Breakfast with Professor Advances in ovarian cancer first-line treatment : The role of anti angiogenics

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1 Breakfast with Professor Advances in ovarian cancer first-line treatment : The role of anti angiogenics CLAUDIO CALAZAN Oncologia D Or Oncologistas Associados

2 First-line treatment : The role of anti angiogenics Focus of Discussion Current standart of care in ovarian cancer for locally advanced/ metastatic disease Inhibiting angiogenesis in upfront Active options Complete and ongoing trials Future Prospects up front

3 Ovarian Carcinoma Mininum Standart of Care Maximum attempt at surgical cytoreduction Chemotherapy following surgery

4 Does Cytoreduction Matter? Residual Disease PFS med, m P value OS med, m P value Microscopic 33,0 < 0,001 71,9 < 0,001 0,1-1 cm 16,8 42,4 > 1 cm 14,1 35,0 Platinun Compounds Response Rate Optimal Suboptimal Clinical CR 95% 75% Pathologic CR 50% 25% Winter WE III, et al. J Clin Oncol. 2007;25:3621.

5 FDA-Approved Drugs in Ovarian Cancer

6 Phase III trials in advanced ovarian cancer: no improvement over platinum/taxane Trial n Regimens compared Outcome GOG Cis/cyclo vs cis/cyclo + doxorubicin Efficacy similar; toxicity worse with triplet GOG Observation vs IP 32 P as consolidation IP 32 P not effective GOG Standard cis/cyclo vs dose-intense cis/cyclo Efficacy similar; toxicity worse with dose intense cis GOG GOG IV cisplatin/iv cyclo vs IP cisplatin/iv cyclo IP more effective/less toxic 386 Cis/cyclo vs cis/pac Cis/pac provides better OS OV Cis/cyclo vs cis/pac Cis/pac provides better PFS and OS GOG GOG GOG GOG Cis/pac vs carbo (AUC 9) IP cis/iv pac PFS improved/toxicity worse with IP 648 Cis/pac vs cis vs pac Cis and cis/pac have similar efficacy; combination better tolerated 550 Cis/pac x6 vs cis/pac x3 2 surgery cis/pac x3 No benefit of 2 surgery 792 Cis/pac vs carbo/pac Efficacy similar; tolerability better with carbo/pac ICON3 2,074 Carbo/pac vs carbo vs cyclo/doxorubicin/cis All 3 regimens have similar efficacy; single-agent carbo better tolerated OVAR Cis/pac vs carbo/pac Efficacy similar; tolerability better with carbo/pac Carbo = carboplatin; cis = cisplatin; cyclo = cyclophosphamide; IP = intraperitoneal; IV = intravenous; pac = paclitaxel Omura, et al. JCO 1989; Varia, et al. JCO 2003; McGuire, et al. JCO 1995 Alberts et al. NEJM 1996; McGuire, et al. NEJM 1996; Piccart, et al. JNCI 2000 Markman, et al. JCO 2001; Muggia, et al. JCO 2000; Rose, et al. NEJM 2004 Ozols, et al. JCO 2003; International Collaborative Ovarian Neoplasm Group. Lancet 2002; du Bois, et al. JNCI 2003

