Current options and future opportunities in platinum-resistant ovarian cancer. Aknar Calabrich AMO

Transcription

1 Current options and future opportunities in platinum-resistant ovarian cancer Aknar Calabrich AMO

2 LACOG CONFERENCE 2013 Current options and future opportunities in platinum-resistant ovarian cancer Aknar Calabrich AMO Abril, 2013

3 PFS in Advanced Ovarian Cancer Du Bois et al. Cancer 2009

4 Recurrent Ovarian Cancer: Effect of Platinum- Free Interval and Survival Day ys Perce entage 0-3 Prog 0-3 Non-PD 3-12 Mos Mos 18+ Mos PFS, days OS, days Response, % Pujade-Lauraine E, et al. ASCO Abstract 829.

5 Treatment History Diagnosis Progression Symptoms Primary Chemo x 6 Recurrent Chemo x 6 5 mos? Staging Now What?

6 Practice Guideline 2013 Patients who progress on two consecutive therapy regimens without evidence of clinical benefits have diminished likelihood of benefitting from additional therapy. Single-agent non-platinumbased if platinum resistant Docetaxel Etoposide, oral Gemcitabine Liposomal doxorubicin Paclitaxel, weekly Topotecan

7 Summary of Phase III Single-Agent Trials: Recurrent Ovarian Cancer Drug A Drug B N TTP (wks) P OS (wks) P Comment Topotecan Paclitaxel vs 14 NS 61 vs 43 NS 50% Cross-over Paclitaxel (bolus) Paclitaxel (weekly) vs 26 NS 34 vs 59 NS Less toxicity w/ weekly Oxaliplatin Paclitaxel vs 14 NS 42 vs 37 NS 74% platinum resistant PLD Topotecan vs 17 NS 60 vs 57 NS 54% platinum resistant; OS benefit in platinumsensitive subgroup PLD Paclitaxel vs 22 NS 46 vs 56 NS All pts taxanenaive Topotecan Treosulfan vs vs nd 3 rd line therapy PLD Gemcitabine vs 13 NS 59 vs 55 NS PLD Gemcitabine vs 20 NS 55 vs 50 NS 56% platinum resistant PLD or Topotecan Canfosfamide vs 9 < vs 37 (PLD: 62 vs Topo: 47) <.0001 ASSIST-1 trial All 3 rd line

8 PLD + Trabectedin vs PLD: Phase III Registration Trial Recurrent ovarian cancer One prior regimen Evaluable and measurable disease Platinum sensitive and resistant Accrual goal: 650 patients Primary endpoint: OS Other endpoints: PFS, RR, safety Monk BJ, et al. J Clin Oncol, R A N D O M I Z E PLD 30 mg/m 2 + q3 weeks Trabectedin 1.1 mg/m 2 PLD 50 mg/m 2 q 4 wks Translational research Pharmacokinetics Pharmacogenomics Pharmacoeconomics Quality of life Circulating tumor cells

9 OVA-301: PFS (TFI < 6 mos) Percent of Subjects PLD 3.7 mos Trabectedin+PLD 4.0 mos PFS events: 163 HR: 0.95 ( ) P =.7540 # censored: RR: 12% vs 13% (rad review) Progression-free survival (months) No. Subjects at Risk PLD Trabectedin/PLD Monk BJ, et al. J Clin Oncol. 2010

10 Other Potentially Active Agents Single agents Altretamine Capecitabine Cyclophosphamide Ifosfamide Irinotecan Melphalan Oxaliplatin Hormonal Therapy Anastrozole Letrozole Leuprolide acetate Megestrol acetate Tamoxifen

11 Chemotherapy vshormones N = 241 platinum/taxane-resistant 1.00 PFS 1.00 OS 0.75 Chemotherapy (PLD vs Pac-Wkly) 0.75 Chemotherapy (PLD vs Pac-Wkly) d vs 62 d P = d vs 278 d P = Tamoxifen months 0.00 Tamoxifen months 50 Kristensen GB, et al. IGCS Abstract 2008_1175.

