1746P - Disease-free survival (DFS) and distant metastasis-free survival (DMFS) as surrogates for overall survival (OS) in adjuvant treatment of muscle-invasive bladder cancer (MIBC)

Background

OS is the gold standard efficacy measure in oncology, and historically a primary endpoint for majority of randomized controlled trials (RCTs) of adjuvant chemotherapy in MIBC. Despite prolonged times to observe mature OS, there is a lack of well-established surrogates that can enable earlier evaluation of efficacy.

Methods

DFS and DMFS were assessed as potential surrogates for OS using individual patient data from 9 RCTs (median follow-up: 3.5-14.6 years) comparing cisplatin-based combination chemotherapy vs observation +/- deferred chemotherapy at relapse. Strength of patient-level associations between DFS/DMFS and OS was measured by Spearman’s (ρ) rank correlation and derived from copula functions. Strength of trial-level associations between treatment effects on the surrogates and OS was measured by coefficient of determination (R²) and derived from regression, the robustness of which tested by cross validation. Primary analyses used all patients (n=1075) from all RCTs. Sensitivity analyses were performed with respect to trial follow-up and among lymph-node negative (N0) patients (n=607).

Results

At the patient level, both DFS and DMFS were strongly correlated with OS, and at the trial level, correlation was moderate for DFS, but much stronger for DMFS (Table). For both surrogates, truncating events beyond 7 years had a modest impact on both correlations (<0.01 change in ρ, <0.05 change in R², with narrower 95% CIs), whereas limiting the focus to the N0 subgroup of patients strengthened both correlations (Table). The regression model’s 95% prediction intervals for OS hazard ratios contained the observed OS hazard ratios for all RCTs in cross-validation. Table: 1746P

Conclusions

DFS and particularly DMFS are potentially important surrogates for OS for patients with MIBC treated with adjuvant cisplatin-based chemotherapy; predictions from DFS are subject to higher uncertainty than those from DMFS.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

IDDI.

Funding

Bristol Myers Squibb.

Disclosure

C. Sternberg: Financial Interests, Personal, Other, Honoraria or consultation fees: Astellas Pharma, AstraZeneca, Bayer, Genzyme, Gilead, Medscape, Janssen, Bristol Myers Squibb, Merck, MSD, Pfizer, Roche, Impact, Pharma, Sanofi-Genzyme, UroToday, CCO Clinical, NCI. P. Squifflet: Financial Interests, Personal, Full or part-time Employment: IDDI; Financial Interests, Institutional, Funding, Current research: Bristol Myers Squibb. S. Burdett, D. Fisher, J. Tierney: Financial Interests, Personal and Institutional, Funding, Current research: Bristol Myers Squibb. E.D. Saad: Financial Interests, Personal, Full or part-time Employment: IDDI; Financial Interests, Institutional, Funding, Current research: 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. S. Teitsson: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Brystol Myers Squibb. J.R. May: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. A. Zhegalik: Financial Interests, Personal, Other: Personal fees, outside the current submitted work. 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. All other authors have declared no conflicts of interest.