7 Phase III trials in advanced ovarian cancer: no improvement over platinum/taxane Trial n Regimens compared Outcome GOG Cis + either 24 h or 96 h pac Efficacy similar AGO- GINECO 1,282 Carbo/pac vs carbo/pac/epirubicin No benefit of a third agent MITO Carbo/pac x6 topo x4 or surveillance No PFS benefit with topo maintenance GOG IV cis/iv pac vs IP cis/ip pac IP has better efficacy/worse toxicity and QoL GCIG 887 Carbo/pac vs carbo/pac/epirubicin No benefit of a third agent AGO- GINECO 1,308 Carbo/pac topo x4 or surveillance No benefit of topo maintenance GOG Cis/pac pac x3 vs x12 cycles in patients in CR PFS improved with pac x12 cycles/no OS difference in a selected patient population GOG ,312 Carbo/pac vs carbo/pac/gem (2 regimens) vs carbo/pac/topo vs carbo/pac/pld No benefit of a third agent OV Carbo/pac x8 vs cis/topo x4 carbo/pac x4 Efficacy similar; tolerability better with carbo/pac AGO- OVAR9 1,742 Carbo/pac vs carbo/pac/gem No benefit of a third agent Carbo = carboplatin; cis = cisplatin; CR = complete response; gem = gemcitabine; IP = intraperitoneal; IV = intravenous; pac = paclitaxel; PLD = pegylated liposomal doxorubicin; topo = topotecan Spriggs, et al. JCO 2007; du Bois, et al. JCO 2006; de Placido, et al. JCO 2004 Armstrong et al. NEJM 2006; Kristensen, et al. Int J Gynecol Cancer 2003 Pfisterer, et al. JNCI 2006; Markman, et al. JCO 2003; Bookman, et al. JCO 2009 Hoskins, et al. JNCI 2010 Markman, et al. Gynecol Oncol 2009; du Bois, et al. JCO 2010

8 Ovarian Cancer: Initial Chemotherapy JGOG: Dose-Dense Weekly Paclitaxel Treatment Arm n Median PFS (mos) Carboplatin AUC 6 Paclitaxel 180 mg/m 2 3 x wkly Carboplatin AUC 6 Paclitaxel 80 mg/m 2 /wk x P Value.015 (HR: (95% CI: ) OS at 3 yrs: wkly (72.1%) > 3 wkly (65.1%); HR: 0.75 (95% CI: ; P =.03) Katsumata N, et al. Lancet. 2009;374:

9 Ovarian Cancer: Initial Chemotherapy Standard frontline chemotherapy is paclitaxel 175 mg/m 2 plus carboplatin AUC 6-7, every 21 days for 6 cycles Result of several studies over last decade GOG 111 [1] and OV 10 [2] : paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 158 [3] and AGO OVAR-3 [4] : carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334: Piccart MJ, et al. J Natl Cancer Inst. 2000;92: Ozols RF, et al. J Clin Oncol. 2003;21: du Bois AD, et al. J Natl Cancer Inst. 2003;95:

10 Minimal improvement in ovarian cancer mortality rates no new front-line therapy for >15 years Alkylating agents (melphalan or cyclophosphamide) 20 Platinum-based therapy Platinum/taxane therapy Mortality per 100,000 women Year Jemal et al. CA Cancer J Clin 2009

11 Up front treatment in ovarian cancer: The role of anti angiogenics

12 Tumor Angiogenesis and Neovasculature A, Tumors less than 1 mm 3 receive oxygen and nutrients by diffusion from host vasculature. B, Larger tumors require new vessel network. Tumor secretes angiogenic factors that stimulate migration, proliferation, and neovessel formation by endothelial cells in adjacent established vessels. C, Newly vascularized tumor no longer relies solely on diffusion from host vasculature, facilitating progressive growth.

13 VEGF is an early and persistent promoter of tumour angiogenesis 1 4 VEGF VEGF bfgf TGFβ-1 VEGF bfgf TGFβ-1 PLGF VEGF bfgf TGFβ-1 PLGF PD-ECGF VEGF bfgf TGFβ-1 PLGF PD-ECGF Pleiotrophin Continued VEGF expression 3 Tumours continually require VEGF to recruit new vasculature 5 VEGF continues to be expressed throughout tumour progression, even as secondary pathways emerge 2,3,6,7 1. Bergers, Benjamin. Nat Rev Cancer 2003; 2. Kim, et al. Nature 1993; 3. Folkman. In: DeVita, Hellman, Rosenberg, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins;2005; 4. Ferrara, et al. Nat Med Inoue, et al. Cancer Cell 2002; 6. Mesiano, et al. Am J Pathol 1998; 7. Melnyk, et al. J Urol 1999

