Frontline pembrolizumab (Keytruda) significantly improved progression-free survival (PFS) compared with chemotherapy among patients with microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) metastatic colorectal cancer, according to results from the KEYNOTE-177 study.
At a median follow-up of 32.4 months, PFS was 16.5 months for patients who received pembrolizumab, vs 8.2 months for the chemotherapy group.
“In the past, no medical treatment has shown such difference in terms of improvement of PFS in metastatic colorectal cancer,” commented lead author Thierry André, MD, of Hôpital Saint Antoine, Paris, France, when presenting this study earlier this year at the annual meeting of the American Society of Clinical Oncology (ASCO),.
“I think this is setting a new standard of care,” said Michael J. Overman, MD, of the University of Texas MD Anderson Cancer Center, Houston, Texas, who was the invited discussant at the ASCO meeting. However, he also pointed out that despite the higher overall response rate (43.8% vs 33.1% with chemotherapy), the rate of progressive disease was higher in the pembrolizumab arm than in the chemotherapy arm (29.4% vs 12.3% for patients who received chemotherapy).
The study has now been published in The New England Journal of Medicine.
Pembrolizumab is the “preferred choice” for patients with MSI-H/dMMR colorectal cancer because of “the durability of response, better safety profile, and improved quality of life associated with immunotherapy as compared with chemotherapy,” comments Axel Grothey, MD, GI Cancer Research, West Cancer Center and Research Institute, Germantown, Tennessee, in an accompanying editorial.
He notes that in colorectal cancer, only 4% to 5% of metastatic cancers show the MSI-H/dMMR phenotype; the prevalence is greater in BRAF V600E–mutated cancers, in cancers originating on the right side, and among female patients.
Immune checkpoint inhibitors have already demonstrated “convincing activity” in MSI-H/dMMR colorectal cancers, and pembrolizumab as well as nivolumab (Opdivo), with or without ipilimumab (Yervoy), are approved for use as salvage therapy in colorectal cancer, he noted.
These results for use as a first-line therapy in his patient population have been “long awaited,” he commented.
The KEYNOTE-177 trial included 307 patients with confirmed, untreated MSI-H/dMMR metastatic colorectal cancer who were randomly assigned to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles (n = 153) or the investigators’ choice of chemotherapy (n = 154). Chemotherapy regimens included modified FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) alone or in combination with either bevacizumab or cetuximab, or FOLFIRI (leucovorin, fluorouracil, irinotecan) alone or in combination with either bevacizumab or cetuximab. Patients in the chemotherapy group could cross over to pembrolizumab therapy after disease progression.
The study’s two primary endpoints were PFS and overall survival.
At the second interim analysis, at a median follow-up (from randomization to data cutoff) of 32.4 months, pembrolizumab proved superior to chemotherapy with regard to PFS (hazard ratio, 0.60; P = .0002).
At 12 months and at 24 months, the estimated percentages of those alive without disease progression were 55.3% and 48.3%, respectively (95% CI, 39.9 – 56.2) in the pembrolizumab group and 37.3% and 18.6%, respectively, in the chemotherapy group.
The mean PFS after 24 months of follow-up was 13.7 months for patients who received pembrolizumab, vs 10.8 months for those who received chemotherapy. PFS was consistently longer with pembrolizumab across key prespecified subgroups. Complete responses were achieved in 11% of patients treated with pembrolizumab and in 4% of those treated with chemotherapy. At 24 months, 83% of patients in the pembrolizumab group had ongoing responses, as compared with 35% in the chemotherapy group.
Overall survival data continue to evolve, the authors comment. They note that 56 patients in the pembrolizumab group and 69 in the chemotherapy group have died. The independent data monitoring committee has recommended that the trial continue without any changes to the final analysis for assessment of overall survival until 190 overall deaths have occurred or until 12 months after the second interim analysis.
Crossover will be a factor when overall survival is assessed, the authors note. At the time of data cutoff, 56 of 154 patients (36%) who received chemotherapy had crossed over to the pembrolizumab group after their disease had progressed. In addition, 35 patients in the chemotherapy group received anti–PD-1 or PD-L1 therapies outside the trial. This extrapolates to a crossover rate of 59% in the intention-to-treat population.
Treatment-related adverse events of grade 3 or higher were more common in the chemotherapy group (66% vs 22%). Immune-mediated adverse events and infusion reactions were more common with pembrolizumab than with chemotherapy (31% and 13%, respectively). Adverse events that were common with chemotherapy included gastrointestinal events, fatigue, neutropenia, and peripheral sensory neuropathy.
In the accompanying editorial, Grothey points out that the results of this trial “deserve some scrutiny,” because disease progression was higher in the pembrolizumab group. This is mirrored by early poorer performance among patients treated with pembrolizumab vs chemotherapy until about 6.5 months after onset of therapy, he notes. After that, the “pembrolizumab group showed protracted improvement — a phenomenon seen in various other trials with PD-1 antibodies in gastrointestinal cancers.
“It appears that a subgroup not yet clearly defined within the MSI-H–dMMR population does not have a response to immune checkpoint inhibitors,” Grothey writes.
The study was funded by Merck. André has received honoraria from Amgen, GlaxoSmithKline, and Pierre Fabre Pharmaceuticals; consulting fees and travel support from Bristol-Myers Squibb; advisory board fees and honoraria from F. Hoffmann–La Roche; advisory board fees from Gritstone Oncology, Halliodx, and Tesaro; grant support, paid to Hôpitaux de Paris; advisory board fees, honoraria, and travel support from Merck Sharp and Dohme; consulting fees and honoraria from Servier; and honoraria and travel support from Ventana Medical Systems. Grothey has received grants and nonfinancial support from Bayer; grants from Boston Biomedicals; grants from OBI Pharmaceuticals, Array/Pfizer, Natera, Merck, and Bristol-Myers Squibb and grants and nonfinancial support from Roche/ Genentech outside the submitted work.
N Engl J Med. 2020;383:2207-2218, 2283-2285