The efficacy and predictive factors of first-line immune checkpoint inhibitors for advanced non-small cell lung cancer with driver or non-driver gene alterations: a retrospective cohort study.

[BACKGROUND] The efficacy of first-line immune checkpoint inhibitor (ICI)-based therapy remains to be established for patients with advanced non-small cell lung cancer (NSCLC) harboring specific driver mutations for which effective first-line targeted therapies are unavailable. This study aims to examine the outcomes of first-line ICIs for advanced NSCLC with gene alterations in China and explore predictive factors of survival in this cohort.

[METHODS] This retrospective study analyzed pathologically diagnosed advanced NSCLC with , insensitive , or non-driver gene alterations that received first-line ICIs at Peking Union Medical College Hospital (PUMCH) in China between January 2017 and June 2023. Clinical, genomic, and serological information before first-line treatment was collected from an electronic medical database. Best overall response, progression-free survival (PFS), and overall survival (OS) were evaluated.

[RESULTS] There are 138 patients enrolled, including 96 with driver gene alterations and 42 with non-driver alterations. Driver gene alterations were insensitive (n=14), (n=45), (n=8), (n=2), (n=11), or (n=5), and concurrent driver genes (n=11). The objective response rate (ORR) was 44.9%, the median PFS was 11.3 months, and the median OS was 24.4 months. Survival was similar among different gene alteration subgroups. However, those with [14.6 months, 95% confidence interval (CI): 9.7-not reached (NR)] had longer PFS, while (7.97 months, 95% CI: 6.13-NR) and (7.4 months, 95% CI: not calculable) showed an inferior PFS. Programmed death ligand 1 (PD-L1) ≥50% was a consistent protective factor in univariate [hazard ratio (HR) 0.402, 95% CI: 0.196-0.827, P=0.01] and multivariate (HR 0.409, 95% CI: 0.186-0.903, P=0.03) Cox regression models, and PFS varied significantly among patients with PD-L1 <1%, 1-49%, and ≥50% (7.97 11.27 11.77 months, P=0.04). In mutant NSCLC, patients with mutations exhibited longer PFS (19.9 10.3 months, P=0.71) and OS (NR 14.2 months, P=0.36) compared to non-G12C mutations. Similarly, mutant patients with co-mutation had numerically prolonged PFS (25.9 10.5 months, P=0.16) and OS (NR 20.4 months, P=0.06), compared to those without co-mutation.

[CONCLUSIONS] Among different gene alteration subgroups for advanced NSCLC, the efficacy of first-line ICIs did not differ with statistical significance, with high PD-L1 expression as a predictive factor for better survival. In mutant patients, mutation or co-mutation might indicate improved survival.