ASCO- GYN Abstracts 8/3/2011. Susana Campos, MD, MPH. Boston Mass. Prevention. Maintenance. Recurrent Disease.

Transcription

1 ASCO- GYN Susana Campos, MD, MPH Dana Farber Cancer Institute Boston Mass Prevention Maintenance Recurrent Disease Abstracts 5001: Effect of screening on ovarian cancer mortality in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer randomized screening trial. 5003: Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). 5004: A phase II trial of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GC) in patients with platinum-sensitive recurrent ovarian cancer. 5005: A phase II trial of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GC) in patients with platinum-resistant recurrent ovarian cancer 5007: OCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC). Upfront Therapy 5006: Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer. 5023: Independent radiologic review of GOG218, a phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian (EOC), primary peritoneal (PPC) or Fallopian tube cancer (FTC). Experimental Therapy 5008 :Activity of cabozantinib (XL184) in advanced ovarian cancer patients (pts): Results from a phase II randomized discontinuation trial (RDT). 1

2 The role of screening? Study design & Results Aim: Evaluate effect of screening on mortality for ovarian cancer using CA- 125 & transvaginal ultrasound (TVU) 10 US screening centers 78,216 women recruited (55-74 years) R A N D O M I Z E Intervention arm (n=39,105) Annual screening (CA-125 x 6 yrs & TVU x 4 yrs) 212 Ov Ca = 118 deaths (56%) 3,285 FP s = 166 SAE s Usual care (n=39,111) 176 Ov Ca = 100 deaths (57%) Participants & health care providers received screening test results All followed for up to 13 years for cancer diagnoses & death Primary outcome: ovarian cancer mortality Secondary outcomes: ovarian cancer incidence, complications associated with screening exams & diagnostic procedures Buys et al. J Clin Oncol 2011;29 (suppl; abstr 5001) 2

3 Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinumsensitive relapsed serous ovarian cancer Jonathan A. Ledermann Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003) PARP inhibition and tumor-selective synthetic lethality γh2ax SSB PARPi DSB Normal HR repair DNA replication fork arrest and collapse Impaired HR repair RAD51 Alternative error-prone repair HR-based repair Chromosome stability Cell survival Chromosomal instability Cell death HR, homologous recombination; SSB, single-strand break; DSB, double-strand break Farmer H et al. Nature 2005;434: ; Bryant HE et al. Nature 2005;434:

4 Homologous recombination repair deficiency in ovarian cancer 10 15% of epithelial ovarian cancers are deficient in homologous recombination repair due to BRCA1 or BRCA2 mutations 1 Up to 50% of high-grade serous ovarian cancer patients could be deficient in homologous recombination repair because of: 2 Germ-line or somatically acquired BRCA1 or BRCA2 mutations Epigenetic inactivation of BRCA1 BRCA1/BRCA2-independent defects in the homologous recombination pathway 1. Bast Jr, RC et al. Nat Rev Oncol 2009;9: ; 2. Press JZ et al. BMC Cancer 2008;8:17 Maintenance Olaparib: Study design Patients Platinum-sensitive highgrade serous ovarian cancer 2 previous platinum regimens Maintained PR or CR following last platinum regimen Olaparib 400mg bid, orally (n=136) Randomized 1:1 Placebo (n=129) Primary endpoint PFS by RECIST Secondary endpoints TTP by CA-125 (GCIG criteria) or RECIST, OS, safety 82 sites in 16 countries Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003) 4

5 Time to progression by CA125 (GCIG) or RECIST Proportion of patients progression free At risk (n) Olaparib Placebo 0 0 Randomized treatment Placebo Olaparib 400 mg bid Olaparib Placebo No. of events: Total patients (%) 66:136 (48.5) 106:129 (82.2) Median TTP (months) Hazard ratio 0.35 (95% CI, ) P< Time from randomization (months) Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003) Tolerability Olaparib (n=136) Placebo (n=129) AEs more commonly reported on olaparib than placebo (by >10%) Nausea 68% 35% Fatigue 49% 38% Vomiting 21% 14% Anemia 17% 5% AEs leading to treatment discontinuation 2.2% 0.8% Dose reductions and interruptions 23% 7% Majority of AEs CTCAE grade 1 or 2 Most frequent CTCAE grade 3 events Olaparib: fatigue (9 pts), anemia (7 pts) Placebo: abdominal pain and fatigue (4 pts each) Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003) 5

