Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer
Lung cancers with more mutations, typically those caused by smoking, were more likely to respond to pembrolizumab, the study that established tumour mutational burden as a biomarker for immunotherapy.
Overview
Rizvi, Hellmann, Snyder and colleagues at Memorial Sloan Kettering sequenced the exomes of non-small-cell lung cancers from patients treated with pembrolizumab in a discovery cohort of 16 and a validation cohort of 18. A higher number of nonsynonymous mutations was associated with a higher response rate, more durable clinical benefit and longer progression-free survival. A molecular smoking signature, a higher predicted neoantigen burden and mutations in DNA repair genes also tracked with benefit, and in one responder the team detected T cells recognising a specific neoantigen.
- Whole-exome sequencing of NSCLC from 16 patients (discovery) and 18 (validation) treated with pembrolizumab.
- Higher nonsynonymous mutation burden was associated with durable clinical benefit (73% vs 13% in the discovery cohort) and longer progression-free survival.
- A transversion-high smoking signature, predicted neoantigen burden and DNA repair pathway mutations were also associated with benefit.
- Neoantigen-specific T cells were detected in a responding patient.
This paper turned a hypothesis into a biomarker: tumour mutational burden is now measured by commercial panels and underpins the tissue-agnostic approval of pembrolizumab for TMB-high tumours. It also explains why smokers' lung cancers, long the hardest to treat, respond better to immunotherapy than never-smokers' cancers.
- Small cohorts; the mutation burden cut-off was set within the study.
- TMB has proved a weaker and less consistent predictor in later, larger trials, and panel-based estimates differ between assays.
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