Abstract 57P
Background
Validation of surrogate endpoints for overall survival (OS) requires strong association at both the individual and trial levels. This study investigated the patient-level correlation between progression-free survival (PFS) and OS among patients with MSI-H/dMMR mCRC treated with nivolumab (NIVO) or nivolumab plus low-dose ipilimumab (NIVO+IPI) in the phase II CheckMate 142 study.
Methods
Correlation was analysed in the previously treated NIVO cohort (74 patients, 69.5 months median follow-up), combined treatment-naïve and previously treated NIVO+IPI cohorts (164 patients, 62.8 months median follow-up), and treatment-naïve NIVO+IPI cohort (45 patients, 52.6 months median follow-up). Copula functions (Clayton, Frank, Hougaard, Joe, and Plackett) were used to model PFS-OS dependence, and PFS and OS curves were represented by commonly used parametric distributions. Joint PFS-OS models were evaluated based on statistical goodness-of-fit criteria, visual fit to Kaplan-Meier curves, and clinical plausibility of survival extrapolations beyond the follow-up period. Correlation strength was measured by Spearman’s rho.
Results
The range of estimates for Spearman’s rho across all models was 0.80-0.89 for the NIVO cohort, 0.82-0.96 for the combined NIVO+IPI cohorts, and 0.82-0.95 for the treatment-naïve NIVO+IPI cohort. The estimates of Spearman’s rho from the selected copula models were 0.83 [95% confidence interval (CI): 0.73-0.89] for the NIVO cohort, 0.85 [95% CI: 0.77-0.90] for the combined NIVO+IPI cohorts, and 0.92 [95% CI: 0.78-0.98] for the treatment-naïve NIVO+IPI cohort. For the NIVO and combined NIVO+IPI cohorts, the lower bound of the 95% CIs for Spearman’s rho was >0.7 regardless of model choice, indicating stability of the evidence for strong association.
Conclusions
Patient-level correlation between PFS and OS was strong in all cohorts of the CheckMate-142 study, providing supportive evidence for the validation of PFS as a suitable surrogate endpoint for OS for patients with MSI-H/dMMR mCRC receiving immunotherapy.
Clinical trial identification
NCT02060188.
Legal entity responsible for the study
Bristol Myers Squibb.
Funding
Bristol Myers Squibb.
Disclosure
J.M.L. Roodhart: Financial Interests, Institutional, Advisory Board: GSK, Servier, Amgen, BMS; Financial Interests, Institutional, Invited Speaker: Servier, Pierre Fabre, GSK, Amgen, BMS, Pfizer; Financial Interests, Institutional, Research Grant: GSK, Xilis, Cleara, HUB Organoids BV; Non-Financial Interests, Member of Board of Directors: Board Member Foundation Hubrecht Organoid Biobank; Non-Financial Interests, Advisory Role: ONCODE clinical advisory board, KWF scientific board; Non-Financial Interests, Other, member guideline committee: member national guideline committee lower digestive track Netherlands; Non-Financial Interests, Institutional, Other, organoids: HUB Organoids. D.J. Sharpe: Financial Interests, Institutional, Full or part-time Employment: Parexel International; Financial Interests, Institutional, Other, Received research grants/funds from BMS to conduct this research: Bristol Myers Squibb. A.E. Tate: Financial Interests, Institutional, Full or part-time Employment, Currently an employee: Parexel. D. Bertwistle: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb, GSK, HLN; Financial Interests, Personal, Royalties, Royalties from licensing monoclonal antibodies I generated while working at St Jude Children's Research Hospital: St Jude Children's Research Hospital. M. Dixon: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. H. Chen: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. M. Kurt: Financial Interests, Personal, Full or part-time Employment, Employee of Bristol Myers Squibb since June-2018: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares, Owns restricted shares of Bristol Myers Squibb since 2019: Bristol Myers Squibb; Non-Financial Interests, Project Lead: Bristol Myers Squibb.