Outcomes in patients treated with frontline immune checkpoint inhibition (ICI) for advanced NSCLC with KRAS mutations and STK11/KEAP1 comutations across PD-L1 levels

Lova Sun, Elizabeth A. Handorf, Yunyun Zhou, Hossein Borghaei, Charu Aggarwal, Jessica Bauman

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: In patients with advanced NSCLC (aNSCLC), the impact of KRAS mutations (m) and comutations with STK11 and KEAP1 on outcomes across different PD-L1 levels remains incompletely understood. We aimed to investigate the frequency of KRAS mutations and comutations across PD-L1 levels, and the association between these mutations and survival, stratified by PD-L1 expression. Methods: We conducted a nationwide cohort study of patients diagnosed with aNSCLC between 2016 and 2021 treated with frontline (chemo)immunotherapy, who underwent molecular genotyping including KRAS, STK11, and KEAP1. Real-world overall survival (OS) and progression-free survival (rwPFS) were estimated using Kaplan-Meier methodology. Cox multivariable regressions were used to evaluate the association between KRASm and survival across different PD-L1 strata, and to assess whether the association between KRASm and survival differed by PD-L1 level. Finally, within subgroups defined by PD-L1 expression, we used interaction terms to assess whether co-mutations with STK11 and KEAP1 moderated the association between KRAS mutation and survival. Results: Of our 2593-patient cohort, 982 (37.9 %) were KRASm and 1611 (62.1 %) KRASwt. KRASm were enriched in the PD-L1 ≥50 % cohort (334/743, 45 %), but within patients with KRASm, co-mutations with STK11 and KEAP1 were enriched in the PD-L1 0 % cohort. KRASm was associated with significantly worse OS in the PD-L1 0 % cohort compared to the PD-L1 ≥50 % cohort (P for interaction = 0.008). On adjusted analyses stratified by PD-L1, KRASm was associated with worse survival only in the PD-L1 0 % group (OS HR 1.46, p = 0.001). KEAP1 and STK11 comutations were most strongly associated with worse OS in the PD-L1 0 % subgroup; patients with triple KRASm/KEAPm/STK11m PD-L1 0 % NSCLC experienced the worst outcomes. Conclusions: KRASm are associated with worse overall survival in PD-L1 negative NSCLC; however, this association is largely driven by comutations with STK11 and KEAP1, which are enriched in PD-L1 negative tumors.

Original languageEnglish
Article number107510
Pages (from-to)107510
JournalLung Cancer
Volume190
DOIs
StatePublished - Apr 2024

Keywords

  • Immunotherapy
  • KRAS mutation
  • Non small cell lung cancer
  • Real world data
  • Immune Checkpoint Inhibitors/therapeutic use
  • Humans
  • Proto-Oncogene Proteins p21(ras)/genetics
  • AMP-Activated Protein Kinase Kinases
  • Kelch-Like ECH-Associated Protein 1/genetics
  • Lung Neoplasms/drug therapy
  • Carcinoma, Non-Small-Cell Lung/drug therapy
  • Mutation
  • B7-H1 Antigen/genetics
  • NF-E2-Related Factor 2/genetics
  • Protein Serine-Threonine Kinases/genetics
  • Cohort Studies

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