Optimal adjuvant therapy for colon cancer is FOLFOX for 6 cycles YES

Transcription

1 Optimal adjuvant therapy for colon cancer is FOLFOX for 6 cycles YES Bassel F. El-Rayes 1

2 Background Standard of care for resected stage III colon cancer is six months of adjuvant oxaliplatin-based therapy FOLFOX4/mFOLFOX6, CAPOX regimens are used interchangeably Addition of oxaliplatin to 5-FU adds an absolute improvement in DFS at 5 years of 5-7% (HR 0.8) Oxaliplatin is associated with cumulative dose-dependent neurotoxicity 12.5% grade 3 neuropathy with 6 months of FOLFOX Shorter duration treatment without loss of efficacy would be of benefit to patients and health care resources Lombardi L, et al. Cancer Treat Rev. 2010;36(Suppl 3): S34-S41. André T, et al. J Clin Oncol. 2009;27(19):

3 Prospective Pooled Analysis of Six Phase III Trials Investigating Duration of Adjuvant Oxaliplatin-based therapy (3 vs. 6 months) for Patients with Stage III Colon Cancer: The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration Qian Shi, Alberto F. Sobrero, Anthony F. Shields, Takayuki Yoshino, James Paul, Julien Taieb, Ioannis Souglakos, Rachel Kerr, Roberto Labianca, Jeffrey A. Meyerhardt, Franck Bonnetain, Toshiaki Watanabe, Ioannis Boukovinas, Lindsay A. Renfro, Axel Grothey, Donna Niedzwiecki, Valter Torri, Thierry Andre, Daniel J. Sargent, Timothy Iveson ASCO Annual Meeting 2017

4 IDEA Trials Summary Trial Regimen(s) Stage III Colon Cancer Patients * Enrolling Country TOSCA CAPOX or FOLFOX Italy SCOT CAPOX or mfolfox UK, Denmark, Spain, Australia, Sweden, New Zealand IDEA France CAPOX or mfolfox France C80702 mfolfox US, Canada HORG CAPOX or FOLFOX4 708 Greece ACHIEVE CAPOX or mfolfox Japan *Only stage III colon cancer patients were included in the primary analysis Presented by: Qian Shi, PhD on behalf of IDEA collaborators ASCO Annual Meeting

5 Study Overview Objective To evaluate the non-inferiority (NI) of 3m compared with 6m of adjuvant oxaliplatin-based treatment in stage III colon cancer Primary Endpoint: Disease-free survival (DFS) Approach Prospectively-designed, pooled analysis of individual patient data from six concurrently conducted phase III randomized trials Pre-planned Subgroup Analyses: By regimen and T/N stage 5

6 Rationale for Non-inferiority Margin Historical Data from MOSAIC 5FU/LV + Oxaliplatin vs. 5FU/LV 24% relative risk reduction; 6.9% in 3-year DFS rate IDEA Non-inferiority Design Oxaliplatin-based Treatment: 3m vs. 6m 12% relative risk increase (upper 95% CI) NI Margin: DFS HR = % in 3-year DFS rate (upper 95% CI) 6

7 Results: mitt Population N patients 12,834 Total DFS events 3,263 (96% of planned) ECOG PS 0 / 1 79% / 21% N1 / N2 72% / 28% T1-2 13% T3 66% T4 21% FOLFOX 89% / power CAPOX at one-sided significance 60% level / 40% of Data frozen on Feb 1 st,

8 Patient Characteristics Patient characteristics * 1% of PS 2 in FOLFOX treated patients 3m Arm (N=3870) FOLFOX 6m Arm (N=3893) 3m Arm (N=2554) CAPOX 6m Arm (N=2517) Median Age, years ECOG PS * 0 77% 77% 82% 81% 1 22% 22% 18% 19% T Stage T1-2 13% 14% 13% 12% T3 68% 67% 63% 63% T4 19% 19% 24% 25% N Stage N1 72% 73% 71% 71% N2 28% 27% 29% 29% 8

9 Adverse Events FOLFOX CAPOX Adverse Events 3m Arm 6m Arm p-value 1 3m Arm 6m Arm p-value 1 Overall G2 G3-4 Neurotoxicity G2 G3-4 Diarrhea G2 G3-4 32% 38% 14% 3% 11% 5% 32% 57% 32% 16% 13% 7% < % 24% < % 3% < % 7% 48% 37% 36% 9% 13% 9% <.0001 <

10 Non-inferiority Hypothesis Testing Statistical Conclusions Under Different Scenarios 3m TRT better Superiority Non-inferiority Not proven 6m TRT better One-sided Type I Error Rate = Power = 90% Require 3390 DFS Events Inferiority Hazard Ratio Non-Inferiority Margin Piaggio et al. JAMA 2012;308(24):

11 Primary DFS Analysis (mitt) Statistical Conclusions 3m TRT better 6m TRT better Not proven DFS HR = % CI, 1.00 to 1.15 Hazard Ratio Non-Inferiority Margin TRT: treatment 11

12 Summary 3m (vs. 6m) treatment: higher treatment compliance 3m (vs. 6m) treatment: substantially lower (G2+) neurotoxicity FOLFOX: 17% (3m) vs. 48% (6m) CAPOX: 15% (3m) vs. 45% (6m) The DFS non-inferiority of 3m oxaliplatin-based adjuvant therapy was not established in overall stage III colon caner 12

13 Statistically vs Clinically Meaningful In the IIT population 6 months of chemotherapy improves DFS by 0.9% over 3 months 3 months has significantly less side effects including neuropathy The real question is: Are there subgroups that have higher clinical benefit justifying 6 months? 13

14 DFS Comparison by Risk Group and Regimen Risk Group Regimen 3m TRT better 6m TRT better DFS HR; 95% CI T1-3 N1 FOLFOX Not proven 1.10; 0.96 to 1.26 T1-3 N1 CAPOX Non-Inferior 0.85; 0.71 to 1.01 T4 or N2 FOLFOX Inferior 1.20; 1.07 to 1.35 T4 or N2 CAPOX Not proven 1.02; 0.89 to 1.17 HR Non-Inferiority Margin 14

15 Optimal adjuvant therapy for colon cancer is 6 cycles The answer is YES for stage III especially the T4 and/or N2 disease if using FOLFOX The answer is possibly YES for T4 and/or N2 if using CapOX Benefit in T1-3N1 group for 6 months is outweighed by risk for side effects 15