14 VEGF is highly expressed in ovarian cancer, with multiple effects Switch from benign to malignant growth pattern 1 Formation of the metastases typical of ovarian cancer on the peritoneum 3 Accumulation of ascites, by increasing peritoneal blood vessel permeability Schumacher et al. Cancer Res Ramakrishnan et al. Angiogenesis 2005; 3. Zhang et al. Am J Pathol Trinh, et al. Br J Cancer 2009; 5. Belotti, et al. Cancer Res 2003

15 VEGF levels correlate with ascites volume in preclinical models VEGF enhances permeability of peritoneal vessels causing ascites development 1 5 Ascites VEGF 750 Positive correlation between ascites volume and VEGF concentrations in a mouse model of ovarian cancer 5 Ascites (ml) VEGF (ng/ml) Time (days) 1. Schumacher et al. Cancer Res 2007; 2. Ramakrishnan et al. Angiogenesis Zhang et al. Am J Pathol 2002; 4. Trinh, et al. Br J Cancer 2009; 5. Belotti, et al. Cancer Res 2003

16 Clinical association of VEGF expression with poor survival creates rationale for its inhibition Survival (%) VEGF ( )/(+) VEGF (++) High VEGF levels (n=39) Low VEGF levels (n=31) p<0.01 (n=31) p<0.01 (n=39) Years Yamamoto, et al. BJC 1997

17 Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10): Burger RA. J Clin Oncol. 2007;25(20): VEGF = vascular endothelial growth factor

18 Agents Targeting the VEGF Pathway Anti-VEGF Antibodies VEGF Soluble VEGFRs (bevacizumab) (VEGF-TRAP) Anti-VEGFR Antibodies P P P P VEGFR-1 P P VEGFR-2 Endothelial Cell Podar K, et al. Blood. 2005;105(4): P P Small-Molecule Inhibitors VEGF = vascular endothelial growth factor VEGFR = VEGF receptor

19 GOG0170D: Bevacizumab Progression-Free Survival. 1,0 0,8 0,6 0,4 0,2 0,0 Phase II GOG0170-D AVASTIN (n = 62) 6 m = 0.42 GOG0126 Series (n = 220) Platinum-Resistant Disease 6 m = 0.16 ( SE 0.025) Months on Study Burger et al., Proc Ann Meet ASCO 24:A5009

20 Conclusions -A significant unmet clinical need exists in ovarian cancer, with no treatment innovation over the past 15 years and minimal improvement in outcomes 1 -Ovarian cancer is a VEGF-driven disease, creating a strong rationale to use bevacizumab to improve patient outcomes 2 -Phase II trials indicate that bevacizumab has single-agent activity in ovarian cancer Jemal et al. CA Cancer J Clin 2009; 2. Ramakrishnan, et al. Angiogenesis Burger, et al. JCO 2007; 4. Micha, et al. Int J Gynecol Cancer Penson, et al. JCO 2010

21 GOG-0218 Phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian, primary peritoneal or fallopian tube cancer: A Gynecologic Oncology Group (GOG) study

22 GOG-0218: a randomized, double-blind phase III trial Front-line: epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV N=1,873 R A N D O M I S E 1:1:1 Bev 15mg/kg Carboplatin AUC6 Paclitaxel 175mg/m 2 Placebo q3w Carboplatin AUC6 Paclitaxel 175mg/m 2 Placebo q3w Carboplatin AUC6 Paclitaxel 175mg/m 2 Bevacizumab 15mg/kg q3w Arm I II III 15 months Stratification variables GOG performance status stage/debulking status OV = ovarian; PP = primary peritoneal FT = fallopian tube; Av =Avastin Burger et al. NEJM 2011;365 (26): Massachusetts Medical Society