12 What Is Ovarian Cancer? Picture clipping

13 Different diseases

14 Different diseases Bowtell D 2010

15 Altered pathways in HGS-OvCa

16

17 GOG 170 Series: Track Record Bevacizumab Sorafenib Temsirolimus PFS Dasatinib Imatinib Gefitinib Mifepristone Enzastaurin Trastuzumab Vorinostat Lapatinib Response Rate (%)

18 Role of VEGF throughout ovarian cancer development creates rationale for its inhibition VEGF promotes angiogenesis in early-stage ovarian cancer 1 VEGF transduction can transform normal ovarian epithelium into ascites-producing cancers 2,3 VEGF enhances permeability of peritoneal vessels causing ascites development 2,4,5 Ascites (ml) 10 5 Ascites VEGF VEGF (ng/ml) positive correlation between ascites volume and VEGF expression in preclinical models 6,7 Clinically, VEGF expression is associated with ovarian cancer recurrence Time (days) 0 1. Hefler, et al. Clin Cancer Res 2007; 2. Ramakrishnan, et al. Angiogenesis 2005; 3. Schumacher, et al. Cancer Res 2007; 4. Zhang, et al. Am J Pathol 2002; 5. Trinh, et al. BJC 2009; 6. Belotti, et al. Cancer Res Alvarez, et al. Clin Cancer Res 1999; 8. Hazelton, et al. Clin Cancer Res 1999

19 Anti-VEGF agents

20 Anti-VEGF therapies in ovarian cancer Target Class Agent Phase Ligand VEGF-A MoAb Bevacizumab III VEGR Receptor Soluble decoy receptor VEGF trap VEGFR2 MoAb Ramucirumab II VEGFR + PDGFR TKI Sunitinib II VEGFR, PDGFR, Raf TKI Sorafenib II VEGFR + PDGFR TKI Motesanib II VEGFR, EGFR, RET TKI Vandetanib II II/III VEGFR + PDGFR TKI Pasopanib III (ongoing) VEGFR + PDGFR + FGFR TKI Cediranib III (ongoing) VEGFR + PDGFR + FGFR TKI BIBF 1120 III (ongoing)

21 AURELIA trial design Platinum-resistant OC a 2 prior anticancer regimens No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoidinvolvement involvement PD 6 mosafter 4 cycles platinum-based therapy R 1:1 Chemotherapy BEV 15 mg/kg q3w b + chemotherapy Treat to PD/toxicity Treat to PD/toxicity Optional BEV monotherapy c Investigator s choice (without BEV) Stratification factors: Chemotherapy selected Prior anti-angiogenic therapy Treatment-free interval (<3 vs 3 6 months from previous platinum to subsequent PD) Chemotherapy options (investigator s choice): Paclitaxel 80 mg/m 2 days 1, 8, 15, & 22 q4w Topotecan 4 mg/m 2 days 1, 8, & 15 q4w (or 1.25 mg/m 2, days 1 5 q3w) PLD 40 mg/m 2 day 1 q4w PD = progressive disease; PLD = pegylated liposomal doxorubicin a Epithelialovarian, primary peritoneal or fallopian tube cancer b Or10 mg/kg q2w c 15 mg/kg q3w, permitted on clear evidence of progression

22 Baseline characteristics: Generally balanced between arms, some differences between cohorts Weekly paclitaxel PLD Topotecan Characteristic, % CT (N=55) BEV + CT (N=60) CT (N=64) BEV + CT (N=62) CT (N=63) BEV + CT (N=57) Median age, years (range) (25 80) (25 79) (32 77) (39 78) (35 84) (26 80) Age 65 years Histology at diagnosis a Serous/adenocarcinoma Clear cell FIGO stage III/IV Grade at diagnosis Missing prior chemotherapy regimens PFI <3 months b ECOG PS PFI = platinum-free interval. a Multipleanswers possible. b Fromlast platinum to subsequent PD