6 Conclusions The study achieved primary objective: Olaparib significantly prolonged PFS First study to demonstrate statistically significant benefit of maintenance treatment for platinum-sensitive relapsed serous ovarian cancer 50% of olaparib and 16% of placebo patients still on treatment at time of the analysis Olaparib well tolerated and toxicities consistent with those of previous studies Further studies will be performed to determine the role of olaparib in the routine treatment of ovarian cancer Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003) A phase II trial of iniparib in combination with gemcitabine/carboplatin in patients with Platinum-Sensitive ROC R. T. Penson Platinum-Resistant ROC M. J. Birrer Penson et al. J Clin Oncol 2011;29 (suppl; abstr 5004) Birrer et al. J Clin Oncol 2011;29 (suppl; abstr 5005) 6

7 Study details Multicenter, single-arm phase II study Patients with epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma Treatment (21-day cycles) Carboplatin: AUC 4, IV, day 1 Gemcitabine: 1000 mg/m 2, IV, days 1 and 8 Iniparib: ib 5.6 mg/kg, IV, days 1, 4, 8, and 11 Primary endpoint: ORR (RECIST 1.0) Secondary endpoints: Safety, PFS Penson et al. J Clin Oncol 2011;29 (suppl; abstr 5004) Results: platinum-sensitive disease Patients with platinum-sensitive disease (relapse 6 months following primary treatment termination) Analysis for first 41 patients ORR of 65 % PFS:9.4 months No indication of relationship between BRCA status and objective response Safety profiles: consistent with previous studies Conclusions Iniparib + GC demonstrated activity in patients with platinum-sensitive recurrent ovarian cancer No unexpected toxicities Penson et al. J Clin Oncol 2011;29 (suppl; abstr 5004) 7

8 Results: platinum-resistant disease Patients with platinum-resistant disease (relapse 2-6 months following primary treatment termination) Analysis patients n=48 ORR of 25% CBR: 81 % median PFS 6.4 months (95% CI, 3.0-NE) Safety profiles consistent with previous studies Conclusions Iniparib + GC demonstrated activity in patients with platinum-resistant recurrent ovarian cancer No unexpected toxicities Birrer et al. J Clin Oncol 2011;29 (suppl; abstr 5005) ASCO 2011 PARP Studies Ab. Title Author N = Results Comments 2520 Ph I Olaparib + Carbo BRCA+ Ov /Br pts 3102 Ph I MK-4827 Adv BrCA+/-Ov 5003 R Ph II Olaparib or placebo Plat-S ov after Plat resp 5004 Ph II Iniparib + Carbo/Gem Plat-S 5005 Ph II Iniparib + Carbo/Gem Plat-R 5025 Sequence Specific efects of Olaparib/Carbo 5028 Ph I Olaparib/Cediranib Lee J ov 83% Clin benefit C =AUC5; O=400 mg bid d 1-7 q 21d Schelman 60 MTD=300 mg d1-21 q28; 12 (20%) PR Ledermann 265 PFS mg bid) vs 4.8 mos. Penson R 41 ORR = 65% PFS 9.4 mos Birrer M 48 ORR = 25% PFS = 6.4 mos. Hays JL Cell lines Liu J ov O Then C is less effective C = 30 & O = 200 bid; 56% RR DLT not reached > 2 prior plat Maintenance BrCa status independent BrCa status independent 8

9 Angiogenesis is a target for anti-cancer therapy 1 7 Bevacizumab VEGFR c-kit PDGFR VEGFR PDGFR Tumour cell VEGF-A Endothelial cell P P P P P P P P P P P P P P P P P P P P Pericyte/ Stromal cell Sunitinib Sorafenib Temsirolimus Everolimus Cell proliferation P13K Ras Raf AKT Mek mtor Erk Transcription factors Nucleus Angiogenesis Cell adhesion Apoptosis Cell survival Cell differentiation Sunitinib Sorafenib Sorafenib 1. Rini. Clin Cancer Res 2007;13: ; 2. Faivre et al. Nat Rev Drug Disc 2007;6:734 45; 3. Homsi and Daud. Cancer Control 2007;14:285 94; 4. Andrae et al. Genes Dev 2008;22: ; 5. Kerbel. N Engl J Med 2008;358: ; 6. Sonpavde et al. Expert Opin Investig Drugs 2008;17:253 61; 7. Ma and Adjei. CA Cancer J Clin 2009;59: ICON7: a phase III Gynaecologic Cancer InterGroup (GCIG) trial of adding bevacizumab to standard chemotherapy in women with newly diagnosed epithelial ovarian, primary peritoneal or fallopian tube cancer Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Philip Beale, Andreas Cervantes, Amit Oza on behalf of GCIG ICON7 collaborators (MRC/NCRI, AGO-OVAR, OVAR, GINECO, NSGO, ANZGOG, GEICO, NCIC-CTG) CTG) ESMO

