# Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status

Source: https://onco.cc/key-papers/paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022/  
OnCo record `paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Two genes long blamed for immunotherapy failure in lung cancer turn out to matter only when the tumour also has a mutated KRAS gene. In tumours without it, the same mutations made no difference at all.

## Summary

Clinicopathological and genomic data were collected from patients with advanced lung adenocarcinoma at two multi-institutional cohorts, and outcomes on PD-(L)1 inhibition were analysed by KRAS, STK11 and KEAP1 mutation status. In the combined cohort of 1,261 patients, KRAS mutations were detected in 536 cases, 42.5%, deleterious STK11 mutations in 260 of 1,261, 20.6%, and deleterious KEAP1 mutations in 231 of 1,202 assessable cases, 19.2%. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free survival (hazard ratios 2.04 and 2.05) and overall survival (2.09 and 2.24) on immunotherapy uniquely among KRAS-mutant but not KRAS wild-type adenocarcinomas. Gene expression and immune cell enrichment analyses showed that STK11 or KEAP1 mutation produced distinct immunophenotypes only in KRAS-mutant tumours.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Journal of Thoracic Oncology
- Year: 2022
- DOI: 10.1016/j.jtho.2021.10.013
- Authors: Ricciuti B, Arbour KC, Lin JJ, et al.
- Findings: STK11 mutation in 20.6% and KEAP1 mutation in 19.2% of lung adenocarcinomas across two cohorts.; Both predicted worse progression-free and overall survival on PD-(L)1 blockade only in KRAS-mutant tumours.; In KRAS wild-type tumours neither mutation affected outcome.; The immune phenotype differences were also confined to KRAS-mutant disease.
- What it means: It corrected a widely repeated simplification. An STK11 or KEAP1 mutation is not by itself a reason to expect immunotherapy to fail; it is a reason to expect it in a KRAS-mutant tumour, which is how the result should be read on a report.
- Caveats: Retrospective across two cohorts with different treatment practices.; Deleterious mutation calling depends on the annotation pipeline.; Patients received several different regimens.

## Sources

- Ricciuti et al., J Thorac Oncol 2022: STK11 and KEAP1 mutations and PD-(L)1 inhibition in 1,261 lung adenocarcinomas, by KRAS status: https://doi.org/10.1016/j.jtho.2021.10.013
- PubMed: https://pubmed.ncbi.nlm.nih.gov/34740862/

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [KEAP1](https://onco.cc/targets/keap1/), [KRAS](https://onco.cc/targets/kras/), [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/), [STK11](https://onco.cc/targets/stk11/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/), [Massachusetts General Hospital Cancer Center](https://onco.cc/institutions/mgh/), [MD Anderson Cancer Center](https://onco.cc/institutions/md-anderson/), [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- pathways: [KEAP1-NRF2 antioxidant pathway](https://onco.cc/pathways/keap1-nrf2/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [T-cell exhaustion](https://onco.cc/pathways/t-cell-exhaustion/)
- terms: [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [KRAS mutation subtypes (G12C, G12D, G12V)](https://onco.cc/terms/kras-mutation-subtypes/), [STK11 / KEAP1 co-mutations](https://onco.cc/terms/stk11-keap1/)
- people: [Ferdinandos Skoulidis](https://onco.cc/people/ferdinandos-skoulidis/)
- journals: [Journal of Thoracic Oncology](https://onco.cc/journals/journal-of-thoracic-oncology/)
- biomarkers: [STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma](https://onco.cc/biomarkers/stk11-keap1-loss/)

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