Time to achieve response and depth of maximal tumor response as potential surrogates for overall survival in advanced non-small cell lung cancer

INTRODUCTION: Objective response rate (ORR) is a common early endpoint in NSCLC trials, but its ability to predict overall survival (OS) is limited, especially for immunotherapy and targeted treatments. Alternative metrics like time to and depth of response are under evaluation as surrogate endpoints. METHODS: We analyzed pooled data from two randomized trials (OAK, POPLAR) comparing atezolizumab to docetaxel. Tumor response metrics, including RECIST response, time to response, response nadir, time to nadir, and duration of response (DOR), were correlated with OS using landmark survival analyses at 6, 12, and 18 weeks. RESULTS: Of 1137 patients, 31.2% achieved best RECIST response by week 6, with 17.5% and 12.7% by weeks 12 and 18. Patients with CR/PR had a 61% reduced risk of death versus those with PD. Longer DOR correlated with improved 12-month OS: 54.6% (6 weeks), 67.5% (12 weeks), and 82.1% (18 weeks). Mean target lesion reduction was -33.9%. Greater tumor reduction improved survival, but timing of nadir did not significantly affect OS or differ by treatment arm. CONCLUSION: Depth and duration of response are predictive of OS in NSCLC and may aid patient management, however are not adequate surrogate endpoints for OS in clinical trials.