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.

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. This retrospective study analyzed pathologically diagnosed advanced NSCLC with KRAS, insensitive EGFR, HER2, MET, BRAF, RET, NTRK, 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. There are 138 patients enrolled, including 96 with driver gene alterations and 42 with non-driver alterations. Driver gene alterations were insensitive EGFR (n=14), KRAS (n=45), HER2 (n=8), MET (n=2), BRAF (n=11), RET or NTRK (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 KRAS [14.6 months, 95% confidence interval (CI): 9.7-not reached (NR)] had longer PFS, while EGFR (7.97 months, 95% CI: 6.13-NR) and MET (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 vs. 11.27 vs. 11.77 months, P=0.04). In KRAS mutant NSCLC, patients with KRAS G12C mutations exhibited longer PFS (19.9 vs. 10.3 months, P=0.71) and OS (NR vs. 14.2 months, P=0.36) compared to non-G12C mutations. Similarly, KRAS mutant patients with TP53 co-mutation had numerically prolonged PFS (25.9 vs. 10.5 months, P=0.16) and OS (NR vs. 20.4 months, P=0.06), compared to those without TP53 co-mutation. 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 KRAS mutant patients, KRAS G12C mutation or TP53 co-mutation might indicate improved survival.