GOG-172: Survival Outcomes

Transcription

1 CHEMOTHERAPY

2 GOG-172: Survival Outcomes Progression-Free Survival Overall Survival Proportion Progression-Free Rx Group IV IP PF Failed Total IV: 18 mos IP: 24 mos HR: 0.80, P = Months on Study IV: 50 mos IP: 66 mos HR: 0.75, P = 0.03 Rx Group IV IP Alive Dead Total Months on Study Armstrong DK, et al. N Engl J Med. 2006;354(11):

3 Combined Analysis of GOG 114 and 172

4 GOG 252

5 JGOG: Dose-Dense Weekly Paclitaxel Epithelial Ovarian or Peritoneal Stage II - IV I Paclitaxel 180 mg/m 2 Carboplatin AUC = 6 x6-9 No prior therapy Stratified: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS II Carboplatin AUC = 6 Paclitaxel 80 mg/m 2 /w x3 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS and OS with dose-dense regimen Accrual: 637 pts (intent-to-treat) Katsumata N, et al Lancet 374:1331 8, 2009

6 JGOG: Dose-Dense Weekly Paclitaxel 1.0 Proportion Progression-Free Carboplatin Paclitaxel (n = 319) Median = 17.2 m Carboplatin Paclitaxel (Dose-Dense) (n = 312) Median = 28.0 m Updated (Median observation 6.4 y): PFS HR (95% CI) = 0.71 ( ) p = Months on Study Katsumata N, et al Lancet 374:1331 8, 2009

7 GOG 262 Primary and Subgroup Analyses of Progression-free Survival, According to Treatment Group Chan JK et al. N Engl J Med 2016;374:

8 ICON 8

9 GOG218: CP +/- Bevacizumab (22) Epithelial Ovarian or Primary Peritoneal Cancer Suboptimal and Macroscopic-Optimal Cytoreduction Collaborative design (GOG, NCI, Genentech) I Paclitaxel 175 mg/m 2 (3 h) Carboplatin AUC=6.0 Placebo q21d* x 6 Placebo (14 m total) II Paclitaxel 175 mg/m 2 (3 h) Carboplatin AUC=6.0 Bevacizumab 15 mg/kg q21d* x 6 Placebo (14 m total) III Paclitaxel 175 mg/m 2 (3 h) Carboplatin AUC=6.0 Bevacizumab 15 mg/kg q21d* x 6 Bevacizumab (14 m total) Open: Closed: Accrual: 26-Sep Aug pts *starting with C2 Burger RA, et al. J Clin Oncol 28:18s, 2010 (LBA1)

10 Investigator-Assessed PFS Median FU: 17.4 mos Proportion PFS (%) Arm I CP + PLA PLA (n = 625) Arm II CP + BEV PLA (n = 625) Arm III CP + BEV BEV (n = 623) Patients with event, n (%) 375 (60) 405 (67) 363 (71) Median PFS (mos) HR (stratified) (95% CI) ( ) ( ) One-sided log-rank p value.0218 a <.0001 a CP (arm I) + BEV (arm II) + BEV BEV (arm III) Time (mos since randomization) a p value boundary =.0116 PFS = progression-free survival; FU = follow-up; HR = hazard ration; CI = confidence interval. Burger et al, 2010.

11 ICON7: CP +/- Bev Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer Optimal or Suboptimal Cytoreduction, Stage I - IV GCIG Trial (MRC, AGO, ANZGOG, GEICO, GINECO, NCIC, NSGO) Primary Endpoint: PFS I Paclitaxel 175 mg/m 2 (3 h) Carboplatin AUC=6.0 x 6 II Paclitaxel 175 mg/m 2 (3 h) Carboplatin AUC=6.0 Bevacizumab 7.5 mg/kg q21d* x 6 Bevacizumab (36 wks total) Open: 20-Oct-06 *starting with C1 or C2 Closed: 16-Feb-09 Accrual: 1528 pts Perren, et al. ESMO 2010 (LBA4)

