Immunotherapy Shows Promise in MSI-High Colorectal Cancer

Drugs that inhibit immune checkpoints have largely failed in advanced colorectal cancer (CRC) trials, despite demonstrating significant activity against other solid tumors. One explanation for this finding is that cancers with a higher number of somatic mutations and, potentially, a higher antigen burden, may stimulate a greater immune response.

To test whether microsatellite-instability (MSI)–high tumors — which have a high rate of somatic mutation — are more responsive to blockade of the programmed-death 1 (PD-1) pathway than microsatellite-stable (MSS) tumors, investigators conducted an industry-sponsored, multicenter, phase II trial of the anti–PD-1 agent pembrolizumab in three patient cohorts. Two cohorts had advanced chemotherapy-refractory CRC with either MSI (DNA mismatch-repair–deficient) or MSS (DNA mismatch-repair–proficient) tumors. A third cohort included patients with various cancers that tested MSI high. Of the 42 patients, 11 had MSI-high CRC, 21 had MSS CRC, and 9 had other MSI-high tumors, including cholangiocarcinoma, endometrial, small bowel, and gastric cancer.

Patients with MSI-high CRC and other MSI-high tumors had high rates of immune-related objective response (40% and 71%, respectively) and high rates of immune-related progression-free survival (PFS) at 20 weeks (78% and 67%). No responses were seen in MSS CRC patients, and the 20-week PFS was only 11%. No new toxicity signals were observed.