# Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer

Source: https://onco.cc/key-papers/paper-rizvi-mutational-landscape-pd1-science-2015/  
OnCo record `paper-rizvi-mutational-landscape-pd1-science-2015` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: Science
- Year: 2015
- DOI: 10.1126/science.aaa1348
- Authors: Rizvi NA, Hellmann MD, Snyder A, et al.
- Findings: 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.
- What it means: 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.
- Caveats: 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.

## Sources

- Full text (DOI): https://doi.org/10.1126/science.aaa1348

## Connected records

- key papers: [Pardoll 2012: the blockade of immune checkpoints in cancer immunotherapy](https://onco.cc/key-papers/paper-pardoll-immune-checkpoint-blockade-nrc-2012/), [Tumeh 2014: PD-1 blockade works by releasing T cells already present at the tumour edge](https://onco.cc/key-papers/paper-tumeh-pd1-adaptive-immune-resistance-nature-2014/)
- biomarkers: [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: [KRAS](https://onco.cc/targets/kras/), [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- pathways: [Mutagenesis & mutational signatures](https://onco.cc/pathways/mutagenesis-signatures/), [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: [Mutational signature](https://onco.cc/terms/mutational-signature/), [Neoantigen](https://onco.cc/terms/neoantigen/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)

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