Impact of <i>KRAS</i> co-mutations on the efficacy of durvalumab in patients with locally advanced non–small cell lung cancer (LA-NSCLC) treated with concurrent chemoradiotherapy (ChRT).

Abstract

8550 Background: Durvalumab improves survival after platinum-based ChRT in LA-NSCLC. Although immunotherapy is effective in KRAS-mutant tumors across treatment lines, co-mutations are associated with poorer prognosis and treatment resistance. Data efficacy in this context remains limited. Methods: We conducted a retrospective, single-institution analysis of patients with locally advanced NSCLC to evaluate the impact of KRAS mutations on progression-free survival (PFS) and overall survival (OS) after concurrent chemoradiotherapy (ChRT) and durvalumab, accounting for key clinical factors and co-mutations (TP53, STK11, KEAP1). Patients with other actionable genomic alterations (EGFR, ALK, ROS1, BRAF, MET, HER2, RET, FGFR) were excluded. PFS was defined from the first durvalumab dose to progression or death and estimated using the Kaplan–Meier method with comparisons by log-rank test. Results: A total of 290 patients were included (113 KRAS-mutant, 177 non-KRAS [non-AGA]). Median age was similar (69.7 vs 68.5 years), and baseline characteristics were comparable, except that KRAS-mutant patients were more often female(65% vs 38%, p &lt; 0.001) and enriched for adenocarcinoma histology (90% vs 42%; squamous 2.7% vs 49%; p = 0.009) and PD-L1 expression (negative: 34% vs 48%; 1–49%: 25% vs 28%; ≥50%: 41% vs 34%). No significant differences in PFS were observed between KRAS and non-KRAS patients (median PFS: 22.9 months [95% CI, 16.0–29.2] vs 19.6 months [95% CI, 13.4–35.2]; log-rank p = 0.087), nor in overall survival (OS) (median OS: 44.5 months [95% CI, 34.4–NR] vs 40.9 months [95% CI, 30.0–59.4]; log-rank p = 0.40). In contrast, PFS differed significantly across KRAS-mutant subgroups: isolated KRAS mutations (median PFS 23.9 months [95% CI, 17.4–30.0]), KRAS with STK11 or KEAP1 co-mutations (8.3 months [95% CI, 3.8–20.8]), and concurrent KRAS/STK11/KEAP1 mutations (3.0 months [95% CI, 2.7–NR]; log-rank p &lt; 0.0001). OS showed a similar numerical trend without statistical significance (49.4 months [95% CI, 37.4–NR], 27.3 months [95% CI, 18.4–NR], and 10.0 months [95% CI, 6.7–NR], respectively; log-rank p = 0.08). Conclusions: While KRAS mutations alone were not associated with inferior outcomes with durvalumab, concurrent STK11 and KEAP1 co-mutations were associated with markedly worse clinical outcomes.