This is the first time that an immunotherapy agent has been approved in this setting and as monotherapy, without added chemotherapy.
“Metastatic colorectal cancer is a serious and life-threatening disease with a poor prognosis,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Oncologic Diseases at the FDA Center for Drug Evaluation and Research, in a statement. “Available current therapy with chemotherapy combinations and other biologics are associated with substantial toxicity.”
“Having a nonchemotherapy option available for selected patients is a noteworthy paradigm shift in treatment,” he commented.
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, and has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types.
The current approval is based on data from the multicenter, randomized KEYNOTE-177 trial, which found that pembrolizumab more than doubled median progression-free survival (PFS) compared with chemotherapy, the current standard of care. The study results were presented earlier this year at the American Society of Clinical Oncology (ASCO) virtual scientific program, as reported by Medscape Medical News. In a commentary about that study, David Kerr, MD, professor of cancer medicine at the Oxford Cancer Centre, UK, said: “We know that MSI-H/dMMR tumors occur in only 4% or 5% of all patients in the advanced setting. Nevertheless, for that small but important subgroup, we now have a well-tolerated new treatment.”
New standard of care
The KEYNOTE-177 trial involved 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR colorectal cancer. They were randomized to receive either pembrolizumab at 200 mg every 3 weeks for up to 35 cycles (n = 153) or to the investigators’ choice of chemotherapy (n = 154).
Chemotherapy regimens were modified FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) used alone or in combination with either bevacizumab or cetuximab, or FOLFIRI (leucovorin, fluorouracil, irinotecan) alone or in combination with either bevacizumab or cetuximab.
Crossover from the chemotherapy arm to immunotherapy was permitted for up to 35 cycles if the patient experienced disease progression confirmed by central review.
The primary endpoints were PFS and overall survival, and the trial would be considered successful if either primary endpoint was met.
Treatment with pembrolizumab monotherapy significantly reduced the risk of disease progression or death by 40% (HR, 0.60; 95% CI, 0.45 - 0.80; P = .0004), with a median PFS of 16.5 months versus 8.2 months for chemotherapy. At the time of the PFS analysis, overall survival data were not yet mature (66% of the required number of events for final analysis).
The overall response rate with pembrolizumab was 44%, with a complete response achieved in 11% of patients and a partial response rate of 33%. For the chemotherapy arm, the overall response rate was 33%, with a complete response rate of 4% and a partial response rate of 29%.
The median duration of response was not reached in the pembrolizumab arm versus 10.6 months with chemotherapy.
“In the past, no medical treatment has shown such difference in terms of improvement of PFS in metastatic colorectal cancer,” said study investigator Thierry André, MD, of Hôpital Saint Antoine in Paris, France, at a press briefing held prior to the presentation at the ASCO meeting.
At that time, Michael J. Overman, MD, of the University of Texas MD Anderson Cancer Center in Houston, told Medscape Medical News that “I think this is setting a new standard of care.”
Grade 3 or greater treatment-related adverse events occurred in 22% of patients on pembrolizumab and 66% on chemotherapy.
Immune-mediated adverse events and infusion reactions were more common with pembrolizumab than chemotherapy (31% and 13%, respectively). Adverse events that were common with chemotherapy included gastrointestinal events, fatigue, neutropenia, and peripheral sensory neuropathy.
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