The U.S. Food and Drug Administration (FDA) has ordered Merck to suspend two Phase 3 and part of a Phase 1 clinical trials in which Keytruda (pembrolizumab) is tested in combination with the drugs Pomalyst (pomalidomide) or Revlimid (lenalidomide) for multiple myeloma.
The clinical hold — an order issued by the FDA to suspend or delay an ongoing trial — comes after the external Data Monitoring Committee of the Phase 3 trials KEYNOTE-183 and KEYNOTE-185 flagged unexplained deaths among Keytruda-treated patients in June.
Merck stopped enrolling patients in the studies at the time, allowing researchers to look into the causes of death, although patients already enrolled continued treatment. But the newly issued FDA clinical hold means those patients who are already enrolled and receiving Keytruda will also stop treatment.
In addition to the two trials in which the committee uncovered patient deaths, a third trial, KEYNOTE-023, in which patients receive a similar drug combination, has been put on a partial clinical hold.
Other Keytruda trials are not affected by the decision.
The FDA decided that the available data suggest that the risks of combining Keytruda with Pomalyst or Revlimid outweigh any potential benefit for patients with multiple myeloma.
“Patient safety is Merck’s primary concern, and we are grateful to the study investigators and patients involved in these studies for their commitment to this important research,” Roger M. Perlmutter, MD, PhD, president of Merck Research Laboratories, said in a press release.
“Merck’s development program for Keytruda, spanning more than 30 different tumor types, has one priority: helping patients suffering from cancer,” he said.
KEYNOTE-183 (NCT02576977) enrolled myeloma patients who relapsed or were refractory to standard treatment. These patients had gone through at least two previous treatment rounds that failed to clear their cancer.
Participants were randomly assigned to receive Keytruda in combination with Pomalyst and low-dose dexamethasone or Pomalyst and dexamethasone alone. They will now continue treatment only with Pomalyst and dexamethasone.
The KEYNOTE-185 (NCT02579863) trial focused on newly diagnosed myeloma patients who had not received other treatments for their cancer. Patients were split into two groups in which researchers compared a triple combination of Keytruda, Revlimid, and dexamethasone with the duo Revlimid and dexamethasone.
The third trial, the KEYNOTE-023 Phase 1 study (NCT02036502), contains one group of patients treated with the triple-combo Keytruda, Revlimid, and dexamethasone. This group, referred to as Cohort 1, will also stop Keytruda treatment.
This trial also recruited patients with refractory or relapsed and refractory myeloma. These patients had received previous treatment with one of the immunomodulatory drugs Pomalyst, Revlimid, or thalidomide.
Cohort 2 of the study, in which patients receive another Keytruda combination — including Kyprolis (carfilzomib) and dexamethasone — is not affected by the clinical hold.
As a harsh cancer therapy targeting the immune system, Keytruda is known to bring about severe, even fatal, side effects. Although Merck has not disclosed the number of treatment-related deaths in the Phase 3 myeloma trials, the clinical hold indicates that the safety, when used in combination with Pomalyst and Revlimid, was particularly poor.
In September 2014, Keytruda was approved for melanoma under an accelerated approval regulatory pathway. Since then, it has also been approved for a range of other solid tumors — lung cancer, head and neck cancer, urothelial cancer — and the blood cancer classical Hodgkin’s lymphoma.
In addition, the drug made headlines on May 23, when it was the first treatment to be approved for all cancers sharing a common genetic feature — so-called microsatellite instability-high (MSI-H) cancer — rather than a particular cancer type.
Keytruda is currently being evaluated in other clinical trials for multiple myeloma, alone or in combination with other treatments.