816P Investigating surrogate endpoints (SE) for overall survival (OS) in first-line (1L) advanced melanoma: A pooled-analysis of immune checkpoint inhibitor (ICI) trials

Abstract

ICIs transformed the treatment of advanced melanoma with substantial improvements in OS. Establishing valid SEs for OS enables earlier assessment of randomized controlled trials (RCTs) of ICIs due to lengthy follow-up required to observe mature OS data. We examined progression-free survival (PFS), time-to-next treatment (TNT) and objective response rate (ORR) as potential SEs for OS in 1L advanced melanoma by pooling patient-level data from 4 RCTs (CheckMate [CM] 066, 067, 069 & 511) of nivolumab, ipilimumab, and their combinations. Individual-level (IL)-correlation measures - Spearman’s (ρ) & Kendall’s (τ) rank correlation coefficients for PFS and TNT, and an odds ratio (OR) for survival due to presence of objective response - were derived from copula models. For the trial-level (TL)-correlation, surrogacy equations and coefficients of determination (R2) between the treatment effects on SEs and OS were estimated via regression. Primary analyses used all patients (n=1865) from all RCTs. Sensitivity of the results were tested with respect to BRAF-status and removal of CM 069 due to imbalances in subsequent systemic therapy and ICI use between the arms of this study. At the IL, ORR was strongly correlated with OS, whereas both PFS & TNT showed moderate correlation with OS. All SEs were moderately correlated with OS at the TL (Table). Removing CM 069 from the analyses only marginally affected IL-correlations (≤ 0.01 change in ρ and τ, 4.5% change in the OR) but greatly strengthened TL-correlations for all SEs (R2 ≥ 0.87 with significantly narrower 95% CIs for all SEs). IL-correlations were insensitive to BRAF status, whereas TL-correlations were slightly stronger for the BRAF wild-type.Table: 816PCorrelationρ [95% CI]τ [95% CI]R2 [95% CI]PFS - OS0.72 [0.71, 0.73]0.53 [0.49, 0.57]0.71 [0.23, 1.00]TNT - OS0.77 [0.76, 0.78]0.58 [0.55, 0.62]0.75 [0.32, 1.00]ORR - OSOR12.29 [9.78-14.80]0.62 [0, 1.00] Open table in a new tab With moderate-to-strong correlation to OS on both levels, all candidate SEs can assist predictions for OS benefits of ICIs with a range of uncertainty depending on BRAF-status and subsequent treatment patterns.