10 ICON7: Study Design Frontline EOC, PP or FT cancer Stage I-IIA IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Stratification variables: Stage / surgery Time since surgery GCIG group Carboplatin AUC 6* Paclitaxel 175 mg/m 2 Carboplatin AUC 6* Paclitaxel 175 mg/m 2 Bevacizumab 7.5 mg/kg Primary endpoint: PFS Secondary endpoints: OS, RR, safety, QOL, cost- effectiveness, translational No IRC present 12 months *Might vary based on GCIG group. Omit cycle 1 bevacizumab if < 4 weeks from surgery. on Alive Without Progre ession Proporti ICON7 PFS Benefit: Academic Analysis CP ESMO 2010 CP CPB7.5+ Events, n (%) 392 (51) 367 (48) Median, months Log-rank test P = HR (95% CI) 0.81 ( ) Time (months) Number at risk CP CPB Perren T, et al. Annals Oncol. 2010;21(suppl 8). Abstract LBA4. CPB

11 ASCO 2011 Kristensen G et al J Clin Oncol 29: 2011 (suppl; abstr LBA5006) 1.00 ICON7: Preliminary Analysis of Overall Survival* ESMO 2010 Proportion Surviving CP CPB7.5+ Patients with event, n (%) 130 (17) 111 (15) Log-rank test P = Hazard ratio (95% CI) 0.81 ( ) 1-year survival rate, % Anti-VEGF after progression, n (%) 30 (4) 14 (2) Time (months) Number at risk CP CPB *Based on immature OS data (241 of 715 required events, 16% of all patients) as required by regulatory authorities (approved by IDMC and TSC). Perren T, et al. Annals Oncol. 2010;21(suppl 8). Abstract LBA4. 11

12 ASCO 2011 Kristensen G et al J Clin Oncol 29: 2011 (suppl; abstr LBA5006) Frontline: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV N = 1800 (planned) GOG-0218: Schema R A N D O M I Z E 1:1:1 BEV 15 mg/kg Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Arm I II Stratification variables: GOG performance status (PS) Stage / debulking status Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 BEV 15 mg/kg III Burger RA, et al. J Clin Oncol. 2010;28(18s). Abstract LBA1. Cytotoxic (6 cycles) Maintenance (16 cycles) 15 months 12

13 GOG-0218: Investigator-Assessed PFS sion Free rtion Surviving Progress Propor CP (Arm I) + BEV (Arm II) Patients with event, n (%) Arm I CP (n = 625) 423 (67.7) Arm II CP + BEV (n = 625) 418 (66.9) Median PFS, months Stratified analysis HR (95% CI) ( ) One-sided P value (log rank) 0.080* + BEV BEV maintenance (Arm III) Months Since Randomization Arm III CP + BEV BEV (n = 623) 360 (57.8) ( ) < * Burger RA, et al. J Clin Oncol. 2010;28(18s). Abstract LBA1. *P value boundary = GOG 218: Estimates of PFS as determined by the IRC b PFS as determined by the IRC b Arm I CP (n=625) Arm II CP + BEV (n = 625) c Arm III CP + BEV BEV (n=623) c Patients with events Median, mos d Hazard ratio, stratified e % CI 0.779, , sided log-rank P-value f.2663 <.0001 a Events prior to cycle 7 from the concurrent CP + BEV and CP + BEV BEV arms (Arms II and III) were pooled for analysis b Censored for non-protocol therapy Burger RA et al J Clin Oncol 29: 2011 (suppl; abstr 5023) 13

14 GOG-0218: Overall Survival Analysis At time of final PFS analysis (January 2010) Arm I CP (n = 625) Arm II CP + BEV (n = 625) Arm III CP + BEV BEV (n = 623) roportion Surviving Pr Patients with events, n (%) 156 (25.0) 150 (24.0) 138 (22.2) 1.0 Median OS, months Stratified analysis HR (95% CI) ( ) ( ) One-sided P value CP (Arm I) + BEV (Arm II) + BEV BEV maintenance (Arm III) Months Since Randomization Burger RA, et al. J Clin Oncol. 2010;28(18s). Abstract LBA1. Will bevacizumab have a role in the upfront management of ovarian cancer? GOG 252 GOG

