMedian PFSMedian OS GOG 111 1 (all IV) Cisplatin/cyclophosphamide13.3 mos24.8 mos Cisplatin/paclitaxel18 mos36.9 mos GOG 172 2 IV cisplatin/paclitaxel18.3 mos49.7 mos IP cis/paclitaxel and IV paclitaxel23.8 mos65.6 mos Isonishi et al 3 (all IV) Carbo/paclitaxel q 2117.2 mos3 yrs 65.1% Carbo/paclitaxel qwk28 mos3 yrs 72.1% Improvements in OS achieved with paclitaxel, weekly paclitaxel and IP chemotherapy 1 McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 2006 3 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.

9. Clique para editar o título mestre StudyStudy ArmsMedian PFSMedian OS GOG 111 1 (all IV) Cisplatin/cyclophosphamide13.3 mos24.8 mos Cisplatin/paclitaxel18 mos36.9 mos GOG 172 2 IV cisplatin/paclitaxel18.3 mos49.7 mos IP cis/paclitaxel and IV paclitaxel23.8 mos65.6 mos Isonishi et al 3 (all IV) Carbo/paclitaxel q 2117.2 mos3 yrs 65.1% Carbo/paclitaxel qwk28 mos3 yrs 72.1% Neoadjuvant EORTC study 4 Surgery, then carbo/paclitaxel12 mos29 mos Carbo/paclitaxel, interval debulking, then carbo/paclitaxel 12 mos30 mos Improvements in OS achieved with paclitaxel, weekly paclitaxel and IP chemotherapy 1 McGuire et al, NEJM 334(1):1-6, 1996, 2 Armstrong DK, et al, NEJM 354(1):34-43, 2006 3 Katsumata et al, Lancet 374(9698):1331-8, 2009, 4 Vergote I et al. NEJM 363(10):943-53, 2010.

10. Addition of biologics to upfront chemotherapy: bevacizumab Optimal or Suboptimal stage III or IV Ovarian cancer, peritoneal cancer, tubal cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab ×15 months GOG-218GOG-218 Placebo ×15 months Placebo ×15 months Burger et al, N Engl J Med. 2011 Primary outcome: PFS

11. Study design NEJM 365:2473, 2011

12. 3.8 month PFS improvement for bev with chemotherapy and bev maintenance NEJM 365:2473, 2011 Primary analysis Updated analysis

13. No overall survival benefit with addition of bevacizumab Burger RA et al. N Engl J Med 2011;365:2473-2483 Primary analysis Updated analysis

14. Subgroup analysis NEJM 365:2473, 2011

15. Toxicities NEJM 365:2473, 2011

16. Women with stage II through IV ovarian cancer were randomized to: 1) Carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles OR 2) Carboplatin + paclitaxel plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival (primary endpoint) and interim overall survival. Not blinded and no placebo. ICON7 Perren et al, NEJM 2011

17. Results A total of 1528 women from 11 countries were enrolled. Median age was 57 years 90% had epithelial ovarian cancer 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (HR 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004) So, 1.5 month PFS difference. NO overall survival benefit. Perren et al, NEJM 2011 ICON7: addition of bevacizumab improves PFS but no effect on overall survival

18. ICON7: toxicities Bevacizumab was associated with more toxic effects: 5 pt deaths in study overall: 4 in bev arm (2 GIP, 1 intracranial bleeding and 1 of neutropenic sepsis). Specific toxicities: -Hypertension of grade 2 or higher: (18% bev vs. 2% with chemotherapy alone). -Thromboembolic events of grade 3 or higher (7% with bevacizumab vs. 3% with standard) -Bleeding was higher with bevacizumab (mostly grade 1 mucocutaneous bleeding) - Higher # of GIP’s in the bev group (10 pts in bev arm versus 3 pts in non bev arm) Perren et al, NEJM 2011

19. Updated Progression-free Survival and Overall Survival Curves Perren TJ et al. N Engl J Med 2011;365:2484-2496 Perren et al, NEJM 2011 Unplanned analyses

20. Bevacizumab for newly diagnosed advanced ovarian cancer Gastrointestinal events and hypertension were higher in bevacizumab arms 1,2 To date, no overall survival advantage has been observed with addition of bevacizumab to upfront carboplatin and paclitaxel chemotherapy 1,2 Thus, our group does not use bevacizumab for newly diagnosed ovarian cancer 1 Burger et al, NEJM 2011 2 Perren et al, NEJM 2011

