FDA analyses of survival in older adults with metastatic non-small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies.

BACKGROUND: Among patients with newly diagnosed non-small cell lung cancer (NSCLC), approximately 70% occur in those above 65 years of age and more than half are metastatic or locally advanced NSCLC. METHODS: Retrospective analyses pooling data across 4 randomized clinical trials comparing programmed death 1 receptor (PD-1) or programmed death ligand 1 (PD-L1) to docetaxel for the treatment of patients with advanced or metastatic NSCLC with disease progression on or after a platinum-containing therapy were conducted. Demographics, efficacy, and safety data from these trials were pooled and aggregated based on age. The relative treatment effects on overall survival (OS) across age groups were evaluated using Kaplan-Meier methodology. A meta-analysis was performed comparing OS across age groups treated with PD-1/PD-L1 blocking antibodies compared with those treated with docetaxel, as a common control arm across trials. A Cox Proportional Hazards model, stratified by clinical trial, was used and a univariate and multivariate adjusted analysis of OS to further identify trends in efficacy across age groups. RESULTS: Among patients treated with PD-1/PD-L1 blocking antibodies enrolled across the 4 clinical trials, 42% were >65 years of age, 99% had ECOG performance status of 0-1, 75% had received 1 prior therapy, and 76% were diagnosed with Stage IV disease. In the pooled analysis of 2,824 patients across both arms, the treatment effects in age-defined subgroups were similar, with a hazard ratios (HR), unadjusted or adjusted, for OS of 0.71 (95% confidence interval 0.63, 0.80) in patients <65 years and 0.66 (0.57, 0.76) in patients ≥65 years of age. In patients ≥70 years, the HR for OS was 0.67 (0.55. 0.82) and in patients ≥ 75 years, the HR was 0.81 (0.58, 1.13). Estimated median OS in patients receiving PD-1/PD-L1 blocking antibodies versus docetaxel was 14.5 months versus 8.8 months in patients <65 years, 14.2 months versus 9 months in patients ≥65 years, 14.1 versus 9.2 months in patients ≥70 years, and 14.7 versus 9.5 months in the patients ≥75years. Grade 3 or 4 treatment-related adverse events with PD-1/PD-L1 blocking antibodies were less frequent in patients ≥75 years (23%) compared to patients> 65 year ( 49%) and <65 years (47%), as were serious adverse events (30%, 32.5%, 15%); however, treatment-emergent adverse events leading to discontinuation of treatment (7%, 7%, and 5%) in those subgroups ≤65 years, >65 years, and >75 years, respectively, were similar. CONCLUSIONS: Patients 65 and older with advanced and metastatic NSCLC, including those ≥75 years, seem to derive similar survival benefits from treatment with PD-1/PD-L1 blocking antibodies as patients <65 years of age. Patients 75 and older enrolled on these trials appear to tolerate PD-1/PD-L1 blocking antibodies and have a lower incidence of grade 3 or 4 treatment-emergent adverse events compared to the subgroup of patients <65 years of age.