15 OCEANS: A randomized, double-blinded,,placebo- controlled, phase III trial of chemotherapy with or without bevacizumab in patients with platinumsensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer PI = Carol Aghajanian Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) OCEANS: Study schema Platinum-sensitive recurrent OC a Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) Stratification variables: Platinum-free interval (6 12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) CG + PL CG + BV C AUC 4 G 1000 mg/m 2, d1 & 8 PL q3w until progression C AUC 4 G 1000 mg/m 2, d1 & 8 BV 15 mg/kg q3w until progression CG for 6 (up to 10) cycles BV = bevacizumab; PL = placebo a Epithelial ovarian, primary peritoneal, or fallopian tube cancer 15

16 OCEANS: Patient characteristics Characteristic CG + PL (n=242) CG + BV (n=242) Median age, years (range) (28 86) (38 87) Age 65 years, % Race, % White Other ECOG PS 0, % Histologic subtype, % Serous Mucinous/clear cell Other Platinum-free interval, % 6 12 months >12 months Cytoreductive surgery for recurrent disease, % Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) ree Prop portion progression f No. at risk CG + PL CG + BV OCEANS: Primary analysis of PFS CG + PL (n=242) CG + BV (n=242) Events, n (%) 187 (77) 151 (62) Median PFS, months (95% CI) ( ) ( ) Stratified analysis HR (95% CI) Log-rank p-value ( ) < Months Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) 16

17 OCEANS: PFS subgroup analyses Median PFS (months) Baseline risk factor No. of CG + PL CG + BV patients (n=242) (n=242) HR (95% CI) All patients ( ) Platinum-free interval, ( ) months > ( ) Cytoreductive surgery Yes ( ) for recurrent disease No ( ) Age, years < ( ) CG + BV better CG + PL better ( ) Baseline ECOG PS ( ) ( ) HR Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) OCEANS: Objective response % Difference: 21.1% p< PR = 61 PR = 48 CR = 9 CG + PL (n=242) CR = 17 CG + BV (n=242) Duration of response CG + PL (n=139) CG + BV (n=190) Median, months HR (95% CI) ( ) a Compared for descriptive purposes only p< a Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) 17

18 OCEANS: Interim OS 1.0 Proportion alive CG + PL (n=242) CG + BV (n=242) Events, n (%) 78 (32) 63 (26) 0.4 Median OS, months (95% CI) (26.4 NE) (30.0 NE) Stratified analysis HR (95% CI) ( ) Log-rank p-value a Months No. at risk: CG + PL CG + BV NE = not estimable a p-value does not cross pre-specified boundary of Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) OCEANS: Treatment exposure Treatment delivered Chemotherapy CG + PL (n=233) CG + BV (n=247) Median No. of cycles (range) 6 (1 10) Patients receiving 7 10 cycles, % Carboplatin Gemcitabine Bevacizumab/placebo Median No. of cycles (range) 10 (1 36) 6 (1 10) (1 43) Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) 18

19 OCEANS: Study drug discontinuation Patients, % CG + PL (n=242) CG + BV (n=242) Patients received BV/PL treatment Not yet discontinued BV/PL treatment 7 12 Discontinued BV/PL treatment Disease progression per RECIST Clinical progression 1 2 Adverse event (AE) 5 23 Physician s decision to discontinue treatment 8 11 Patient s decision to discontinue treatment Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) OCEANS: Overview of AEs CG + PL CG + BV Patients, % (n=233) (n=247) Any AE Serious AE Grade 3 5 AE Grade 3 5 AE of special interest Grade 5 AE <1 a <1 b a Acute myocardial infarction in one patient b Intracranial hemorrhage in one patient Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) 19

