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Pembrolizumab (Keytruda)
The US Food and Drug Administration (FDA) has issued a statement warning about an increased risk of death associated with an unapproved use of pembrolizumab (Keytruda).
Results from 2 clinical trials have shown that combining pembrolizumab with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) increases the risk of death in patients with multiple myeloma (MM).
The FDA issued its statement to remind doctors and patients that pembrolizumab is not approved to treat MM and should not be given in combination with immunomodulatory agents to treat MM.
Pembrolizumab is currently FDA-approved to treat classical Hodgkin lymphoma, melanoma, lung cancer, head and neck cancer, urothelial carcinoma, and microsatellite instability-high cancer.
The FDA believes the benefits of taking pembrolizumab and other PD-1/PD-L1 inhibitors for their approved uses continue to outweigh the risks, according to Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research.
However, the FDA is investigating trials of pembrolizumab as well as trials of other PD-1/PD-L1 inhibitors.
Pembrolizumab in MM
The FDA’s warning is based on a review of data from 2 clinical trials—KEYNOTE-183 and KEYNOTE-185. The FDA placed a clinical hold on these trials—as well as KEYNOTE-023—in July.
KEYNOTE-183 is a phase 3 study of pomalidomide and low-dose dexamethasone, given with or without pembrolizumab, to patients with refractory or relapsed and refractory MM.
KEYNOTE-185 is a phase 3 study of lenalidomide and low-dose dexamethasone, given with or without pembrolizumab, to patients with newly diagnosed and treatment-naïve MM.
KEYNOTE-023 is a phase 1 trial of pembrolizumab in combination with backbone treatments. Cohort 1 of this trial was designed to evaluate pembrolizumab in combination with lenalidomide and dexamethasone in MM patients who received prior treatment with an immunomodulatory agent (lenalidomide, pomalidomide, or thalidomide).
Interim results from KEYNOTE-183 and KEYNOTE-185 revealed an increased risk of death for patients receiving pembrolizumab, when compared to patients receiving the control therapies.
Merck & Co., Inc., the company developing pembrolizumab, was informed of this risk by an external data monitoring committee. The company suspended enrollment in the trials and notified the FDA of the issue in June.
The following month, the FDA announced that all patients enrolled in KEYNOTE-183 and KEYNOTE-185, as well as patients in the pembrolizumab/lenalidomide/dexamethasone cohort of KEYNOTE-023, would discontinue investigational treatment with pembrolizumab.
FDA investigation
The FDA is examining data from the pembrolizumab trials and working with Merck to better understand the cause of the safety concerns, according to Woodcock.
The agency is also working with sponsors of other PD-1/PD-L1 inhibitors to examine other trials in which these drugs are being studied in combination with immunomodulatory agents and trials in which the inhibitors are being studied in combination with other classes of drugs in patients with hematologic malignancies.
Woodcock said the FDA will take appropriate action as warranted to ensure patients enrolled in these trials are protected and that doctors and researchers understand the risks associated with this investigational use.
The agency is also encouraging healthcare professionals and consumers to report any adverse events or side effects related to the use of pembrolizumab and other PD-1/PD-L1 inhibitors to FDA’s MedWatch Adverse Event Reporting Program.
