The Lynx Group

Pembrolizumab Shows Long-Term Benefits in Metastatic Colorectal Cancer and MSI-H or dMMR

February 2021, Vol 12, No 1

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 death (PD)-1 inhibitors have emerged as a highly effective therapy in this setting. A new study investigated the PD-1 inhibitor pembrolizumab (Keytruda) in patients with MSI-H or dMMR metastatic CRC (André T, et al. N Engl J Med. 2020;383:2207-2218).

KEYNOTE-177 was a multicenter, international, open-label, phase 3 study of 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 to pembrolizumab was allowed after disease progression.

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 (OS).

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 OS were still evolving and remain blinded until the final analysis.

The overall response rate (ORR) was 43.8% with pembrolizumab versus 33.1% with chemotherapy. The ORR at 24 months was also greater in the pembrolizumab arm (83%) compared with chemotherapy arm (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. Treatment with pembrolizumab led to significantly longer progression-free survival and fewer treatment-related adverse events than chemotherapy,” the researchers noted. “As a result, pembrolizumab should be considered an option for initial therapy for patients with MSI-H–dMMR metastatic colorectal cancer.”

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