Background Anti-programmed death-(ligand)1 (PD-[L]1) therapies, either as monotherapy or in combination, have demonstrated remarkable efficacy in first-line (1L) treatment for metastatic non-small cell lung cancer (mNSCLC). Treatment decisions are often influenced by multiple factors, e.g., PD-L1 expression level or adverse event (AE) profile. Model-based meta-analyses (MBMA) of safety and efficacy can evaluate clinical risk-benefit ratio among FDA-approved IO therapies and inform treatment decisions in mNSCLC patients.
Methods MBMA of median overall survival (mOS) and treatment-related AEs Grade 3–5 (TRAEs Gr3+) were conducted using a curated database containing results from both randomized controlled and single-arm studies (published from 2015 to 2022) with FDA-approved (as of January 2023) IO-based treatments in mNSCLC patients. The analysis dataset comprised mOS and TRAEs Gr3+ results from 49 and 45 studies, and represented 17,918 and 19,238 patients, respectively. The mOS dataset included 34, 28, and 11 studies containing treatment of IO monotherapy, CT, and IO+CT, respectively. In the TRAE analysis, there were 33, 23, and 12 studies containing treatment of IO monotherapy, CT, and IO+CT, respectively. Analyses of endpoints utilized linear models in appropriately transformed domains (i.e., log for mOS, logit for TRAE Gr3+) and data were weighted by standard error of the outcome. After accounting for differential outcomes from specific treatments, potential impact of baseline characteristics (e.g., PD-L1 expression, line of therapy, ECOG PS, sex, histology, and geography/race) on the risk and benefit was evaluated. Models included between-study random effects and all covariates were additive.
Results Regardless of specific IO agent or PD-L1 expression level, fewer patients experienced TRAEs Gr3+ with IO alone (14% [6.2–29]) compared to CT alone (39% [21–61]) or IO+CT (48% [27–70]). Among patients with PD-L1 expression ³50%, mOS was comparable for IO with or without CT (figure 1A,B). In patients with PD-L1 expression <1% (figure 1C,D), therapeutic benefit was higher for IO+CT (16 months [13–19]) than IO alone (12 months [10–15]), justifying the choice of IO+CT in this patient population despite higher TRAEs than IO alone. table 1 summarizes all model parameter estimates, including influential covariates on mOS. No clinically meaningful covariates were identified for TRAEs Gr3+.
Conclusions This MBMA evaluates the risk-benefit ratio and provides quantitative insight into the therapeutic utility of IO agents. Our findings are consistent with treatment guidelines for 1L patients with mNSCLC, highlighting the potential utility of a quantitative model-based approach to strengthen clinical recommendations and to facilitate decision making.
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