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Clique para editar o título mestre 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: [email protected] Agenda • State of the art of treatment for newly diagnosed ovarian cancer • Upfront bevacizumab trials • Ongoing studies using bevacizumab and other anti-angiogenic agents Basic principles of management • • Surgery ideally performed by a gynecologic oncologist1 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. 1Elit et al, Gynecologic Oncology 87(3):260-7, 2002. Standard of Care for pts with advanced epithelial ovarian cancer: 20121 • If optimally cytoreduced (i.e. ≤ 1cm tumor remaining), options are: *Placement of an IP port and IP/IV tx2, *IV carboplatin/paclitaxel (q21d or weekly paclitaxel) *Clinical trial. • If suboptimally cytoreduced, options are: *IV carboplatin/paclitaxel (q21d or weekly paclitaxel) *clinical trial • Neoadjuvant chemotherapy3 has demonstrated equivalent results to upfront cytoreduction → chemotherapy • IV carboplatin and paclitaxel dosing is: Carboplatin AUC 6 via Cockgroft Gault and Paclitaxel 175 mg/m2 1NCCN ovarian cancer guidelines, nccn.org (2012 version) DK, et al, N Engl J Med 354(1):34-43, 2006. 3Vergote I et al. N Engl J Med. 2010 Sep 2;363(10):943-53. 2Armstrong Improvements in OS achieved with paclitaxel, weekly paclitaxel and IP chemotherapy Clique para editar o título mestre Study Study Arms Median PFS Median OS GOG 1111 (all IV) Cisplatin/cyclophosphamide 13.3 mos 24.8 mos Cisplatin/paclitaxel 18 mos 36.9 mos 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. Improvements in OS achieved with paclitaxel, weekly paclitaxel and IP chemotherapy Clique para editar o título mestre Study Study Arms Median PFS Median OS GOG 1111 (all IV) Cisplatin/cyclophosphamide 13.3 mos 24.8 mos Cisplatin/paclitaxel 18 mos 36.9 mos GOG 1722 IV cisplatin/paclitaxel 18.3 mos 49.7 mos IP cis/paclitaxel and IV paclitaxel 23.8 mos 65.6 mos 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. Improvements in OS achieved with paclitaxel, weekly paclitaxel and IP chemotherapy Clique para editar o título mestre Study Study Arms Median PFS Median OS GOG 1111 (all IV) Cisplatin/cyclophosphamide 13.3 mos 24.8 mos Cisplatin/paclitaxel 18 mos 36.9 mos GOG 1722 IV cisplatin/paclitaxel 18.3 mos 49.7 mos IP cis/paclitaxel and IV paclitaxel 23.8 mos 65.6 mos Carbo/paclitaxel q 21 17.2 mos 3 yrs 65.1% Carbo/paclitaxel qwk 28 mos 3 yrs 72.1% Isonishi et al3 (all IV) 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. Improvements in OS achieved with paclitaxel, weekly paclitaxel and IP chemotherapy Clique para editar o título mestre Study Study Arms Median PFS Median OS GOG 1111 (all IV) Cisplatin/cyclophosphamide 13.3 mos 24.8 mos Cisplatin/paclitaxel 18 mos 36.9 mos GOG 1722 IV cisplatin/paclitaxel 18.3 mos 49.7 mos IP cis/paclitaxel and IV paclitaxel 23.8 mos 65.6 mos Carbo/paclitaxel q 21 17.2 mos 3 yrs 65.1% Carbo/paclitaxel qwk 28 mos 3 yrs 72.1% Surgery, then carbo/paclitaxel 12 mos 29 mos Carbo/paclitaxel, interval debulking, then carbo/paclitaxel 12 mos 30 mos Isonishi et al3 (all IV) Neoadjuvant EORTC study4 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. Addition of biologics to upfront chemotherapy: bevacizumab GOG-218 Optimal or Suboptimal stage III or IV Ovarian cancer, peritoneal cancer, tubal cancer Paclitaxel Paclitaxel Paclitaxel Carboplatin Carboplatin Carboplatin Placebo Bevacizumab Bevacizumab Placebo Placebo ×15 months ×15 months Bevacizumab ×15 months Primary outcome: PFS Burger et al, N Engl J Med. 2011 Study design NEJM 365:2473, 2011 3.8 month PFS improvement for bev with chemotherapy and bev maintenance Primary analysis Updated analysis NEJM 365:2473, 2011 No overall survival benefit with addition of bevacizumab Primary analysis Updated analysis Burger RA et al. N Engl J Med 2011;365:2473-2483 Subgroup analysis NEJM 365:2473, 2011 Toxicities NEJM 365:2473, 2011 ICON7 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. Perren et al, NEJM 2011 ICON7: addition of bevacizumab improves PFS but no effect on overall survival 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: 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 Updated Progression-free Survival and Overall Survival Curves Unplanned analyses Perren TJ et al. N Engl J Med 2011;365:2484-2496 Perren et al, NEJM 2011 Bevacizumab for newly diagnosed advanced ovarian cancer • Gastrointestinal events and hypertension were higher in bevacizumab arms1,2 • To date, no overall survival advantage has been observed with addition of bevacizumab to upfront carboplatin and paclitaxel chemotherapy1,2 • Thus, our group does not use bevacizumab for newly diagnosed ovarian cancer 1Burger et al, NEJM 2011 2 Perren et al, NEJM 2011 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 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 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 Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer Study Agents being tested Primary 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 Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer Study Agents being tested Primary 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 Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer Study Agents being tested Primary 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 Ongoing studies testing anti-angiogenics in newly diagnosed ovarian cancer Study Agents being tested Primary 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 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