Dung T. Le
First author of the studies that showed mismatch-repair-deficient tumours respond to PD-1 blockade regardless of origin.
Led the KEYNOTE-016 study and its extension establishing pembrolizumab's tissue-agnostic activity in dMMR tumours; also works on GVAX and pancreatic cancer vaccines.
| Title | Journal | Year |
|---|---|---|
| PD-1 blockade in tumors with mismatch-repair deficiency | New England Journal of Medicine | 2015 |
Every colorectal cancer should be tested for mismatch repair deficiency, because patients whose metastatic tumour is dMMR should receive pembrolizumab rather than chemotherapy as first treatment, gaining a much better chance of durable remission with fewer side effects. About a third of dMMR tumours do not respond initially, so early scans are essential and chemotherapy remains available. The trial does not apply to the 95% of colorectal cancers that are mismatch-repair proficient.
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.
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.