12 ICON7 PFS: Updated Control 17.4 Research 19.8 Kristensen et al, 2011.

13 OV21/PETROC: A Randomized Gynecologic Cancer Intergroup (GCIG) Phase II Study of Intraperitoneal (IP) vs. Intravenous (IV) Chemotherapy Following Neoadjuvant Chemotherapy and Optimal Debulking Surgery in Epithelial Ovarian Cancer Co-Chairs Helen J MacKay and Diane Provencher On behalf of the OV21/PETROC Investigators CCTG, NCRI (UK), GEICO and SWOG

14 What have I learned? 1. Intraperitoneal chemotherapy is very effective, especially if surgery successful, but without Bevacizumab 2. Weekly taxol is more effective in Japan 3. Bevacizumab is helpful, but costly, and does not improve overall survival 4. Maintenance taxol does not help 5. There may be a role for intraperitoneal chemotherapy after interval debulking

15 SURGERY

16 EORTC 55971: Ovarian Neoadjuvant Epithelial Ovarian, Fallopian, or Peritoneal Cancer Stage IIIC IV with minimum of FNA biopsy (pelvic mass) Primary Endpoint: OS Planned combined analysis with MRC CHORUS study I Maximal Cytoreduction Cisplatin- or Carboplatin-based Chemo (second agent not specified) cycles Optional: Interval Cytoreduction II No Initial Surgery Cisplatin- or Carboplatin-based Chemo (second agent not specified) cycles Optional: Interval Cytoreduction (stable or responding disease) Open: Closed: Target Accrual: 21-Sep Dec pts Vergote I, et al. N Engl J Med 363:943-53, 2010

17 EORTC-NCIC: OS (ITT) Median 29 m Median 30 m HR for IDS (95% CI): 0.98 (0.85, 1.13) Vergote I, et al. N Engl J Med 363:943-53, 2010

18 Overall Survival in the Intention-to-Treat Population and Overall Survival According to Treatment Received and Status with Respect to Residual Tumor. Vergote I et al. N Engl J Med 2010;363:

19 CHORUS Lancet 2015; 386:

20 CHORUS SURVIVAL CURVES 4 5

21 2935 per group, matched cohort

22 Trends in the use of Neoadjuvant Chemotherapy for Advanced Ovarian Cancer in the United States Melamed, et al, Gynecol Oncol 2016

23 Olympia MITO-13 Fagotti, et al, AJOG 2013

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26 What have I learned? 1. Be careful about the results of the neoadjuvant treatment studies. The approach is not worse and the results tell us that the patients do not represent all women with ovarian cancer 2. Surgery, like many things in cancer, is a targeted treatment 3. If a surgeon is not prepared to do aggressive debulking surgery in appropriate patients, then refer them to someone who will

27 TARGETED THERAPIES

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29 Definitions Prognostic biomarker Predictor of disease outcome regardless of the intervention. (eg., presence of metastasis) Predictive biomarker Predictor of disease outcome only for a particular type of intervention (eg., presence of a hormone receptor, platinum free interval) Integral vs. Integrated

30 Required Sample Size Randomized vs Ideal Trial Design Randomized design Probability of Response Std. Therapy Std.+Targeted Required Sample size Ideal 20% 60% 60 Traditional 20% 24% 4040 Design parameters: H 0 : P 0 >P 1, alpha=0.05, beta=0.10, Fisher s Exact test

31 56

32 Red arrows point to target lesion in T0, T1, and T2 CTP study of a neoadjuvant patient in the weekly paclitaxel treatment arm (patient 27). Chaan S. Ng et al. Clin Cancer Res 2017;23: by American Association for Cancer Research

33 TCGA, Doug Levine

34 Poly (ADP)-ribose polymerase: PARP If PARP is inhibited, SSB repair is prevented, leading to increased double-strand DNA breaks

35 Olaparib Consolidation Ledermann, et al, NEJM, 2012

36 ENGOT-OV16 / NOVA Phase 3 Randomized Double-Blind Trial of Maintenance with Niraparib Versus Placebo in Patients with Platinum Sensitive Ovarian Cancer NCT Sponsor: Tesaro ENGOT Lead: NSGO Primary Investigators Mirza (ENGOT); Matulonis (US) mansoor@rh.regionh.dk

