Luis A. Diaz Jr.
Co-led the work that made pembrolizumab the first tumour-agnostic cancer drug approval, for mismatch-repair-deficient tumours.
Trained at Johns Hopkins with Vogelstein and Kinzler, where he co-founded Personal Genome Diagnostics and helped establish circulating tumour DNA as a clinical tool. The 2015 and 2017 studies of PD-1 blockade in dMMR tumours led to the 2017 tissue-agnostic approval of pembrolizumab. At MSK he co-led the dostarlimab rectal cancer programme.
| Title | Journal | Year |
|---|---|---|
| PD-1 blockade in tumors with mismatch-repair deficiency | New England Journal of Medicine | 2015 |
| Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade | Science | 2017 |
Cercek's dostarlimab study is the clearest demonstration that immunotherapy can replace surgery in a solid tumour: patients with dMMR rectal cancer can keep their rectum and avoid the permanent effects of pelvic radiotherapy and surgery. Non-operative management after PD-1 blockade is now in guidelines for this group, and MMR testing before treatment of rectal cancer is essential. The approach applies only to the 5-10% of rectal cancers that are dMMR.
Patients with rectal cancer whose tumour is mismatch-repair deficient (about 5-10% of rectal cancers) can now be offered immunotherapy alone with the realistic expectation of avoiding surgery, radiotherapy and a permanent stoma. This requires mismatch repair testing on the diagnostic biopsy, close endoscopic and MRI surveillance, and treatment in an experienced centre. It does not apply to the 90% of rectal cancers that are mismatch-repair proficient.
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.