23 GOG-0218: key eligibility criteria Histologic diagnosis of epithelial OV, PP, or FT cancer Following maximal debulking surgery: stage III optimal (macroscopic residual disease 1 cm) or suboptimal (>1 cm), or stage IV No prior chemotherapy 1 12 weeks after initial surgery GOG PS 0 2 No history of significant vascular events No evidence of intestinal obstruction requiring parenteral support Written informed consent Burger, et al. NEJM 2011

24 Statistical analysis Primary analysis: Comparison of PFS (investigator-assessed) in each bevacizumab arm vs control Disease progression determined according to RECIST or CA-125 only Planned sample size of 1800 based on: 90% power to detect a PFS hazard ratio (HR) 0.77 Secondary analyses: Overall survival (OS), safety, quality of life and correlative laboratory studies Burger, et al. NEJM 2011

25 GOG-0218: disease assessment CP + Pl/B15 (6 cycles) Maintenance Pl/B15 (16 cycles) Post-treatment follow-up Months Imaging* CA-125 Exam Same intervals for all modalities: every 3 months for 2 years, then every 6 months for 3 years, then annually *Conventional CT or MRI Burger, et al. NEJM 2011 (Supplementary information)

26 GOG-0218: baseline characteristics were well balanced between the three arms Characteristic, % Arm I CP + Pl (n=625) Arm II CP + B15 Pl (n=625) Arm III CP + B15 B15 (n=623) Age in years, median (range) 60 (25 86) 60 (24 88) 60 (22 89) GOG PS 0/1/2, % 50/44/7 50/43/6 49/43/8 Stage/debulking status% III (macroscopic, 1 cm) III (>1 cm) IV Histology % Serous Endometrioid Clear cell Mucinous < Tumour grade, % 1/2/3* Not graded 6/16/71 7 *Grade 3 includes all clear-cell tumours Percentages may not total 100% due to rounding or categorisation 5/14/74 7 3/16/74 8 Burger, et al. NEJM 2011

27 PFS significantly improved with bevacizumab plus chemotherapy and continued as a single agent 1.0 I CP + Pl Pl (n=625) II CP + Bev15 Pl (n=625) III CP + Bev15 Av15 (n=623) Median PFS (months) Stratified analysis HR (95% CI) 0.89 ( ) 0.70 ( ) p value one-sided (log rank) * <0.0001* PFS estimate CP + Pl Pl (Arm I) CP + Bev15 Pl (Arm II) CP + Bev15 Bev15 (Arm III) Time (months) PFS analysis determined using RECIST, global deterioration or CA125 progression p value boundary = Burger et al. NEJM 2011;365 (26): Massachusetts Medical Society

28 Significant PFS improvement, censored for CA-125 events and non-protocol therapy CP + Pl Pl (n=625) CP + Bev15 Bev15 (n=623) Median PFS (months) Stratified analysis HR (95% CI) 0.62 ( ) p value one-sided (log rank) <0.0001* PFS estimate CP + Pl Pl 0 CP + Bev15 Av PFS (months) *p value boundary = Data cut-off date: September 29, 2009 Burger et al. NEJM 2011;365 (26): Massachusetts Medical Society

29 GOG-0218: PFS by disease stage and debulking status Arm I CP + Pl Pl Arm II CP + B15 Pl Randomised patients with stage III optimally debulked disease 2,3 Arm III CP + B15 B15 n Median PFS (months) Hazard ratio (95% CI) (0.62, 1.05) 0.66 (0.50, 0.86) Randomised patients with stage III suboptimally debulked disease 3 n ) 242) Median PFS (months) Hazard ratio (95% CI) (0.77, 1.14) 0.78 (0.63, 0.96) Randomised patients with stage IV disease n Median PFS (months) Hazard ratio (95% CI) (0.70, 1.16) 0.64 (0.49, 0.82)

