Prognostic significance of STK11, KEAP1, and NFE2L2- mutations in lung squamous cell carcinoma treated with immunotherapy with or without chemotherapy.

Abstract

e20635 Background: Mutations in STK11 and KEAP1 are consistently associated with poor prognosis in NSCLC. In the lung squamous cell carcinoma (LSCC) subtype, KEAP1 and NFE2L2 mutations converge on constitutive activation of NRF2, a key oncogenic driver of tumor progression. Although KEAP1 and NFE2L2 are among the most frequently mutated genes in LSCC, their combined prognostic significance along with STK11 in LSCC remains poorly characterized. Methods: This multicenter retrospective study enrolled patients with LSCC treated at Dana-Farber Cancer Institute, Memorial Sloan Ketting Cancer Center, and MD Anderson Cancer Center. Genomic and clinicopathologic data were collected for all patients. Eligible patients received immunotherapy, and with or without chemotherapy. Baseline characteristics and clinical outcomes were systematically assessed. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared between groups using the log-rank test. Results: Across the three combined cohorts, a total of 407 patients were included, 99 (24.3%) harbored mutations in at least one of the three genes of interest. The median age was 68 years; 75.4% (n = 307) were male, and 89.9% (n = 366) had a history of smoking. Among mutation carriers, 42 had STK11 mutations, 33 had KEAP1 mutations, and 32 had NFE2L2 mutations, with 8 patients exhibiting co-occurring mutations. Baseline clinicopathologic features were generally well balanced between patients with versus without STK11/KEAP1/NFE2L2 mutations. However tumor mutational burden was higher among STK11/KEAP1/NFE2L2 mutant compared wild-type cases (harmonized TMB 0.35 vs -0.03, p < 0.01). In the pooled cohort, the presence of STK11/KEAP1/NFE2L2 was not associated with response rate (37.4% vs 26.9%, p = 0.06) progression-free survival (PFS HR 1.22; p = 0.10) or overall survival (OS HR 1.09; p = 0.57). When stratified by individual gene (STK11, KEAP1 and NFE2L2), none demonstrated a statistically significant association with, ORR, PFS or OS. Conclusions: STK11, KEAP1, and NFE2L2 mutations, alone or in combination, were not associated with inferior outcomes in patients treated with immunotherapy with or without chemotherapy in LSCC. Unlike non-squamous NSCLC, these alterations appear to have limited clinical impact in LSCC, with important implications for clinical decision-making and for the interpretation and design of future trials.