37 ENGOT-OV16 / NOVA Phase 3 Randomized Double-Blind Trial of Maintenance with Niraparib Versus Placebo in Patients with Platinum Sensitive Ovarian Cancer Platinum-sensitive ovarian cancer with high-grade serous histology (N=490) (N=180) gbrca mut (N=310) Non-gBRCA mut 2:1 Randomization 2:1 Randomization Niraparib 300 mg Placebo Niraparib 300 mg Placebo Endpoint assessment Endpoint assessment Primary Endpoint PFS in gbrca mut and non-gbrca mut cohorts (HRD positive subset followed by overall) Key Secondary Endpoints Overall survival (OS) Patient-reported outcomes (PRO) Chemotherapy-free interval (CFI) Safety and tolerability PFS2 Evaluation of QTc NSGO mansoor@rh.regionh.dk PFS=progression-free survival; QTc=corrected QT interval. Accessed February 26, 2015.

38 Kaplan Meier Estimates of Progression-free Survival. Mirza MR et al. N Engl J Med DOI: /NEJMoa

39 PARP INHIBITOR STUDIES WORLDWIDE

40 SOLO 1

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43 Generation and regulation of antitumour immunity. I Mellman et al. Nature 480, (2011) doi: /nature10673

44 Recurrent Measurable OC, PPC, FTC PS Prior Regimens PFI* < 12 Months Stratify by PFI < 6 months vs. PFI 6 12 months Disease Assessment R A N D O M I Z E NRG GY003 Schema Initiation Maintenance Nivolumab Reference Regimen Nivolumab** 3 mg/kg IV q 2 weeks x 4 Experimental Regimen Nivolumab 3 mg/kg IV + Ipilimumab*** 1 mg/kg IV q 3 weeks x 4 Nivolumab** 3 mg/kg IV q 2 weeks Maximum of 42 doses Nivolumab** 3 mg/kg IV q 2 weeks Maximum of 42 doses Weeks TR Time Points *Platinum-Free Interval ** Nivolumab *** Ipilimumab Primary Endpoint: Response Rate within 6 months, RECIST 1.1 N = 48 patients per arm, two-stage design Protocol-directed therapy until progression or unacceptable toxicity

45 IMMUNOTHERAPY STUDIES WORLDWIDE

46 Targeting Angiogenesis by targeting VEGFR and PDGFR Bevacizumab VEGF PDGF VEGFR VEGF PDGF PDGFR Vascular Endothelial Cell Pericyte/Fibroblast/ Vascular Smooth Muscle Vascular permeability Pazopanib Sorafenib Sunitinib Cell survival, proliferation Axitinib Inhibition of progression Vascular formation, maturation

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48 MRC Clinical Trials Unit at UCL

49 Rationale for combining anti-pdl-1 with anti-vegf therapy VEGF exerts an immunosuppressive effect in cancer Inverse correlation between VEGF levels and presence of TILs Zhang L et al N Engl J Med 2003;348: VEGFR2 is selectively expressed in Treg CD4+FoxP3 + cells and VEGF directly suppresses activation of T Cells H. Suzuki Eur J of Immunology, vol. 40, no. 1,2010; Gavalas NG et al British Journal of Cancer (2012) 107, 1869 In response to VEGF, immature DCs acquire a pro angiogenic phenotype and contribute to ovarian cancer progression Coukos G Br J Cancer. 2005;92:

50 Rationale for PARPi and Angiogenesis Inhibitors

51 Study Schema: NRG-GY004 Target accrual: 450 pts Stratify: Germline BRCA status (testing required on all pts) Prior anti-angiogenic Plat-free interval Primary study endpoint: Efficacy (PFS) Key secondary study endpoints: Patient-related outcomes (NFOSI- DRS-P) assessments continue postprogression Additional efficacy endpoints

52 ANGIOGENESIS STUDIES WORLDWIDE

53 What have I learned about targeted therapies? 1. Olaparib and Bevacizumab are the first FDA approved targeted therapies in Ovarian Cancer 2 This is an exciting time for clinical trials research in Ovarian Cancer 3. Our challenge is to pick the right treatment for the individual patient

54 My Ovarian Cancer Journey 1. Am I smarter? Not sure about that! 2. Have I learned much? Absolutely 3. Am I older? What happened to this poor guy s hair???

55 THANK YOU