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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.
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.
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.
Shares STK11 / KEAP1 co-mutations, STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma, Tumour mutational burden testing, KEAP1.
Shares STK11 / KEAP1 co-mutations, Tumour mutational burden testing, STK11, TMB-high (tumour mutational burden >= 10 mutations per megabase).
Shares Tumour mutational burden testing, TMB-high (tumour mutational burden >= 10 mutations per megabase), The cancer-immunity cycle, Tumour mutational burden (TMB).
Shares Tumour mutational burden testing, TMB-high (tumour mutational burden >= 10 mutations per megabase), The cancer-immunity cycle, Tumour mutational burden (TMB).
Shares STK11 / KEAP1 co-mutations, STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma, KEAP1, STK11.
Shares STK11 / KEAP1 co-mutations, STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma, KEAP1, STK11.
Shares Tumour mutational burden testing, TMB-high (tumour mutational burden >= 10 mutations per megabase), The cancer-immunity cycle, Tumour mutational burden (TMB).
Shares Tumour mutational burden testing, TMB-high (tumour mutational burden >= 10 mutations per megabase), Tumour mutational burden (TMB), PD-1 / PD-L1 immune checkpoint & T-cell activation.