21. Other anti-angiogenics being tested for newly diagnosed ovarian cancer AMG386 is a first in class, peptide-Fc fusion protein (peptibody) that neutralizes the interaction between Tie2 receptor and angiopoietin 1 and angiopoietin 2. AMG386 targets a parallel angiogenic pathway from VEGFR. BIBF1120 (nintedanib) is an oral anti-angiogenic TKI with activity against VEGFR, PDGFR, and FGFR

22. AMG386: results in recurrent cancer AMG386 has been tested in a randomized phase II study of weekly paclitaxel plus AMG386 versus weekly paclitaxel alone in patients with recurrent platinum resistant ovarian cancer. Pts were randomized 1:1:1: to either AMG 10mg/kg, 3 mg/kg or placebo. Results: Non-significant prolongation of PFS from 4.6 mos for paclitaxel and placebo to 7.2 mos for paclitaxel and AMG386 at a dose of 10mg/kg (p = 0.23). Karlan et al, JCO 2012

23. BIBF1120: results in recurrent ovarian cancer BIBF1120: Tested in a double-blinded randomized phase II study versus placebo for up to 9 months in patients with recurrent ovarian cancer whose cancer responded to the most recent chemotherapy in the second-line or greater setting. 36 week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P =.06). OS not different between both arms: HR for OS was 0.84 (95% CI, 0.51 to 1.39; P =.51). Ledermann et al, JCO 2011

24. Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer StudyAgents being testedPrimary Endpoint GOG 252 (NCT00951496) n=1500 1) IV Carboplatin/IV weekly Paclitaxel 2) IP Carboplatin/IV weekly Paclitaxel 3) IP Cisplatin/IV 3hr P/day 8 IP Paclitaxel. All arms contain bevacizumab during chemo and Maintenance. PFS

25. Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer StudyAgents being testedPrimary Endpoint GOG 252 (NCT00951496) n=1500 1) IV Carboplatin/IV weekly Paclitaxel 2) IP Carboplatin/IV weekly Paclitaxel 3) IP Cisplatin/IV 3hr P/day 8 IP Paclitaxel. All arms contain bevacizumab during chemo and Maintenance. PFS GOG 262 (NCT01167712) n=625 1) Carbo/Pac, 2) Carbo/weekly Pac (both arms all IV) Bevacizumab is optional for both arms PFS

26. Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer StudyAgents being testedPrimary Endpoint GOG 252 (NCT00951496) n=1500 1) IV Carboplatin/IV weekly Paclitaxel 2) IP Carboplatin/IV weekly Paclitaxel 3) IP Cisplatin/IV 3hr P/day 8 IP Paclitaxel. All arms contain bevacizumab during chemo and Maintenance. PFS GOG 262 (NCT01167712) n=625 1) Carbo/Pac, 2) Carbo/weekly Pac (both arms all IV) Bevacizumab is optional for both arms PFS LUME-Ovar 1 (NCT01015118) n=1300 1) Carboplatin/Paclitaxel or 2) Carboplatin/Paclitaxel + BIBF1120 Eligibility: stage IIB-IV cancer PFS

27. Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer StudyAgents being testedPrimary Endpoint GOG 252 (NCT00951496) n=1500 1) IV Carboplatin/IV weekly Paclitaxel 2) IP Carboplatin/IV weekly Paclitaxel 3) IP Cisplatin/IV 3hr P/day 8 IP Paclitaxel. All arms contain bevacizumab during chemo and Maintenance. PFS GOG 262 (NCT01167712) n=625 1) Carbo/Pac, 2) Carbo/weekly Pac (both arms all IV) Bevacizumab is optional for both arms PFS LUME-Ovar 1 (NCT01015118) n=1300 1) Carboplatin/Paclitaxel or 2) Carboplatin/Paclitaxel + BIBF1120 Eligibility: stage IIB-IV cancer PFS TRINOVA-3 (NCT01493505) n=2000 1) IV Carbo/Pac + placebo + placebo maintenace for 18 months 2) IV Carbo/Pac/AMG386 plus AMG386 maintenance for 18 months Eligibility: stage III or IV cancer PFS

28. Conclusions Bevacizumab added to upfront chemotherapy for newly diagnosed ovarian cancer patients prolongs PFS but does not prolong overall survival. Other agents are undergoing phase III testing