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Impact of the STK11/KRAS co-mutation on the response to immunotherapy in a real-world pan-cancer cohort
Andrea Olsen1, Alexandra Lebedeva1, Polina Nosova2
1OncoAtlas, LLC, Moscow, Russia.
Introduction:
Immune checkpoint inhibitors are highly effective in treating various cancers. We analyzed the significance of the KRAS/STK11 co-mutation in relation to the efficacy of immune checkpoint inhibitors in pan-cancer patient cohort.
Methods:
We analyzed data from open-access research: MSK-IMPACT (molecular profiling data from patients receiving systemic antitumor therapy) and MSK-TMB (molecular profiling data from patients receiving immune checkpoint inhibitors). In both studies, high throughput sequencing was used for molecular profiling.
Results:
A total of 10,336 patients receiving antitumor therapy (MSK-IMPACT study) and 1661 patients receiving immune checkpoint inhibitors (MSK-TMB study) were included in the analysis. Co-mutation STK11/KRAS was found in 156 (1.5%) and 46 (2.8%) patients in the two studies, respectively. Most patients with the STK11/KRAS co-mutation had non-small cell lung cancer (83% and 85% in the two studies, respectively). Among non-small cell lung cancer patients, the STK11 mutation was associated with a worse outcome for patients receiving systemic antitumor therapy, but not immune checkpoint inhibition therapy (HR for OS 1.90 [95% CI 1.36-2.65] and 1.44 [95% CI 0.88-2.37]). Co-mutation STK11/KRAS was also not associated with patient outcome in any of the studies (HR for OS 0.93 [95% CI 0.56-1.52] and 1.09 [95% CI 0.54-2.19]). High tumor mutational burden was associated with better outcome in the cohort of patients receiving immune checkpoint inhibitors. An analogous analysis among patients in the pan-cancer cohort (excluding patients with non-small cell lung cancer) showed STK11 mutations and high tumor mutational burden have a predictive role for the efficacy of immune checkpoint inhibitors, but not STK11/KRAS co-mutation.
Conclusions:
Co-mutation STK11/KRAS is common among patients with non-small cell lung cancer and is not an independent predictive marker for the efficacy of immune checkpoint inhibitors. Further studies are required to clarify the role of STK11 mutations in immune checkpoint inhibitor treatment response.
Insights
The KRAS/STK11 co-mutation is common in non-small cell lung cancer but does not predict immune checkpoint inhibitor efficacy. STK11 mutations may predict response in other cancers, warranting further research.
Area of Science:
- Oncology
- Cancer Genomics
- Immunotherapy
Background:
- Immune checkpoint inhibitors (ICIs) have transformed cancer treatment.
- The KRAS/STK11 co-mutation is frequently observed, particularly in non-small cell lung cancer (NSCLC).
- Understanding genetic markers predictive of ICI response is crucial for personalized therapy.
Purpose of the Study:
- To investigate the association between the KRAS/STK11 co-mutation and ICI efficacy across a pan-cancer cohort.
- To evaluate the predictive value of STK11 mutations and tumor mutational burden (TMB) for ICI response.
Main Methods:
- Analysis of two large patient cohorts (MSK-IMPACT and MSK-TMB) using high-throughput sequencing.
- Retrospective analysis of outcomes for patients receiving systemic antitumor therapy and ICIs.
- Stratification of patients based on KRAS/STK11 co-mutation status, STK11 mutations, and TMB.
Main Results:
- The KRAS/STK11 co-mutation was present in 1.5-2.8% of patients and predominantly in NSCLC.
- STK11 mutations were associated with worse outcomes in NSCLC patients on systemic therapy but not ICIs.
- KRAS/STK11 co-mutation did not independently predict ICI efficacy in NSCLC or pan-cancer cohorts.
- High TMB predicted better ICI response in the pan-cancer cohort (excluding NSCLC).
- STK11 mutations predicted ICI efficacy in the pan-cancer cohort (excluding NSCLC).
Conclusions:
- The KRAS/STK11 co-mutation is not an independent predictive marker for ICI efficacy, especially in NSCLC.
- STK11 mutations and high TMB may have predictive roles for ICI efficacy in specific pan-cancer patient groups.
- Further research is needed to elucidate the complex role of STK11 mutations in ICI treatment response.
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