BACKGROUND: Chemotherapy is currently the standard of care for patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer (CRC); however, some patients have disease that is refractory to chemotherapy. Programmed-cell death (PD)-1 inhibitors have emerged as a highly effective therapy in this setting.
METHODS: KEYNOTE-177 was a multicenter, international, open-label, phase 3 study that enrolled 307 treatment-naïve patients with metastatic MSI-H or dMMR CRC. Patients were randomized in a 1:1 ratio to pembrolizumab 200 mg every 3 weeks or to chemotherapy with 5-fluorouracil–based therapy (with or without bevacizumab or cetuximab) every 2 weeks. Crossover from chemotherapy to pembrolizumab was allowed after disease progression. The median duration of patients’ exposure to treatment was 11.1 months in the pembrolizumab group and 5.7 months in the chemotherapy group. Pembrolizumab therapy was continued for a maximum of 35 treatments or until disease progression, unacceptable side effects, illness, or withdrawal. The primary end points were progression-free survival (PFS) and overall survival.
RESULTS: After a median follow-up of 32.4 months, PFS was doubled in the pembrolizumab group compared with the chemotherapy group, for a median of 16.5 months versus 8.2 months, respectively (hazard ratio, 0.60; P = .0002). More patients were alive and progression-free at 12 months and at 24 months in the pembrolizumab group (55.3% and 48.3%, respectively) compared with the chemotherapy group (37.3% and 18.6%, respectively). “After an initial crossing of the progression-free survival Kaplan–Meier curves, a pronounced separation of the curves for pembrolizumab and chemotherapy was observed, which indicated a meaningful long-term benefit with pembrolizumab,” the researchers noted. As of the data cutoff date, 56 patients in the pembrolizumab group and 69 patients in the chemotherapy group had died. Data on overall survival were still evolving and remain blinded until the final analysis. The overall (partial or complete) response was 43.8% in the pembrolizumab group versus 33.1% in the chemotherapy group. The overall ongoing response rate at 24 months was also greater in the pembrolizumab group (83%) compared with the chemotherapy group (35%). The incidence of grade 3 or 4 adverse events was lower with pembrolizumab (56%) versus chemotherapy (78%). In addition, patients in the PD-1 inhibitor group had fewer treatment-related adverse events (22%) than in the chemotherapy group (66%), and 1 death was reported in the chemotherapy group. “These data represent another step forward for biomarker-driven studies targeting MSI-H–dMMR colorectal cancers….Pembrolizumab should be considered an option for initial therapy for patients with MSI-H–dMMR metastatic colorectal cancer,” the authors noted.
Source: André T, Shiu KK, Kim TW, et al; for the KEYNOTE-177 investigators. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383:2207-2218.
Commentary by Robert J. Ignoffo
This study is likely to change practice. The PD-1 inhibitor pembrolizumab is significantly more effective than chemotherapy for the treatment of patients with MSI-H or dMMR metastatic CRC. In addition, fewer grade ≥3 toxicities occurred with pembrolizumab (22%) than with chemotherapy (66%). No neutropenia was reported in the pembrolizumab arm versus 15% in the chemotherapy arm. Furthermore, 59% of patients who received chemotherapy crossed over to the immunotherapy cohort.
In his accompanying editorial, Axel Grothey, MD, stated that for CRC with MSI-H or dMMR, “the durability of response, better safety profile, and improved quality of life associated with immunotherapy as compared with chemotherapy make pembrolizumab the preferred choice.” This is a major advance in immunotherapy for this type of CRC. Another PD-1 inhibitor, nivolumab, has also had good responses in phase 2 studies of patients with MSI-H or dMMR CRC.1
What impact will this new treatment standard have in the United States? The prevalence of CRC with MSI-H or dMMR is 4% to 5%.1 Several researchers have indicated that the MSI-H phenotype has a poor prognosis in metastatic CRC.1 There are almost 148,000 new cases of CRC diagnosed annually in the United States, with approximately 22% diagnosed in patients with metastatic disease2; thus, approximately 3000 patients annually will be eligible for treatmzent with a PD-1 inhibitor. A better understanding of MSI-H status and other actionable targets is reshaping the therapeutic approach for metastatic CRC.
- Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142). Lancet Oncol. 2017;18:1182-1191.
- National Cancer Institute SEER Program. Cancer stat facts: colorectal cancer. https://seer.cancer.gov/statfacts/html/colorect.html. Accessed February 9, 2021.