Abstract 816P
Background
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.
Methods
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.
Results
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: 816P
| Correlation | ρ [95% CI] | τ [95% CI] | R2 [95% CI] |
| PFS - OS | 0.72 [0.71, 0.73] | 0.53 [0.49, 0.57] | 0.71 [0.23, 1.00] |
| TNT - OS | 0.77 [0.76, 0.78] | 0.58 [0.55, 0.62] | 0.75 [0.32, 1.00] |
| ORR - OS | OR | ||
| 12.29 [9.78-14.80] | 0.62 [0, 1.00] |
Conclusions
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.
Clinical trial identification
CheckMate 066: NCT01721772, CheckMate 067: NCT01844505, CheckMate 069: NCT01927419, CheckMate 511: NCT02714218.
Editorial acknowledgement
Legal entity responsible for the study
Authors of the study on behalf of Bristol Myers Squibb.
Funding
Bristol Myers Squibb.
Disclosure
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, Debipharm; 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. P. Squifflet: Financial Interests, Personal, Full or part-time Employment, Full time employee of IDDI: IDDI; Financial Interests, Institutional, Research Grant, Received funds from BMS to conduct the research: Bristol Myers Squibb. E.D. Saad: Financial Interests, Personal, Full or part-time Employment, Full time employee of IDDI: IDDI; Financial Interests, Institutional, Research Grant, Received funds from BMS to conduct the research: Bristol Myers Squibb. P. Mohr: Financial Interests, Personal, Advisory Board, Honoraria for lectures and advisory board: Bristol Myers Squibb, Novartis, Roche, MSD, Allmiral-Hermal, Amgen, Merck Serono, Bayer, Pierre-Fabre, Sanofi, SunPharma; Financial Interests, Personal, Advisory Board, Bristol Myers Squibb: Bayersdorf; Financial Interests, Institutional, Funding: Bristol Myers Squibb, Novartis, MSD. 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. A. Moshyk: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. M. Hamilton: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. S. Kotapati: Financial Interests, Institutional, Full or part-time Employment, Employee: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. M.E. Buyse: Financial Interests, Personal, Officer, Chief Scientific Officer: IDDI; Financial Interests, Personal, Invited Speaker, Board Member: CluePoints; Financial Interests, Personal, Stocks/Shares: IDDI, CluePoints.