23 Progression-free survival: Overall population Estimated pr robability CT (N=182) BEV + CT (N=179) Events, n (%) 166 (91) 135 (75) Median PFS, months (95% CI) HR (not stratified) (95% CI) Log-rank p-value a 3.4 ( ) 0.48 ( ) < ( ) a 2-sided, not stratified No. at risk: CT BEV + CT Time (months) Median duration of follow-up: 13.9 months (CT arm) vs13.0 months (BEV + CT arm)

24 Summary of best overall response rates (RECIST, CA- 125 criteria or both) Patients (% %) a [ ] p< ,6 30, a [ ] 28,8 51,7 7,9 CT 10.4 a [ 2.4 to 23.2] 18,3 BEV + CT 19.5 a [ ] 22,8 3,3 0 Overall population Weekly paclitaxel cohort PLD cohort Topotecan cohort a Differencein overall response rate; 95% CI with Hauck Anderson continuity correction

25 Adverse events

26 Additional grade 3 adverse events in 2% of patients in either arm CT (n=181) BEV + CT (n=179) Patient ts (%) HFS = hand-foot syndrome a Preferred terms. b Includes abdominal pain upper

27 Conclusions AURELIA is the first randomized phase III trial in platinum-resistant OC to demonstrate: Benefit with biologic therapy Benefit with a combination regimen versus monotherapy Bevacizumabcombined with chemotherapy should be considered an option in platinum-resistant ovarian cancer

28 Anti-VEGF to treat malignant ascites Intravenous afliberceptfor treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebocontrolled study Malignant ascites Fatal bowel perforation Lancet Oncol Feb;13(2):154-62

29 Poly (ADP-Ribose) Polymerase (PARP) If PARP is inhibited, SSB repair prevented, leading to increased double strand DNA breaks

30 PARP inhibition and tumor-selective synthetic lethality DNA damage (SSBs) DNA replication (accumulation of DNA DSBs) PARP PARP inhibition Normal cell with functional HR pathway HR-deficient tumor cell (e.g. BRCA 1/2 -/- ) HR-mediated DNA repair Cell survival Tumor-selective cytotoxicity Cell death Impaired HRmediated DNA repair DSB, double-strand break; HR, homologous recombination; SSB, single-strand break Farmer H et al. Nature 2005;434: Bryant HE et al. Nature 2005;434: McCabe N et al. Cancer Res 2006;66:

31 Olaparib in platinum-sensitive ovarian cancer Proportion of patients progression free Olaparib Placebo N of event: total patients (%) 60:136 (44) 93:129(72) Median PFS (months) HR 0.35 (CI 95% ) p< Treatment Olaparib Placebo Time from randomization (months) Ledermannet al. N EnglJ Med. 2012

32 Does platinum free interval affect response to PARPi? Results from Phase I expansion cohort 50 patients, all but two with ovarian cancer and BRCA mutations received olaparib20 mg BID continuously ORR RECIST or GCIC: 20/50 (40%) Fong et al. JCO 2010

33 Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer Olaparib 400 mg bid (n=33) Olaparib 100 mg bid (n=24) Response by RECIST, n (%)* 11 (33) 3 (13) Platinum-sensitive 1/7 (14) 2/8 (25) Platinum-resistant 10/26 (38) 1/16 (6) Response by RECIST and/or GCIC, n (%) 20 (61) 4 (17) Median DOR (range) 290 ( ) 269 ( ) Median PFS months *Confirmed responses; there were an additional 3 unconfirmed responders in the 400 mg cohort (unconfirmed ORR 42%) Duration of response is underestimated as some patients are still responding Lancet Jul 24;376(9737):245-51

