FDA Approves Immunotherapy for MSI-High or MMR-Deficient Tumors

This marks the agency’s first cancer-site agnostic approval

The US Food and Drug Administration (FDA) has granted accelerated approval to pembrolizumab (Keytruda) for pediatric and adult patients with microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient solid tumors. The indication is for patients with unresectable or metastatic tumors who have progressed after prior treatments, and for colorectal cancer patients who have progressed after treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

MSI-high or MMR-deficient tumors are most commonly found in endometrial cancer, colorectal cancer (up to 5% of metastatic patients), and other gastrointestinal cancers. But these types of tumors have also been identified in genitourinary cancers, breast cancer, thyroid cancer, and others.

“This is an important first for the cancer community,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a press release. “Until now, the FDA has approved cancer treatments based on where in the body the cancer started-for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”

This approval of pembrolizumab was based on data from five single-arm multi-cohort trials. In total, 149 patients with MSI-high or MMR-deficient tumors were included, 90 of whom had colorectal cancer. Fourteen other cancer types comprised the remaining patients.

Patients were treated with 200-mg pembrolizumab every 3 weeks or 10-mg/kg pembrolizumab every 2 weeks until unacceptable toxicity or either symptomatic disease progression, rapid progression requiring urgent intervention, or progression with a performance status decline. Maximum length of treatment was 24 months.

Among all patients, the objective response rate was 39.6% (95% CI, 31.7%–47.9%), with 48 partial responses and 11 complete responses. Among responders, 78% had responses of 6 months or greater. The objective response rate was 36% in patients with colorectal tumors and 46% in patients with the 14 other tumor types.

In 135 patients, tumor status was determined prospectively by either an investigational polymerase chain reaction test for MSI-high tumors or by immunohistochemistry tests for MMR-deficient tumors. In 14 patients, MSI-high tumor status was determined retrospectively.

Common adverse events due to pembrolizumab included constipation, cough, decreased appetite, diarrhea, dyspnea, fatigue, musculoskeletal pain, nausea, pruritus, pyrexia, and rash. Immune-mediated side effects are also associated with pembrolizumab; these include colitis, endocrinopathies, hepatitis, nephritis, and pneumonitis.

For adults, the recommended dose for this indication is 200 mg every 3 weeks. For children, the recommended dose is 2 mg/kg, up to a maximum of 200 mg, every 3 weeks.

The safety and effectiveness of pembrolizumab in MSI-high central nervous system cancers have not been established in pediatric patients.