Clinical Pearls & Morning Reports
Published December 2, 2020
André et al. conducted a randomized, phase 3 trial that evaluated the efficacy and safety of programmed death 1 (PD-1) blockade with pembrolizumab as compared with standard-of-care chemotherapy as first-line treatment for metastatic microsatellite-instability–high (MSI-H) advanced colorectal cancer. Read the NEJM Original Article here.
Q: Describe features of colorectal cancers with mismatch-repair deficiency.
A: One well-described genetic subset of colorectal cancer is tumors with mismatch-repair deficiency (dMMR), which are found in 15% of all patients with colorectal cancer (12% of whom have sporadic cases, and 3% hereditary cases). The majority (approximately 80%) of cases of sporadic dMMR colorectal cancer are caused by methylation of the MLH1 gene promoter, whereas more than 70% of hereditary cases are associated with germline mutations in the MLH1 and MSH2 genes. Both forms result in the inability of cells to recognize and repair spontaneous mutations, resulting in a very high tumor mutation burden as well as altered microsatellite sequences that render these tumors high in microsatellite instability. Mounting evidence suggests that MSI-H–dMMR tumors are less responsive to conventional chemotherapy, but the literature to date has been inconclusive, and chemotherapy remains the standard of care for patients with MSI-H–dMMR colorectal cancer.
Q: Is PD-1 blockade already used for certain colorectal tumors with mismatch-repair deficiency?
A: PD-1 blockade has emerged as highly effective therapy for patients with MSI-H–dMMR metastatic colorectal cancer that is refractory to standard chemotherapy combinations. The PD-1 inhibitors pembrolizumab and nivolumab led to durable response in some patients with previously treated MSI-H–dMMR metastatic colorectal cancer, a finding that contributed to Food and Drug Administration approvals of pembrolizumab and nivolumab for patients with MSI-H–dMMR metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
A: This trial showed that front-line pembrolizumab was superior to chemotherapy with respect to progression-free survival in patients with MSI-H–dMMR metastatic colorectal cancer. The median progression-free survival was 16.5 months (95% confidence interval [CI], 5.4 to 32.4) with pembrolizumab and 8.2 months (95% CI, 6.1 to 10.2) with chemotherapy. The prespecified statistical criteria for superiority of pembrolizumab over chemotherapy were met (hazard ratio, 0.60; 95% CI, 0.45 to 0.80; P=0.0002). The beneficial effect was observed generally across key patient subgroups and supports previous data showing the benefit of pembrolizumab monotherapy in MSI-H–dMMR solid tumors. At the time of data cutoff, data on overall survival were still evolving, with 125 of the required 190 events for the final analysis of overall survival having occurred.
A: Adverse events of grade 3 or higher occurred in 86 patients (56%) in the pembrolizumab group as compared with 111 (78%) in the chemotherapy group; the most common of these events were decreased neutrophil count (0% vs. 17%), neutropenia (0% vs. 15%), and diarrhea (6% vs. 11%). A total of 21 patients (14%) in the pembrolizumab group and 17 (12%) in the chemotherapy group discontinued treatment owing to adverse events. Treatment-related events of grade 3 or higher occurred in 33 patients (22%) and 94 patients (66%), respectively, including one death in the chemotherapy group.