# Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval

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

## TL;DR

Across 86 patients with 12 different dMMR cancers, pembrolizumab produced responses in 53% and complete responses in 21%, prompting the first approval of a cancer drug based on a genetic marker rather than tumour site.

## Summary

Extending the 2015 study, this report treated 86 patients with treatment-refractory, mismatch-repair-deficient cancers of 12 types (colorectal, endometrial, gastric, biliary, pancreatic, small bowel and others) with pembrolizumab. The objective response rate was 53% (46 of 86) with complete responses in 21% (18); disease control was 77%, and neither median PFS nor OS had been reached at a median follow-up of 12.5 months. Responses were seen in every tumour type. Functional analysis showed rapid in vivo expansion of neoantigen-specific T-cell clones. The FDA approved pembrolizumab for any unresectable or metastatic MSI-H/dMMR solid tumour in May 2017, the first tissue-agnostic cancer drug approval, and the randomised KEYNOTE-177 trial later confirmed first-line benefit in dMMR colorectal cancer (median PFS 16.5 versus 8.2 months).

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: Science
- Year: 2017
- DOI: 10.1126/science.aan6733
- Authors: Le DT, Durham JN, Smith KN, et al.
- Findings: 86 patients with dMMR cancers of 12 types; pembrolizumab 10 mg/kg every 2 weeks.; Objective response 53% (46 of 86); complete response 21% (18 of 86); disease control 77%.; Median PFS and OS not reached at 12.5 months median follow-up; responses in all 12 tumour types.; Neoantigen-specific T-cell clones expanded in blood within weeks of starting therapy.; Estimated that dMMR occurs in about 4% of advanced cancers, roughly 60,000 patients a year in the United States.
- What it means: This paper established a new regulatory paradigm: a drug approved for a molecular feature regardless of organ. It made MSI/MMR testing standard across advanced cancers and remains the clearest example of a biomarker that works across histologies. It also anchored the idea that mutation load, via neoantigens, is what makes tumours visible to T cells.
- Caveats: Single-arm basket study; approvals rested on response rate and durability.; Heterogeneous prior therapies and tumour types; small numbers per type.; Roughly a quarter of dMMR tumours are primary resistant, and mechanisms (B2M loss, JAK mutations) are incompletely understood.; Later data suggest sensitivity varies by MSI assay and tumour type (for example, lower in some dMMR pancreatic and brain tumours).

## Sources

- Full text (DOI): https://doi.org/10.1126/science.aan6733
- ClinicalTrials.gov NCT01876511: https://clinicaltrials.gov/study/NCT01876511
- 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/), [Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ](https://onco.cc/key-papers/paper-le-mmr-deficiency-pd1-nejm-2015/), [NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients](https://onco.cc/key-papers/paper-niche-2-nejm-2024/)
- 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/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Microsatellite-unstable (MSI-high) gastric cancer](https://onco.cc/cancers/gastric-msi-high/), [Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma](https://onco.cc/cancers/msi-high-pdac/), [Mismatch-repair deficient (MSI-high) colorectal cancer](https://onco.cc/cancers/msi-high-colorectal/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- 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/)
- targets: [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- 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/)
- terms: [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [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/)
- trials: [CheckMate 8HW](https://onco.cc/trials/checkmate-8hw/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/)
- people: [Dung T. Le](https://onco.cc/people/dung-le/), [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/), [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [Regulatory divergence between regions](https://onco.cc/bottlenecks/b-regulatory-fragmentation/)
- 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/)

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