Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval
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.
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).
- 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.
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.
- 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).
NICHE-2 shows that a month of immunotherapy before surgery can effectively cure locally advanced dMMR colon cancer, where chemotherapy after surgery has limited benefit. It is changing guidelines towards neoadjuvant checkpoint blockade for this group and raises the question of whether surgery can be omitted altogether, as in dMMR rectal cancer. Whether the same applies to MMR-proficient tumours is being tested but is not established.
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.