# Molecular determinants of response to anti-PD-1 and anti-PD-L1 blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing

Source: https://onco.cc/key-papers/paper-rizvi-targeted-ngs-immunotherapy-determinants-jco-2018/  
OnCo record `paper-rizvi-targeted-ngs-immunotherapy-determinants-jco-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The routine gene panel used in clinic can estimate how many mutations a lung cancer carries almost as well as sequencing the whole exome can, and tumours with more mutations were more likely to benefit from immunotherapy, independently of the PD-L1 stain.

## Summary

Detailed clinical annotation and response data were collected for 240 patients with advanced non-small-cell lung cancer treated with anti-PD-1 or anti-PD-L1 therapy and profiled with a targeted next-generation sequencing panel. Durable clinical benefit was defined as partial response or stable disease lasting more than six months. Panel-based tumour mutation burden correlated well with whole-exome estimates in 49 patients (rho 0.86). Burden was greater in patients with durable benefit than in those without (p = 0.006). Durable benefit was more common and progression-free survival longer above the 50th percentile of burden (38.6% against 25.1%; hazard ratio 1.38). The fraction of copy number-altered genome was highest in patients without durable benefit. Variants in EGFR and STK11 were associated with a lack of benefit. Burden and PD-L1 expression were independent, and a composite of the two enriched further for benefit.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Journal of Clinical Oncology
- Year: 2018
- DOI: 10.1200/JCO.2017.75.3384
- Authors: Rizvi H, Sanchez-Vega F, La K, et al.
- Findings: Panel-based and exome-based mutation burden correlate at rho 0.86.; Durable benefit 38.6% above against 25.1% below the median burden.; Burden and PD-L1 expression are independent variables with similar predictive power.; EGFR and STK11 alterations predicted a lack of benefit.
- What it means: It made tumour mutational burden measurable in routine practice and, in the same stroke, showed it is a second axis alongside PD-L1 rather than a replacement for it.
- Caveats: Retrospective and single centre.; A percentile cut-off is cohort-dependent and does not transfer to another panel.; Durable clinical benefit is a surrogate endpoint.

## Sources

- Rizvi et al., J Clin Oncol 2018: targeted sequencing of 240 non-small-cell lung cancers treated with PD-(L)1 blockade: https://doi.org/10.1200/JCO.2017.75.3384
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29337640/
- cBioPortal study nsclc_pd1_msk_2018 (MSK, J Clin Oncol 2018; 240 non-small-cell lung cancers profiled before PD-(L)1 blockade): https://www.cbioportal.org/study/summary?id=nsclc_pd1_msk_2018

## Connected records

- biomarkers: [PD-L1 TPS (tumour proportion score)](https://onco.cc/biomarkers/pd-l1-tps/), [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: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [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: [EGFR](https://onco.cc/targets/egfr/), [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/), [STK11](https://onco.cc/targets/stk11/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- 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: [Neoantigen](https://onco.cc/terms/neoantigen/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [STK11 / KEAP1 co-mutations](https://onco.cc/terms/stk11-keap1/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- people: [Matthew D. Hellmann](https://onco.cc/people/matthew-hellmann/)
- journals: [Journal of Clinical Oncology](https://onco.cc/journals/jco/)

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