# PD-1 blockade in tumors with mismatch-repair deficiency

Source: https://onco.cc/key-papers/paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015/  
OnCo record `paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Forty-one patients settled a decade of argument: colorectal cancers with a broken DNA spell-checker responded to immunotherapy in 40 percent of cases, and those without responded in none.

## Summary

Le, Uram, Wang and colleagues conducted a phase 2 study of pembrolizumab at 10 mg per kilogram every 14 days in 41 patients with progressive metastatic carcinoma, in three cohorts: mismatch repair-deficient colorectal cancers, mismatch repair-proficient colorectal cancers, and mismatch repair-deficient cancers that were not colorectal. The co-primary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.

Whole-exome sequencing showed a mean of 1,782 somatic mutations per tumour in mismatch repair-deficient tumours against 73 in proficient ones (p=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (p=0.02).

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Journal: New England Journal of Medicine
- Year: 2015
- DOI: 10.1056/NEJMoa1500596
- Authors: Le DT, Uram JN, Wang H, et al.
- Findings: Immune-related objective response 40 percent (4 of 10) and 20-week progression-free survival 78 percent (7 of 9) in mismatch repair-deficient colorectal cancer.; 0 percent (0 of 18) and 11 percent (2 of 18) in mismatch repair-proficient colorectal cancer.; Median progression-free and overall survival not reached in the deficient cohort against 2.2 and 5.0 months in the proficient cohort (hazard ratios 0.10, p<0.001, and 0.22, p=0.05).; In mismatch repair-deficient non-colorectal cancers, response 71 percent (5 of 7).; Mean 1,782 somatic mutations per tumour in deficient against 73 in proficient tumours (p=0.007).
- What it means: The paper that split colorectal cancer into two diseases for immunotherapy purposes, and the direct ancestor of the first tumour-agnostic drug approval two years later.
- Caveats: Ten patients in the key cohort; the effect size is large but the estimate is not precise.; Single-arm phase 2 with immune-related response criteria rather than standard RECIST.; It said nothing about how to treat the 95 percent of metastatic colorectal cancers that are mismatch repair-proficient, and that question is still open.

## Sources

- N Engl J Med 2015: https://doi.org/10.1056/NEJMoa1500596
- PubMed: https://pubmed.ncbi.nlm.nih.gov/26028255/
- Europe PMC full text (PMC4481136): https://europepmc.org/article/MED/26028255

## Connected records

- key papers: [Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial](https://onco.cc/key-papers/paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024/), [Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade](https://onco.cc/key-papers/paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017/), [Pembrolizumab in microsatellite-instability-high advanced colorectal cancer (KEYNOTE-177)](https://onco.cc/key-papers/paper-andre-keynote-177-pembrolizumab-msi-high-nejm-2020/)
- 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/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- 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/)
- companies: [Merck & Co. (MSD)](https://onco.cc/companies/merck/)
- 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: [Bert Vogelstein](https://onco.cc/people/bert-vogelstein/), [Dung T. Le](https://onco.cc/people/dung-le/), [Kenneth W. Kinzler](https://onco.cc/people/kenneth-kinzler/), [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/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- 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/)
- ideas: [Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed](https://onco.cc/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/)

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