1102P - Evaluation of surrogate endpoints for overall survival within the RELATIVITY-047 trial

Background

Advances in the first-line treatment of metastatic melanoma raised the need for earlier assessment of clinical trials using intermediate endpoints that may reach statistical maturity sooner than overall survival (OS) without being influenced by subsequent treatments.

Methods

We evaluated progression-free survival (PFS), time-to-next-treatment-or-death (TNTD) and objective response rate (ORR) as potential surrogate endpoints (SEs) for OS within the phase II/III RELATIVITY-047 trial (n=714) using patient-level data with ≥21 months of follow-up. Individual-level (IL) correlations with OS were derived from copula functions and measured by Spearman’s (ρ) and Kendall’s (τ) rank correlation coefficients for PFS and TNTD, and by an odds ratio (OR) for ORR. Patients were clustered in 8 non-overlapping regions according to their country of enrolment for trial-level (TL) surrogacy assessment. Within each region treatment effects on PFS, TNTD and OS were calculated by Cox-proportional-hazards models. TL correlations between the SEs and OS were estimated by weighted linear regression and measured by coefficient of determination (R²). Sensitivity of the results were tested with respect to alternative geographic clustering.

Results

At the IL, ORR and TNTD were strongly correlated with OS, whereas PFS showed moderate correlation with OS. At the TL, PFS and ORR showed moderate correlation with OS with wide uncertainty whereas TNTD had strong correlation with OS with narrower margin of uncertainty. Alternative geographic clustering of patients had marginal impact on the IL (≤ 0.02 change in all measures for all SEs) and modest impact on TL correlations (≤ 0.08 change in R² for all SEs). Table: 1102P

Conclusions

Within the RELATIVITY-047 trial, TNTD-OS surrogacy was stronger and more stable than PFS-OS and ORR-OS surrogacy. The strength of each surrogacy relationship analyzed in this study and their relative order were consistent with those previously reported from other immune-checkpoint inhibitor studies.

Clinical trial identification

Phase II/III study: RELATIVITY-047 (CA224-047), NCT03470922.

Editorial acknowledgement

Writing of the abstract was led by Dr. Murat Kurt (co-author). All other co-authors provided comments on the abstract draft. Final version of the document was shaped by a consensus of all co-authors.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

P. Mohr: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, GSK, Pierre Fabre, Sanofi; Financial Interests, Personal, Invited Speaker: Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Pierre Fabre, Sanofi, Sun Pharma; Financial Interests, Institutional, Funding: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis; Non-Financial Interests, Principal Investigator: Bristol Myers Squibb, Merck Sharp & Dohme, Regeneron, Sanofi, Novartis, Sun Pharma. P. Squifflet: Financial Interests, Institutional, Speaker, Consultant, Advisor, Pierre Fabre; Squifflet is an employee of IDDI and received consultancy fees from Bristol Myers Squibb through IDDI: Bristol Myers Squibb. E.D. Saad: Financial Interests, Institutional, Speaker, Consultant, Advisor, Everardo Saad is an employee of IDDI and received consultancy fees from Bristol Myers Squibb through IDDI: Bristol Myers Squibb. J. Larkin: Financial Interests, Personal, Invited Speaker: BMS, Pfizer, Roche, Pierre Fabre, AstraZeneca, Novartis, EUSA Pharma, MSD, Merck, GSK, Ipsen, Aptitude, Eisai, Calithera, Ultimovacs, Seagen, Goldman Sachs, eCancer, Inselgruppe, Agence Unik; Financial Interests, Personal, Other, Consultancy: Incyte, iOnctura, Apple Tree, Merck, BMS, Eisai, Debiopharm; Financial Interests, Personal, Other, Honorarium: touchIME, touchEXPERTS, VJOncology, RGCP, Cambridge Healthcare Research, Royal College of Physicians; Financial Interests, Institutional, Funding: BMS, MSD, Novartis, Pfizer, Achilles, Roche, Nektar, Covance, Immunocore, Pharmacyclics, Aveo. M. Kurt, A. Moshyk, F. Ejzykowicz: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks or ownership: Bristol Myers Squibb. M.E. Buyse: Financial Interests, Institutional, Speaker, Consultant, Advisor, Marc Buyse is an employee of IDDI and received consultancy fees from Bristol Myers Squib through IDDI: Bristol Myers Squibb.