In addition to halting enrollment in KEYNOTE-183 and KEYNOTE-185, the FDA in July placed a partial clinical hold on KEYNOTE-023, created to assess the Keytruda/lenalidomide/dexamethasone combination in patients who received prior anti-multiple myeloma treatment with an immunomodulatory drug (IMiD) treatment (lenalidomide, pomalidomide, or thalidomide). The FDA reviewed data from the KEYNOTE-183 and KEYNOTE-185 trials, which evaluated pembrolizumab as part of a combination therapy for multiple myeloma. The partial hold on nivolumab trials is the result of risks identified in studies of pembrolizumab (Keytruda), another anti-PD-1 drug being tested in patients with multiple myeloma. The hazard ratio (HR) for overall survival (OS) for the Keytruda group compared with the control arm was 1.61, translating into a greater than 50 percent increase in the relative risk of death.
On Friday, Bristol-Myers Squibb also released follow-up data which showed a three-year survival benefit to Opdivo versus the chemotherapy docetaxel in two types of NSCLC. The trials put on hold were looking into a new indication, multiple myeloma, a blood cancer that begins in bone marrow. Under the hold, Bristol-Myers Squibb will not be allowed to enroll new patients in the studies, although patients who were experiencing clinical benefits will continue to receive the medications. Only the Revlimid arm was affected by the clinical hold, and the trial will continue to enroll in the other arms as planned.
The agency wanted to alert oncology researchers about the risks associated with treating patients who have myeloma with the regimens explored in the phase 3 KEYNOTE-183 and KEYNOTE-185 trials: Keytruda combined with an immunomodulatory agent (lenalidomide [Revlimid] or Pomalyst [pomalidomide]) and dexamethasone. “The true cause of the safety concerns”, according to an FDA press release, has not yet been determined.
Celgene is now investigating Imfinzi in two lymphoma trials: the Phase 1/2 MEDI4736-NHL-001 (NCT02733042) and the Phase 2 MEDI4736-DLBCL-001 (NCT03003520). A full clinical hold was placed on MEDI4736-MM-002, which is examining durvalumab plus lenalidomide and dexamethasone in multiple myeloma patients.
CheckMate-039 is a study to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab (Darzalex), with or without pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. The decision was later extended to three Bristol-Meyers Squibb trials investigating Opdivo (nivolumab), which also targets the PD-1/PD-L1 pathway.