Keytruda Approval Recommended in EU as First-line Therapy for Certain Colorectal Cancers

Keytruda Approval Recommended in EU as First-line Therapy for Certain Colorectal Cancers

Keytruda (pembrolizumab) has been recommended for approval in the European Union (EU) as a first-line treatment for adults with inoperable or metastatic colorectal cancer with certain genetic features.

These include high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) — both good indicators of impaired DNA repair, which increase the number of mutations in a tumor and the likelihood it will be seen as a threat by the immune system.

An estimated 5%–15% of colorectal cancer patients have tumors that test positive for either of these features.

The recommendation was made by the Committee for Medicinal Products for Human Use (CHMP), an arm of the European Medicines Agency. The CHMP’s recommendations are generally accepted by the European Commission, which makes the final decision about approval. A decision about Keytruda is anticipated for the first months of 2021.

“Patients in Europe with MSI-H/dMMR colorectal cancer have had only chemotherapy-containing regimens available to them in the first-line treatment setting and have historically faced poor outcomes,” Vicki Goodman, MD, vice president of clinical research at Merck Research Laboratories, said in a press release. Merck (known as MSD outside North America) is the developer of Keytruda.

“This positive EU CHMP opinion reinforces the potential of Keytruda as a new option for patients with MSI-H/dMMR colorectal cancer and illustrates our ongoing commitment to pursuing biomarker research to help address the needs of patients who have few effective options,” she added.

The opinion follows Keytruda’s approval in the U.S. for the same indication, making it the first single-agent immunotherapy — and first alternative to chemotherapy — available in the country for this patient population in the first-line setting.

Keytruda is approved in the U.S. and EU for the treatment of different types of cancer, including lung, bladder, stomach, esophageal, and liver cancer, lymphoma, melanoma (a type of skin cancer), and cancers with specific genetic features that failed prior therapies.

An immune checkpoint inhibitor, Keytruda works by preventing an immune evasion mechanism involving the interaction between the PD-1 receptor in T-cells, immune cells involved in the fight against cancer, and the PD-L1 protein in cancer cells. As such, Keytruda is expected to boost anti-cancer immune responses and cancer cell death.

The CHMP’s positive opinion was based on data from the KEYNOTE-177 Phase 3 trial (NCT02563002), which is evaluating the safety and effectiveness of first-line treatment with Keytruda, compared with standard chemotherapy, in 307 adults with advanced colorectal cancer with MSI-H or dMMR.

Participants were randomly assigned to receive either 200 mg of Keytruda, every three weeks (153 patients), or one of six standard chemotherapy regimens selected by the trial investigators, every two weeks (154 patients). Treatment is given directly into the bloodstream in both groups.

Patients will receive treatment until disease progression, unacceptable toxicity, the patient or investigator’s decision to withdraw, or the completion of 35 treatment cycles (about two years) in the case of those assigned to Keytruda. Crossover from chemotherapy to Keytruda was allowed after disease progression.

The trial’s main goals were to assess whether Keytruda was superior to chemotherapy at prolonging the time patients lived without any signs of disease progression, and at extending their overall survival. Secondary goals included the proportion of patients responding to treatment and safety measures.

KEYNOTE-177’s interim data, published in The New England Journal of Medicine, showed that compared with standard chemotherapy, Keytruda doubled the time patients lived without signs of disease progression from 8.2 to 16.5 months, representing a 40% lower risk of disease progression or death.

In addition, a greater proportion of Keytruda-treated patients were alive and without signs of disease progression after one year (55.3% vs. 37.3%) and two years (48.3% vs. 18.6%), compared with those given standard treatment.

Patients receiving Keytruda were also more likely to respond to treatment (43.8% vs. 33.1%), both in terms of partial (33% vs. 29%) and complete (11% vs. 4%) responses, or cancer elimination.

Among participants responding to treatment after two years, 83% in the Keytruda group had ongoing responses after a median follow-up of 32.4 months (nearly three years), compared with 35% in the chemotherapy group.

Median overall survival had not yet been reached, though data thus far is favoring the Keytruda arm. The trial is continuing to complete these final assessments.

Moreover, treatment-related severe or life-threatening adverse events were less common among Keytruda-treated patients than among those on chemotherapy (22% vs. 66%). One patient in the chemotherapy group died due to a treatment-related adverse event.

A slightly greater proportion of patients receiving Keytruda discontinued treatment due to adverse events (14% vs. 12%), but its safety profile was consistent with that reported across multiple types of cancer in previous clinical trials.