BACKGROUND: In patients with non-small cell lung cancer (NSCLC) harboring driver alterations, the efficacy of immune checkpoint inhibitors (ICIs) remains uncertain. Our study aimed to examine the first-line ICI efficacy in patients with NSCLC harboring KRAS, MET, FGFR, RET, BRAF, and HER2 alterations in a real-world setting. METHODS: This single-center, retrospective cohort study included patients with advanced NSCLC harboring KRAS, MET, FGFR, RET, BRAF, HER2 alterations or driver-negative, and were treated with first-line ICI therapy. Best overall response, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: Seventy-eight patients with NSCLC were included (median age, 72 years): 67% were men, 15% were never-smokers, and 83% had adenocarcinoma. The driver alterations involved KRAS (n = 21), MET (n = 6), FGFR (n = 3), RET (n = 2), BRAF (n = 2), HER2 (n = 1), and driver-negative (n = 43). The partial responses for KRAS, MET, FGFR, RET, BRAF, HER2, and driver-negative were 57%, 50%, 100%, 50%, 100%, 0%, and 47%, respectively. The median PFS (months) was 16.2 (95% confidence interval [CI]: 6.3- not reached [NR]) for KRAS, 2.8 (95% CI: 2.7-NR) for MET, 11.7 (95% CI: 5.9-NR) for other alterations (FGFR, RET, BRAF, and HER2), and 10.0 (95% CI: 3.7-14.3) for driver-negative, respectively. The median OS (months) was 31.3 (95% CI: 9.0-NR) for KRAS, not reached for MET, 23.5 (95% CI: 18.3-NR) for other alterations, and 21.1 (95% CI: 15.2-NR) for driver-negative, respectively. CONCLUSIONS: The benefit of the first-line ICI was similar in advanced NSCLC regardless of the driver alterations, except for MET alterations.