# Associations of tissue tumour mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic non-small-cell lung cancer

Source: https://onco.cc/key-papers/paper-keynote-189-407-tmb-jtocrr-2023/  
OnCo record `paper-keynote-189-407-tmb-jtocrr-2023` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

In the two trials that established the treatment most patients with lung cancer actually receive, immunotherapy added to chemotherapy, the number of mutations in the tumour predicted nothing at all.

## Summary

A retrospective exploratory analysis of the phase 3 KEYNOTE-189 (non-squamous) and KEYNOTE-407 (squamous) trials evaluated tissue tumour mutational burden and STK11, KEAP1 and KRAS mutation status, assessed by whole-exome sequencing with matched normal DNA, as biomarkers for pembrolizumab plus platinum-based chemotherapy. Among patients with evaluable data (293 in KEYNOTE-189 and 312 in KEYNOTE-407), no association was found between continuous burden and overall or progression-free survival for the pembrolizumab combination or for placebo plus chemotherapy in either histology. Pembrolizumab combination improved outcomes both above and below the prespecified cut point of 175 mutations per exome, and treatment outcomes were similar regardless of KEAP1, STK11 or KRAS mutation status.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: JTO Clinical and Research Reports
- Year: 2023
- DOI: 10.1016/j.jtocrr.2022.100431
- Authors: Garassino MC, Gadgeel S, Novello S, et al.
- Findings: No association between continuous tissue burden and survival with pembrolizumab plus chemotherapy in either histology.; Benefit was seen above and below the 175 mutations per exome cut point alike.; STK11, KEAP1 and KRAS status did not change the benefit of the combination.; The same held for the chemotherapy-alone arms.
- What it means: This is the result that ended tumour mutational burden as a practical selector in lung cancer: in the regimen most patients receive, it selects nobody, and neither do the co-mutations most often quoted as reasons to withhold immunotherapy.
- Caveats: Exploratory analyses with sequencing available for roughly half of each trial population.; Whole-exome burden, not the panel-based measure used in clinics.; A negative finding within trials that were positive overall, so it cannot exclude small effects.

## Sources

- Garassino et al., JTO Clin Res Rep 2023: tissue tumour mutational burden with pembrolizumab plus chemotherapy in KEYNOTE-189 and KEYNOTE-407: https://doi.org/10.1016/j.jtocrr.2022.100431
- PubMed: https://pubmed.ncbi.nlm.nih.gov/36793385/

## Connected records

- biomarkers: [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: [Luis Paz-Ares](https://onco.cc/people/luis-paz-ares/)

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