Mutations in STK11, KEAP1 Only Reduce Immunotherapy Efficacy in KRAS-Mutant Lung Cancer

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Mutations in STK11 and KEAP1 are associated with worse outcomes of immunotherapy in patients with KRAS-mutant — but not KRAS-wildtype — lung adenocarcinoma, according to research published in the Journal of Thoracic Oncology.

Researchers found that patients with mutations in STK11 or KEAP1 had worse progression-free survival (PFS) and overall survival (OS) with immune checkpoint inhibitor therapy if they had KRAS-mutant disease but not KRAS-wildtype disease.

This study included 1261 patients with advanced lung adenocarcinoma treated with PD-1/PD-L1 inhibitors — 620 patients in a discovery cohort and 641 in a validation cohort. In the entire study population, the median age was 61 years (range, 22-92 years), and 56.1% of patients were women.


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KRAS mutations were detected in 42.5% of patients, STK11 mutations in 20.6%, and KEAP1 mutations in 19.2%. Co-occurring mutations in KRAS/STK11, KRAS/KEAP1, and STK11/KEAP1 were found in 10.9%, 8.4%, and 9.4% of patients, respectively.

In each cohort and in the entire population, STK11 and KEAP1 mutations were associated with significantly worse PFS and OS in patients with KRAS-mutant disease but not KRAS-wildtype disease.

A multivariate analysis in the entire population confirmed that STK11 and KEAP1 mutations were independent predictors of shorter PFS and OS in KRAS-mutant cases.

For PFS, the hazard ratio (HR) was 1.46 for patients with STK11 mutations (P =.01) and 2.15 for those with KEAP1 mutations (P <.0001). For OS, the HRs were 1.73 (P =.002) and 2.44 (P <.0001), respectively.

The researchers found that STK11- and KEAP1-mutant cases had different transcriptomic profiles and immunophenotypes according to KRAS mutation status.

In KRAS-mutant cases, STK11 mutations were associated with downregulation of MHC class II-related genes. KEAP1 mutations were associated with a significant downregulation of positive regulators of type I interferon and other inflammatory cytokines.

“These findings have implications for clinical trial interpretation and design as well as for treatment selection,” the researchers wrote. “Our study suggests that immunotherapy clinical trials should consider employing stratification measures to balance randomized groups for STK11 and KEAP1 co-mutation status and ensure that differences in outcomes are due to therapeutic interventions rather than variations in STK11 and/or KEAP1 mutation frequency, especially in KRAS-mutant NSCLC.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Ricciuti B, Arbour KC, Lin JJ, et al. Diminished efficacy of PD-(L)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is impacted by KRAS mutation status. J Thorac Oncol. Published online November 2, 2021. doi:10.1016/j.jtho.2021.10.013



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