Richard Pazdur, MD
The FDA has granted an accelerated approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR colorectal cancer following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.
The approval was based on data from 149 patients with MSI-H or dMMR cancers enrolled across 5 single-arm clinical trials. Ninety patients had colorectal cancer (CRC) and the remaining 59 patients had 1 of 14 other tumor types.
The objective response rate (ORR) with pembrolizumab was 39.6% (95% CI, 31.7-47.9), including 11 (7.4%) complete responses (CRs) and 48 (32.2%) partial responses (PRs). The ORR was 36% in patients with CRC and 46% in patients with other tumor types. The median duration of response was not yet reached (range, 1.6+ months to 22.7+ months). Among patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 months.
“This is an important first for the cancer community,” Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence, said in a statement. “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.”
The pivotal data for the approval included patients from the KEYNOTE-016 (n = 58), KEYNOTE-164 (n = 61), KEYNOTE-012 (n = 6), KEYNOTE-028 (n = 5), and KEYNOTE-158 (n = 19) trials. Pembrolizumab was administered at 200 mg every 3 weeks or 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months.
The median age among the 149 patients was 55 years, with 36% of patients aged 65 or older. Across the population, 77% of patients were white, 56% were male, 36% had an ECOG performance status (PS) of 0, and 64% had an ECOG PS of 1.
Two percent of patients had locally advanced, unresectable disease, and 98% of patients had metastatic disease. Among patients with metastatic or unresectable disease, the median number of prior therapies was 2. In patients with metastatic CRC, 84% had received at least 2 prior lines of therapy, compared with 53% in patients with other solid tumors.
Beyond CRC, other tumor types in which patients had responses included endometrial cancer (n = 5), biliary cancer (n = 3), gastric or GE junction cancer (n = 5), pancreatic cancer (n = 5), small intestinal cancer (n = 3), breast cancer (n = 2), prostate cancer (n = 1), esophageal cancer (n = 1), retroperitoneal adenocarcinoma (n = 1), and small cell lung cancer (n = 1).
Among the majority (n = 135) of the 149 patients, MSI-H or dMMR tumor status was determined prospectively with IHC tests for dMMR or laboratory-developed, investigational polymerase chain reaction (PCR) tests for MSI-H status. MSI-H status for the remaining 14 patients was determined through a retrospective evaluation of 415 tumor samples using a central laboratory-developed PCR test.
IHC identified dMMR cancer in 47 patients, MSI-H was identified by PCR in 60 patients, and 42 patients were identified with both tests.
In its statement on the approval, the FDA listed common side effects of pembrolizumab, including fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea. Immune-mediated side effects associated with pembrolizumab include pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
The FDA also noted that the label for pembrolizumab includes a “Limitation of Use” indicating that the efficacy and safety of pembrolizumab have not been established in pediatric patients with MSI-H CNS cancers.
The accelerated approval for pembrolizumab in this setting is contingent on the results of a confirmatory trial. The approval was preceded by a breakthrough therapy designation the FDA granted to pembrolizumab in November 2015 as a treatment for patients with MSI-H metastatic CRC.
Pembrolizumab has additional approved indications in melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, and urothelial carcinoma.