# Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Source: https://onco.cc/key-papers/paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017/  
OnCo record `paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The follow-up that took the same test across 12 different cancers and found the same answer, producing the first drug approval in history based on a molecular feature rather than an organ.

## Summary

Le, Durham, Smith and colleagues expanded the 2015 proof-of-concept study to evaluate PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumour types. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones reactive to mutant neopeptides found in the tumour.

The authors concluded that the large proportion of mutant neoantigens in mismatch repair-deficient cancers makes them sensitive to immune checkpoint blockade regardless of tissue of origin, the argument the United States Food and Drug Administration accepted in granting pembrolizumab its tissue-agnostic approval in May 2017.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Journal: Science
- Year: 2017
- DOI: 10.1126/science.aan6733
- Authors: Le DT, Durham JN, Smith KN, et al.
- Findings: Objective radiographic responses in 53 percent of patients and complete responses in 21 percent, across 12 tumour types.; Responses were durable, with median progression-free and overall survival not reached.; Neoantigen-specific T cell clones reactive to mutant neopeptides expanded rapidly in vivo in a responding patient.
- What it means: The first tumour-agnostic approval, and the reason every patient with metastatic colorectal cancer has mismatch repair status tested regardless of where the tumour started.
- Caveats: Single-arm across heterogeneous tumour types; the response rate mixes cancers with very different natural histories.; Mismatch repair testing quality determines who gets the drug, and immunohistochemistry, polymerase chain reaction and sequencing do not always agree.; Around half of mismatch repair-deficient tumours still do not respond, and why is not known.

## Sources

- Science 2017: https://doi.org/10.1126/science.aan6733
- PubMed: https://pubmed.ncbi.nlm.nih.gov/28596308/
- Europe PMC full text (PMC5576142): https://europepmc.org/article/MED/28596308

## Connected records

- key papers: [KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer](https://onco.cc/key-papers/paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020/), [PD-1 blockade in tumors with mismatch-repair deficiency](https://onco.cc/key-papers/paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Mismatch-repair deficient (MSI-high) colorectal cancer](https://onco.cc/cancers/msi-high-colorectal/)
- fronts: [Immunotherapy](https://onco.cc/fronts/immunotherapy/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- institutions: [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/)
- terms: [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Neoantigen](https://onco.cc/terms/neoantigen/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/)
- people: [Dung T. Le](https://onco.cc/people/dung-le/), [Luis A. Diaz Jr.](https://onco.cc/people/luis-diaz/)
- bottlenecks: [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/), [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/)
- journals: [Science](https://onco.cc/journals/science/)
- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/)

---
JSON: https://onco.cc/api/v1/entities/paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017.json