Neoadjuvant immune checkpoint inhibitors (ICIs) have shown improved survival compared with standard chemotherapy in resectable non–small cell lung cancer (NSCLC). However, the role of actionable genomic alterations (AGAs) in shaping response to these therapies remains poorly defined. This study investigates the influence of AGAs on treatment failure (TF) in patients undergoing neoadjuvant ICIs prior to surgical resection.We analyzed tumor molecular profiles from patients with stage I–IIIA resectable NSCLC (AJCC 7th edition) enrolled in a previously reported phase II randomized trial (NCT03158129). Participants received neoadjuvant nivolumab alone (n = 23) or in combination with ipilimumab (n = 21) before surgery. TF was defined as disease progression preventing surgery, confirmed recurrence postoperatively, or death linked to lung cancer or treatment complications. Tumors with AGAs (n = 12) were compared to those without AGAs and non-profiled squamous cell carcinomas (non-AGAs+NP SCC, n = 20).Over a median follow-up of 60.2 months, TF occurred in 34.1% of patients (15/44). Retrospective molecular profiling was available in 47.7% (21/44) of cases, identifying AGAs including EGFR (n = 5), KRAS (n = 2), ERBB2 (n = 1), BRAF (n = 1) mutations, and ALK (n = 2) and RET (n = 1) fusions. Median time to TF in the AGA group was 24.7 months (95% CI: 12.6–40.4), compared with not reached in the non-AGA/NP SCC group. AGAs were associated with a significantly higher TF risk (HR: 5.51; 95% CI: 1.68–18.1), while former or current smoking reduced TF risk (HR: 0.24; 95% CI: 0.08–0.75). Major pathological responses were more likely in the non-AGA/NP SCC group (OR: 4.71; 95% CI: 0.49–45.2), and residual viable tumor burden was higher in AGA tumors (median 72.5% vs 33.0%).NSCLC tumors harboring select AGAs, particularly EGFR mutations and ALK fusions, demonstrate poorer outcomes after neoadjuvant ICI therapy, including higher TF rates, shorter time to failure, and reduced pathological regression. These findings underscore the necessity of pre-treatment molecular profiling to identify patients who may derive limited benefit from chemotherapy-sparing immunotherapy regimens.
