STK11 mutations correlate with poor prognosis for advanced NSCLC treated with first-line immunotherapy or chemo-immunotherapy according to KRAS, TP53, KEAP1, and SMARCA4 status.

Background: The upfront treatment of non-oncogene-addicted NSCLC relies on immunotherapy alone (ICI) or in combination with chemotherapy (CT-ICI). Genomic aberrations such as KRAS, TP53, KEAP1, SMARCA4, or STK11 may impact survival outcomes.
Methods: We performed an observational study of 145 patients treated with first-line IO or CT-ICI for advanced non-squamous (nsq) NSCLC at our institution tested with an extensive lab-developed NGS panel. The primary objective was to assess the clinical outcomes of STK11-mutated patients. Then, we performed an external validation through the public OAK/POPLAR dataset, including nsq NSCLC patients treated with single-agent ICI or CT.
Results: Most patients were male (59.7 %), former smokers (61.1 %), with ECOG PS 0-1 (84 %), and received first-line CT-IO (58.6 %). 44.8 % had a mutation in KRAS, 21.4 % in KEAP1, 50.3 % in TP53, 13.1 % in SMARCA4, and 14.4 % in the STK11 gene. The mOS was 8 mo. (95 % CI, 5-16.7) for STK11 mutated pts and 17.3 mo. for STK11 wild-type patients (95 % CI, 8.9-24.4) (p = 0.038). TP53 (8.3 vs 17.3), KRAS (9.2 vs 15.9), and KEAP1 (8.9 vs 15.9) mutated patients evidenced a trend for dismal mOS. SMARCA4 status had no impact on mOS. STK11 mutations were detrimental to OS in the univariate (HR 1.74, p = 0.041) and multivariate model (HR 1.97, p = 0.025) after adjusting for sex, age, ECOG PS, treatment (ICI vs CT-ICI), KRAS, KEAP1, TP53, and SMARCA4 status. Genomic alterations did not impact the mPFS in our cohort. Within the OAK/POPLAR dataset, STK11 mutations (60/818 pts) were significantly associated with increased death risk in the univariate (HR 2.01, p < 0.001) and multivariate model (HR 1.66, p = 0.001) after adjusting for age, sex, treatment (ICI vs CT), KRAS, KEAP1, TP53, and SMARCA4 status.
Conclusion: STK11 aberrations hampered the mOS of nsq NSCLC patients treated with first-line ICI or CT-ICI. The negative prognostic impact seems to be unrelated to ICI administration.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)