Association of progression-free survival and overall response rate with overall survival in first-line randomized trials of immune checkpoint inhibitor–based regimens for metastatic non–small cell lung cancer (NSCLC): An FDA pooled analysis.

Abstract

9029 Background: Overall Survival (OS) has represented the endpoint of choice to support approvals of Immune Checkpoint Inhibitors (ICIs) in first-line metastatic NSCLC. Despite continued interest in the use of earlier clinical endpoints as true surrogates for OS in this setting, the correlation of Progression-Free Survival (PFS) and Overall Response Rate (ORR) with OS remain an area of active investigation. We conducted a patient-level and trial-level pooled analysis of first-line randomized trials of ICI-based regimens to assess correlations of early clinical endpoints of PFS and ORR with OS in first-line metastatic NSCLC. Methods: The analysis included randomized trials comparing ICI-based regimens (anti-PD-(L)1 with or without anti-CTLA4 antibodies, with or without platinum-based chemotherapy) to platinum-based chemotherapy alone for the first-line treatment of patients with metastatic NSCLC that were submitted to the U.S. Food and Drug Administration between July 2016 to March 2021 to support a marketing application. Patient-level associations were estimated using Spearman (rs) correlation coefficients for PFS and OS, and Cox Proportional Hazards models in RECIST response-based subgroups for ORR and OS. At the trial level, associations were estimated using R2 coefficients from weighted linear regression models, using the log of hazard-ratio (HRs) for PFS and OS and log-odds ratio for ORR. Results: The pooled analysis included 13 trials enrolling 9,285 patients total. Seven trials compared ICIs combined with chemotherapy vs chemotherapy; 6 trials compared ICIs alone vs chemotherapy. Among all patients, the distribution of PD-L1 expression was 31%, 66%, and 32% for PD-L1 <1%, ≥1%, and ≥50%, respectively. The table shows the correlation coefficients for PFS and OS, and ORR and OS at the patient and trial levels. At the patient level, the OS HR comparing ICI-based regimens to chemotherapy was 0.54 (95% CI: 0.48, 0.61) for RECIST responders and 0.96 (95% CI: 0.90, 1.02) for non-responders. Conclusions: This pooled analysis did not indicate a strong correlation between endpoints of PFS and ORR with OS at the patient and trial levels in first-line randomized trials of ICI-based regimens for metastatic NSCLC, potentially because of use of subsequent therapies, cross-over to ICIs, and continuation of ICIs beyond progression. Future research will explore the correlation of alternative endpoints with OS, such as time to treatment discontinuation. Our analysis supports the continued importance of OS as an endpoint for first-line NSCLC trials of ICI-based regimens.[Table: see text]