30 GOG-0218: subgroup analyses of PFS Risk factor Total no. of patients Hazard ratio for Bevacizumab (95% CI) Cancer stage and residual lesion size III, macroscopic 1cm Arm II vs Arm I Arm III vs Arm I III, >1cm Arm II vs Arm I Arm III vs Arm I IV Arm II vs Arm I Arm III vs Arm I Histologic type Serous Arm II vs Arm I Arm III vs Arm I Nonserous Arm II vs Arm I Arm III vs Arm I Tumour grade 1 or 2 Arm II vs Arm I Arm III vs Arm I 3 Arm II vs Arm I Arm III vs Arm I ,066 1, bevacizumab better Control better Burger et al. NEJM 2011;365 (26): Massachusetts Medical Society

31 GOG-0218: subgroup analyses of PFS (cont d) Risk factor Total no. of patients Hazard ratio for Bevacizumab (95% CI) GOG performance status score 0 Arm II vs Arm I Arm III vs Arm I or 2 Arm II vs Arm I Arm III vs Arm I Age <60 years Arm II vs Arm I Arm III vs Arm I years Arm II vs Arm I Arm III vs Arm I years Arm II vs Arm I Arm III vs Arm I bevacizumab better Control better Burger et al. NEJM 2011;365 (26): Massachusetts Medical Society

32 GOG-0218: independent review confirms the PFS benefit IRC-assessed PFS analysis CP + Pl Pl (n=625) CP + Bev15 Bev15 (n=623) Investigator-assessed censored PFS analysis CP + Pl Pl (n=625) CP + Bev15 Bev15 (n=623) Median (months) PFS, months Hazard ratio, stratified (95% CI) 0.62 ( ) 0.62 ( )

33 GOG-0218: conclusions GOG-0218 met the primary objective in the front-line treatment of advanced ovarian (epithelial OV, PP and FT) cancer PFS with CP + Bevacizumab Bevacizumab single agent (Arm III) statistically superior to CP (Arm I) alone Survival effect may be masked by discontinuation of drug or subsequent treatment with bevacizumab after trial Treatment regimen was generally well tolerated; adverse events similar to previous bevacizumab studies CP + bevacizumab bevacizumab single agent can be considered as a standard option

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35 Safety data on Bevacizumab

36 GI Perforations with Bevacizumab in Ovarian Cancer Study Burger (GOG 170D) 0/62 (0) Garcia (ASCO 2005) 2/29 (6.9) Wright (ASCO 2006) 4/62 (6.5) Monk (Gyn Oncol 2006) 1/32 (3.1) Wright (Cancer 2006) 2/23 (8.7) Bidus (Gyn Oncol 2006) 0/3 (0) Penson (ASCO 2006) 0/30 Total 16/298 (5.4%) Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinal

37 Bevacizumab - Toxicity Proteinuria (usually G1 G2) Muco-cutaneous hemorrhage Common G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10): Burger RA. J Clin Oncol. 2007;25(20): G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism

38 Summary of safety: GOG-0218 and ICON7 Grade 3 AE, % Pla + chemo (N=601) GOG-0218 a Bev 15 + chemo (N=607) Chemo (N=763) ICON7 Bev chemo (N=746) Hypertension GI perforation/fistula/abscess Proteinuria Wound-healing complication Non-CNS bleeding CNS bleeding ATE VTE Neutropenia b Febrile neutropenia CHF RPLS a Regulatory analysis; b Includes laboratory abnormality for GOG-0218.

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43 Summary Angiogenesis plays a key role in ovarian tumor growth and development Several compounds are potents inhibitors of proangiogenic factors such as VEFGFR, FGFR, and others and demostrating clinical activity in ovarian cancer Today only one agent (bevacizumab) is confirmed to improve PFS vs standart treatment. Waiting for confirmative studies for others (pazopanib, nintedanib, AMG 386) Then biomarkers and subgroups analyses would be the next step to help us the righ drug for the right patients at the right time

44 Thank you!