# Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ

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

## TL;DR

Pembrolizumab shrank tumours in 40% of colorectal and 71% of other cancers with faulty DNA mismatch repair, but in none with intact repair, tying immunotherapy response to mutation burden.

## Summary

This investigator-initiated phase 2 study tested the hypothesis that tumours with defective DNA mismatch repair (dMMR), which accumulate thousands of mutations and neoantigens, would respond to PD-1 blockade. Forty-one patients with treatment-refractory metastatic cancer were enrolled in three cohorts: dMMR colorectal cancer, MMR-proficient colorectal cancer, and dMMR non-colorectal cancers, all treated with pembrolizumab 10 mg/kg every two weeks. Immune-related objective response rates were 40% (4 of 10) in dMMR colorectal cancer, 0% (0 of 18) in MMR-proficient colorectal cancer and 71% (5 of 7) in dMMR non-colorectal cancers; 20-week PFS was 78% versus 11% in the two colorectal cohorts. Whole-exome sequencing showed a mean of 1782 somatic mutations in dMMR versus 73 in proficient tumours, and higher mutation load correlated with longer PFS.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2015
- DOI: 10.1056/NEJMoa1500596
- Authors: Le DT, Uram JN, Wang H, et al.
- Findings: 41 patients: 11 dMMR colorectal, 21 MMR-proficient colorectal, 9 dMMR non-colorectal; pembrolizumab 10 mg/kg every 2 weeks.; Immune-related objective response: 40% dMMR colorectal, 0% proficient colorectal, 71% dMMR non-colorectal.; Immune-related PFS at 20 weeks: 78% (dMMR colorectal) vs 11% (proficient colorectal).; Mean somatic mutations per tumour 1782 (dMMR) vs 73 (proficient); higher load associated with longer PFS.; Benefit occurred in both Lynch-syndrome and sporadic dMMR tumours.
- What it means: This small trial explained why colorectal cancer had seemed immune-resistant (most is MMR-proficient) and established the principle that a genomic feature, not the tissue of origin, can predict immunotherapy response. It led directly to the 2017 tissue-agnostic approval of pembrolizumab and to routine MMR/MSI testing of many cancers. Every patient with advanced dMMR cancer should now be considered for checkpoint blockade.
- Caveats: Very small cohorts; response rates have wide confidence intervals.; Dose of 10 mg/kg is higher than later standard dosing.; Single-arm; no randomised comparison until KEYNOTE-177.; Mutation burden as a biomarker beyond dMMR has proved less clean than this data suggested.

## Sources

- Full text (DOI): https://doi.org/10.1056/NEJMoa1500596
- ClinicalTrials.gov NCT01876511: https://clinicaltrials.gov/study/NCT01876511
- 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/), [Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency](https://onco.cc/key-papers/paper-cercek-dostarlimab-rectal-nejm-2022/), [KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer](https://onco.cc/key-papers/paper-keynote-177-nejm-2020/), [Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval](https://onco.cc/key-papers/paper-le-mmr-deficiency-science-2017/)
- biomarkers: [dMMR (mismatch repair deficiency by IHC)](https://onco.cc/biomarkers/dmmr-ihc/), [MSI-high (microsatellite instability by PCR or sequencing)](https://onco.cc/biomarkers/msi-high/), [TMB-high (tumour mutational burden >= 10 mutations per megabase)](https://onco.cc/biomarkers/tmb-high/)
- 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/), [MSI and mismatch-repair testing](https://onco.cc/technologies/msi-mmr-testing/), [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/)
- pathways: [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/), [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: [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)](https://onco.cc/terms/mss-pmmr/), [Neoantigen](https://onco.cc/terms/neoantigen/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/)
- people: [Bert Vogelstein](https://onco.cc/people/bert-vogelstein/), [Drew M. Pardoll](https://onco.cc/people/drew-pardoll/), [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: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [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/)
- trials: [CheckMate 8HW](https://onco.cc/trials/checkmate-8hw/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/), [NICHE-2](https://onco.cc/trials/niche-2/)
- ideas: [Making microsatellite-stable colorectal cancer immunotherapy-responsive](https://onco.cc/ideas/idea-immunotherapy-mss-crc/), [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/)
- 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/)

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