34 Iniparibe Phase II trial carboplatin+gemcitabin+ iniparib (BSI-201) Platinunsensitive Platinumresistant n RR 65% 25% PFS 9.5m 6,44m Penson et al. ASCO 2011 Birrer et al. ASCO 2011

35 Developmental Strategies Chemotherapy with biologics Chemotherapy combinations Biological combinations Patient profiling biomarker driven design

36 Target Agents in Development for Advanced Ovarian Cancer AMG-386 (Tie2) Pazopanib BIBF-1120 IMC-1121B Fosbretabulin IMC-3G3 IGF-1R inhibitors Rapalogs PARPi mtor inhibitors EGFR inhibitors Aurora kinase inhibitors PDGR inhibitors Imatinib Cediranib Her-2 receptior antagonist

37 Chemotherapy and Others in Development for Advanced Ovarian Cancer Epothilones Ixabepilone Patupilone BMP-1350 (karenitecan) NKTR-102 EC-145 Farletuzumab Canfosfamide

38 Utilizing the Folate Receptor: EC145 Vintafolide Folate-Vinca conjugate Relevant for imaging targeting and therapy Reddy JA, et al. Cancer Res. 2007;67:

39 EC145: Novel Folate Receptor Targeted Therapeutic Randomized Phase II, Platinum-resistant ovarian Prior therapy: no more than 2 priors Regimen: PLD 50 mg/m 2 IBW q 28 days PLD 50 mg/m 2 IBW q 28 days + EC mg weeks 1 and 3 (cycle: 28 days) Toxicity similar in both arms: total AEs, SAEs, TETs Arm PFS HR P PLD 11.7 wks - - PLD+EC wks Naumann W, et al. ASCO Abstract LBA5012b.

40 PROCEED A Randomized Double-Blind Phase 3 Trial Comparing EC145 and Pegylated Liposomal Doxorubicin (PLD/Doxil /Caelyx ) in Combination Versus PLD in Participants With Platinum-Resistant Ovarian Cancer Primary endpoint: PFS Platinum-resistant OC Participants must have primary or secondary platinum-resistant ovarian cancer 2 prior anticancer regimens Participants must have primary or secondary platinum-resistant ovarian cancer Exclusion criteria: PD 6 mos after of first dose of initial platinum-based therapy R Doxolipossomal+ Placebo Doxolipossomal+ EC145

41 Saracatinib and Paclitaxel in Platinum-resistant Ovarian Cancer (SaPPrOC) A RandomisedPlacebo-controlled Trial of Saracatinib(AZD0530) Plus Weekly Paclitaxel in Platinum Resistant Ovarian, Fallopian Tube or Primary Peritoneal Cancer Primary endpoint: PFS Platinum-resistant OC Participants must have primary or secondary platinum-resistant ovarian cancer At least 2 lines prior hemotherapy Exclusion criteria: previous weekly paclitaxel R Paclitaxel + Placebo Paclitaxel + Saracatinib

42 TRINOVA-2: Trebananibin Ovarian Cancer-2 A Phase 3, Randomized, Double-Blind Trial of PegylatedLiposomal Doxorubicin (PLD) Plus AMG 386 or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer Primary endpoint: PFS Platinum-resistant OC Subjects with platinum-free interval (PFI) < 12 months from their last platinum based therapy one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound. 2 prior anticancer regimens R Doxolipossomal+ Placebo Doxolipossomal+ AMG 386

43 Summary and Future Directions Despite the many advances in therapeutic options for recurrent ovarian cancer, many controversies remain Finding the optimal treatment paradigms for ovarian cancer patients will remain the goal for improving outcomes Understanding of molecular basis of ovarian cancers helps to develop rational treatments

44 Summary and Future Directions Despite the many advances in therapeutic options for recurrent ovarian cancer, many controversies remain Finding the optimal treatment paradigms for ovarian cancer patients will remain the goal for improving outcomes Understanding of molecular basis of ovarian cancers helps to develop rational treatments

45 THANK YOU!