# Associations of tissue tumour mutational burden and mutational status with clinical outcomes in KEYNOTE-042

Source: https://onco.cc/key-papers/paper-keynote-042-tmb-mutations-ann-oncol-2023/  
OnCo record `paper-keynote-042-tmb-mutations-ann-oncol-2023` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

In a large randomised trial of immunotherapy given alone, patients whose tumours carried more mutations did better on the drug than on chemotherapy, and patients with fewer mutations did not.

## Summary

This retrospective exploratory analysis of the phase 3 KEYNOTE-042 trial assessed tissue tumour mutational burden and STK11, KEAP1 and KRAS mutations, determined by whole-exome sequencing of tumour and matched normal DNA, in patients with PD-L1-positive advanced non-small-cell lung cancer without EGFR or ALK alterations. Of 793 patients, 345, 43.5%, had a burden of 175 or more mutations per exome. No association was observed between PD-L1 expression and burden. Continuous burden was associated with improved overall and progression-free survival among patients receiving pembrolizumab but not chemotherapy. A burden of 175 or more favoured pembrolizumab over chemotherapy (overall survival hazard ratio 0.62) where a burden below 175 did not (1.09). Improved overall survival with pembrolizumab was seen regardless of STK11, KEAP1 or KRAS mutation status.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Annals of Oncology
- Year: 2023
- DOI: 10.1016/j.annonc.2023.01.011
- Authors: Mok TSK, Lopes G, Cho BC, et al.
- Findings: Tissue burden of 175 or more mutations per exome identified benefit from pembrolizumab monotherapy (hazard ratio 0.62) where lower burden did not (1.09).; Burden and PD-L1 expression were uncorrelated.; Continuous burden tracked outcome on pembrolizumab and not on chemotherapy.; STK11, KEAP1 and KRAS status did not change the pembrolizumab benefit in this setting.
- What it means: It is the positive half of the tumour mutational burden story and it applies only to single-agent immunotherapy, which is the setting fewest patients are treated in.
- Caveats: Retrospective exploratory analysis of a randomised trial with a prespecified cut point but no prospective validation.; Whole-exome sequencing is not the assay used in practice.; Only PD-L1-positive patients were enrolled.

## Sources

- Mok et al., Ann Oncol 2023: tissue tumour mutational burden and mutation status in KEYNOTE-042 (793 patients): https://doi.org/10.1016/j.annonc.2023.01.011
- PubMed: https://pubmed.ncbi.nlm.nih.gov/36709038/

## Connected records

- biomarkers: [PD-L1 TPS (tumour proportion score)](https://onco.cc/biomarkers/pd-l1-tps/), [STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma](https://onco.cc/biomarkers/stk11-keap1-loss/), [TMB-high (tumour mutational burden >= 10 mutations per megabase)](https://onco.cc/biomarkers/tmb-high/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Tumour mutational burden testing](https://onco.cc/technologies/tmb-testing/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- 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/)
- drugs: [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- pathways: [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [The cancer-immunity cycle](https://onco.cc/pathways/cancer-immunity-cycle/)
- terms: [STK11 / KEAP1 co-mutations](https://onco.cc/terms/stk11-keap1/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- people: [Tony S. K. Mok](https://onco.cc/people/tony-mok/)
- journals: [Annals of Oncology](https://onco.cc/journals/annals-of-oncology/)

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