Colorectal cancer patients with unresectable or metastatic tumors bearing a genetic feature — microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) — will now have access to Merck‘s immune checkpoint inhibitor Keytruda (pembrolizumab).
The U.S. Food and Drug Administration (FDA) on May 23 granted accelerated approval for Keytruda’s use in treating adults and children with any solid tumor having such genetic features, not only colorectal cancer. This is the first time the FDA approveds a medicine for patients with a specific biomarker rather than a certain tumor type.
To be eligible, however, colorectal cancer patients must have progressed following treatment with fluoropyrimidine, Eloxatin (oxaliplatin) and Camptosar (irinotecan). Other cancer patients must have progressed following prior therapy and have no satisfactory alternative treatments.
The accelerated approval, based on tumor response and duration of response, may be contingent upon verification and description of clinical benefit in upcoming confirmatory trials.
“The FDA’s approval of this new indication for Keytruda further supports Merck’s commitment to helping people with difficult-to-treat cancers,” Dr. Roger M. Perlmutter, president of Merck Research Laboratories, said in a press release. “We are thankful to the researchers, as well as the patients and their families who helped make today’s approval possible.”
MSI-H and dMMR tumors have genetic abnormalities that impair proper DNA repair inside cells. This leads to the accumulation of mutations in tumor cells. While these mutations often give cells an adaptive advantage over normal cells, they also lead to the production of abnormal proteins, which the immune system sees as malignant. Removing the breaks of immune cells within these tumors with an immune checkpoint inhibitor like Keytruda could help destroy cancer cells.
About 5 percent of patients with metastatic colorectal cancer have MSI-H or dMMR tumors. But while these genetic biomarkers are most commonly found in colorectal, endometrial and gastrointestinal cancers, they also appear in cancers of the pancreas, breast, bladder, thyroid,and prostate, among others.
The FDA based its on data from five uncontrolled, multi-cohort, multi-center, single-arm trials, including 149 patients with MSI-H or dMMR tumors. Of those, 90 had colorectal cancer,and the remaining 59 had one of 14 other cancer types.
Participants received Keytruda until unacceptable toxicity or disease progression, or for up to 24 months. Keytruda was administered in one of two regimens: 200 mg every three weeks, or 10 mg/kg every two weeks.
The major efficacy outcome measures were objective response rate, assessed by an independent review committee, and duration of response. Results showed an overall response rate of 39.6 percent, including 11 complete responses and 48 partial responses. That rate was similar in patients with colorectal cancer (36 percent) or with a different type of cancer (46 percent). Among the responders, 78 percent had responses lasting at least six months.
The recommended dose of Keytruda for adult patients is 200 mg every three weeks, and for children 2 mg/kg (up to a maximum of 200 mg) every three weeks. Both adults and children are treated for up to 24 months, or until unacceptable toxicity or disease progression. However, the safety and efficacy of Keytruda in children with MSI-H central nervous system cancer has not been established.