The European Commission has approved Keytruda (pembrolizumab) as a first-line therapy for adults with metastatic colorectal cancer whose tumors have certain genetic features, the company announced.
The genetic features, according to a press release, include microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR), both good indicators that tumor cells have impaired DNA repair. These DNA repair deficiencies contribute to increase the number of mutations found in a tumor, as well as the likelihood of it being seen as a threat by the immune system.
With this decision, announced little more than a month after the Committee for Medicinal Products for Human Use recommended its approval, Keytruda now has become the first immune checkpoint inhibitor to be approved for this indication in Europe.
Keytruda’s approval for this indication will be valid in all 27 EU country members, in addition to Iceland, Lichtenstein, Norway, and Northern Ireland. It also will apply to Great Britain, in accordance with the reliance route defined in Brexit.
Keytruda, by Merck (known as MSD outside of the U.S. and Canada), is an immune checkpoint inhibitor that works to inhibit PD-1, a protein receptor found on the surface of immune T-cells that is exploited by cancer cells to help them evade immune responses.
Through this mechanism, Keytruda increases the immune system’s ability to recognize and destroy malignant tumor cells. That is why the medication also is expected to be more effective in patients whose tumors are already seen as a threat by the immune system, such as those that are MSI-H or dMMR.
Keytruda’s recent approval was based on interim data from the KEYNOTE-177 Phase 3 clinical trial (NCT02563002). In that trial the medication lowered the risk of disease progression or death by 40% compared with different chemotherapy regimens, in adults with advanced MSI-H or dMMR colorectal cancer.
“Before the KEYNOTE-177 trial, conventional chemotherapy with targeted therapy was the standard of care for patients with metastatic colorectal cancer who have tumors that are MSI-H/dMMR,” said Thierry Andre, MD, professor of medical oncology at Sorbonne University and head of the medical oncology department at St. Antoine Hospital, which is part of the Assistance Publique Hôpitaux de Paris.
“With this approval, patients with metastatic colorectal cancer that is MSI-H or dMMR status will gain a monotherapy treatment option that has shown superior progression-free survival compared to standard of care chemotherapy,” Andre said.
KEYNOTE-177 enrolled 307 patients with advanced MSI-H or dMMR colorectal cancer, who were assigned randomly to receive either 200 mg of intravenous (into-the-vein) Keytruda every three weeks, or one of six standard chemo regimens selected by the trial’s investigators, given intravenously every two weeks.
Patients assigned to Keytruda were treated for up to 24 months (two years), or until disease progression or unacceptable toxicity. Those originally assigned to chemo were given the option to switch to Keytruda after showing signs of disease worsening.
The study’s main goals were to assess whether Keytruda was superior to chemo at prolonging the time patients lived without disease worsening, and at extending their overall survival. Secondary goals included safety, as well as the proportion of patients responding to treatment.
Interim data from KEYNOTE-177 showed that Keytruda prolonged the time patients lived without worsening from a median of 8.2 months with chemo to 16.5 months, effectively reducing the risk of disease progression or death by 40%.
Analyses of overall survival are still ongoing, although data gathered so far seems to be favoring Keytruda over standard chemotherapy.
The percentage of patients responding to treatment also was higher with Keytruda (44% vs. 33%), as was the proportion of complete responders (11% vs. 4%). Also, while responses lasted a median of 10.6 months among patients receiving chemotherapy, the median response duration has not yet been reached for those on Keytruda, meaning that more than half of the patients are still responding to treatment.
Safety assessments demonstrated that serious treatment-related side effects were three times more frequent with standard chemo than with Keytruda (66% vs. 22%). In general, side effects observed in these patients were consistent with those reported in previous clinical trials of Keytruda. No new safety concerns were identified.
Data from KEYNOTE-177 also supported Keytruda’s approval for the same indication in the U.S. last year.
