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