{"entity":{"id":"paper-keynote-042-tmb-mutations-ann-oncol-2023","kind":"paper","name":"Associations of tissue tumour mutational burden and mutational status with clinical outcomes in KEYNOTE-042","aka":[],"tldr":"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.","asOf":"2026-09-25","links":[{"label":"Mok et al., Ann Oncol 2023: tissue tumour mutational burden and mutation status in KEYNOTE-042 (793 patients)","url":"https://doi.org/10.1016/j.annonc.2023.01.011"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/36709038/"}],"tags":[],"related":["tmb-high","pd-l1-tps"],"cancers":["nsclc"],"sections":[],"technologies":["tmb-testing","wes-wgs","checkpoint-inhibitor"],"targets":["pdl1","pd1","stk11","keap1","kras"],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":["pd1-checkpoint","cancer-immunity-cycle"],"terms":["tmb","stk11-keap1"],"trials":[],"people":["tony-mok"],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2023,"doi":"10.1016/j.annonc.2023.01.011","pmid":"36709038","authors":"Mok TSK, Lopes G, Cho BC, et al.","paperType":"rct","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."],"whatItMeans":"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."],"changedPractice":false,"participants":793},"route":"/key-papers/paper-keynote-042-tmb-mutations-ann-oncol-2023/","neighbours":{"biomarker":[{"id":"pd-l1-tps","kind":"biomarker","name":"PD-L1 TPS (tumour proportion score)","route":"/biomarkers/pd-l1-tps/"},{"id":"stk11-keap1-loss","kind":"biomarker","name":"STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma","route":"/biomarkers/stk11-keap1-loss/"},{"id":"tmb-high","kind":"biomarker","name":"TMB-high (tumour mutational burden >= 10 mutations per megabase)","route":"/biomarkers/tmb-high/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"tmb-testing","kind":"technology","name":"Tumour mutational burden testing","route":"/technologies/tmb-testing/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"keap1","kind":"target","name":"KEAP1","route":"/targets/keap1/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"},{"id":"stk11","kind":"target","name":"STK11","route":"/targets/stk11/"}],"drug":[{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"pathway":[{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"cancer-immunity-cycle","kind":"pathway","name":"The cancer-immunity cycle","route":"/pathways/cancer-immunity-cycle/"}],"term":[{"id":"stk11-keap1","kind":"term","name":"STK11 / KEAP1 co-mutations","route":"/terms/stk11-keap1/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"person":[{"id":"tony-mok","kind":"person","name":"Tony S. K. Mok","route":"/people/tony-mok/"}],"journal":[{"id":"annals-of-oncology","kind":"journal","name":"Annals of Oncology","route":"/journals/annals-of-oncology/"}]}}