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Clinical Trial
. 2024 Apr:190:107508.
doi: 10.1016/j.lungcan.2024.107508. Epub 2024 Feb 19.

STK11/LKB1 alterations worsen the poor prognosis of KRAS mutated early-stage non-squamous non-small cell lung carcinoma, results based on the phase 2 IFCT TASTE trial

Jean Baptiste Oudart  1 , Simon Garinet  2 , Caroline Leger  1 , Fabrice Barlesi  3 , Julien Mazières  4 , Gaelle Jeannin  5 , Clarisse Audigier-Valette  6 , Denis Morot-Sibilot  7 , Alexandra Langlais  8 , Elodie Amour  8 , Nathalie Mathiot  9 , Gary Birsen  10 , Hélène Blons  2 , Marie Wislez  11
Affiliations
Free article
Clinical Trial

STK11/LKB1 alterations worsen the poor prognosis of KRAS mutated early-stage non-squamous non-small cell lung carcinoma, results based on the phase 2 IFCT TASTE trial

Jean Baptiste Oudart et al. Lung Cancer. 2024 Apr.
Free article

Abstract

Background: STK11/LKB1 mutations have been associated with primary resistance to PD-1 axis inhibitors and poor prognosis in advanced KRAS-mutant lung adenocarcinoma. This study aimed to assess the prognostic significance of STK11/LKB1 alterations in localized non-squamous non-small cell lung carcinoma (non-sq NSCLC).

Patients and methods: Surgical samples from patients undergoing complete resection for stage IIa, IIb, or IIIa (N2 excluded) non-sq NSCLC in the randomized adjuvant phase II trial (NCT00775385 IFCT-1801 TASTE trial) were examined. Patients received either standard chemotherapy (Pemetrexed Cisplatin) or personalized treatment based on EGFR mutation (Erlotinib) and ERCC1 expression. Tumor molecular profiles were analyzed using targeted NGS and correlated with overall survival (OS) and disease-free survival (DFS), adjusting for relevant clinical variables. Additionally, interactions between treatment groups and molecular alterations on OS, PD-L1 expression, and tumor-circulating DNA in post-operative plasma samples were evaluated.

Results: Among 134 patients (predominantly male smokers with adenocarcinoma), KRAS mutations were associated with shorter DFS (HR: 1.95, 95 % CI: 1.1-3.4, p = 0.02) and OS (HR: 2.32, 95 % CI: 1.2-4.6, p = 0.014). Isolated STK11/LKB1 mutations (n = 18) did not significantly impact DFS or OS. However, within KRAS-mutated samples (n = 53), patients with concurrent STK11/LKB1 mutations (n = 10) exhibited significantly shorter DFS (HR: 3.85, CI: 1.5-10.2, p = 0.006) and a trend towards shorter OS (HR: 1.80, CI: 0.6-5.3, p = 0.28). No associations were found between PD-L1 expression, other gene mutations, progression-free survival (PFS), or OS.

Conclusion: This analysis reinforces KRAS mutations as predictive factors for relapse and poor survival in localized non-sq NSCLC. Furthermore, the presence of concomitant STK11/LKB1 mutations exacerbated the prognosis within the KRAS-mutated subset. These findings emphasize the clinical relevance of these molecular markers and their potential impact on treatment strategies in non-sq NSCLC.

Keywords: Early-stage; KRAS; Non-squamous NSCLC; Prognosis; STK11/LKB1.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Oudart has received consulting fees from Astra Zeneca and Novartis; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra Zeneca; has received support for attending meetings and/or travel from Astra Zeneca. Dr. Barlesi has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra-Zeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda. Dr. Mazière has received grants from Roche, Astra Zeneca, Pierre Fabre, BMS and Illumina; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Astra Zeneca, Pierre Fabre, Pfizer, Jiangsu Hengruii, Blueprint, Takeda, BMS, MSD, Daiichi, Novartis and Amgen. Dr. Audigier-Valette has received consulting fees from Roche and Abbvie; has received support for attending meetings and/or travel from Pfizer and MSD; has received participation on a Data Safety Monitoring Board or Advisory Board from Roche, Sanofi, MSD, BMS, Lilly, Pfizer, Astra Zeneca, Janssen and Abbvie. Dr. Moro-Sibilot has received consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra Zeneca, Roche, Pfizer, Amgen, BMS, MSD, Lilly and Takeda; has received support for attending meetings and/or travel from Roche, Takeda and BMS. Dr. Blons has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra Zeneca, BMS and MSD. Dr. Wislez has received grants from Astra Zeneca; and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD, Astra Zeneca, Amgen, BMS, Roche, Janssen and Sanofi; and has received support for attending meetings and/or travel from Roche and Janssen; and has received Participation on a Data Safety Monitoring Board or Advisory Board from MSD, Astra Zeneca, Amgen, BMS, Roche, Janssen and Sanofi. The remaining authors declare no conflict of interest.

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