20 OCEANS: AEs of special interest Patients, % CG + PL (n=233) CG + BV (n=247) ATE, all grades 1 3 VTE, grade CNS bleeding, all grades <1 1 Non-CNS bleeding, grades CHF, grades Neutropenia, grade Febrile neutropenia, grade Hypertension, grade 3 <1 17 Fistula/abscess, all grades <1 2 GI perforation, all grades 0 0 a Proteinuria, grade RPLS, all grade 0 1 Wound-healing complication, grades ATE = arterial thromboembolic event; CHF = congestive heart failure; GI = gastrointestinal; RPLS = reversible posterior leukoencephalopathy syndrome; VTE = venous thromboembolic event a Two GI perforations occurred 69 days after last BV dose Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) Conclusions: OCEANS Statistically significant & clinically relevant benefit with addition of bevacizumab to chemotherapy in patients with recurrent, platinum sensitive EOC, PPC, and FTC Improved PFS: HR (p<0.0001); median months Improved ORR and duration of response OS data not yet mature Safety data consistent with bevacizumab profile No GI perforations and no new safety signals First phase III trial of an anti-angiogenic agent to demonstrate clinical benefit for Platinum-Sensitive recurrent disease Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007) 20

21 Activity of cabozantinib (XL184) in advanced ovarian cancer patients: Results from a phase II randomized discontinuation trial Ronald J. Buckanovich Buckanovich et al. J Clin Oncol 2011;29 (suppl; abstr 5008) Cabozantinib: background MET (membrane receptor for hepatocyte growth factor) found in low levels in most normal tissues MET upregulated in many tumors, including ovarian cancer MET upregulation results in more invasive and aggressive behavior of tumor cells, resulting in metastasis Hypoxia resulting from angiogenesis inhibition further upregulates MET Hypoxia also stimulates the expression of VEGF Cabozantinib simultaneously blocks MET and VEGFR2 21

22 Study details Patients (n=68) with epithelial OC and progressive measurable disease (mrecist) n=28 pt-resistant n=17 pt-sensitive n=6 unknown status Treatment Cabozantinib: 100 mg qd PO for 12 weeks Treatment week 12: based on response: PR: patients t continued open-label l cabozantinib ib SD: randomization cabozantinib vs placebo PD: discontinued Primary endpoint: ORR per mrecist in first 12 weeks, PFS in randomized period Buckanovich et al. J Clin Oncol 2011;29 (suppl; abstr 5008) Results ORR at 12 wks (n=51 evaluable) PR 24%, SD 58%, PR pt-resistant 18% PR pt-sensitive 29% CA125 response (n=40 with 1 post-baseline result) 18% Median follow up 4 months Median duration of response and PFS not reached Most common AEs Grade 3: hand-foot syndrome (10%), diarrhea (8%), fatigue (4%) Dose reductions and permanent discontinuations for Aes 43% and 10%, respectively Median maximum increase in hemoglobin Hbin anemic pts (Hb < 11 g/dl): 1.9 g/dl Conclusion Cabozantinib exhibits clinical activity in patients with advanced disease, regardless of prior platinum status Buckanovich et al. J Clin Oncol 2011;29 (suppl; abstr 5008) 22

23 ASCO 2011 PI3 Kinase Endometrial Ab. Title Author N = Results Comments 5013 Ph II Ridaforolimus in Recurrent/Locally Adv Ph II Everolimus & Letrozole in Recurrent 5015 R Ph II Temsirolimus vs. Tem & Megace & Tamoxifen Meas Adv or Recurr; GOG0248 Mackay 30 eval PR = 7.7% SD = 15% (7 mos.) Mucositis & Anorexia = 64% Slomovitz 32 CR = 5% PR = 16% SD = 21% (CB = 42 vs 21% of E alone) Fleming G 20 vs. 21 T alone to 2 nd phase (30% RR) T & HT (14%) but 35% DVT 40 mg/d on d 1-5 q wk PO E = 10 mg po L = 2.5 mg po If recurr prev chemo allowed only 5009 R Ph II Oza A 64 vs. CB= 35% (all SD) vs. BrCa status Ridaforolimus vs. Prog or Chemo in Recurrent/ Meas St III-IV Adv % PFS 3.8 vs. 1.9 mos HR = 0.53 Fav R independent 5016 Predictive Biomarker for mtor Response Meyer L 28 PTEN/PS6K/Kras mutations not helpful; Kras Wt predictive? Used Evero study in recur 21% CB Gyn Onc Summary 2011 Bevaciumab active and tolerable in front-line and recurrent ovarian cancer GI perforation if >2 lines of prior therapy or obstruction PARPi data evolving 3 options in platinum sensitive recurrent ovarian cancer (+Gemcitabine, +PLD, +Paclitaxel) PI3K pathway activated in endometrial cancer 23