The FDA has placed clinical holds on multiple trials in Celgene’s FUSION program, which is exploring regimens combining the PD-L1 inhibitor durvalumab (Imfinzi) with immunomodulatory and chemotherapy agents across several hematologic malignancies.
The agency has stopped 1 trial and put partial holds on 5 others due to safety concerns that arose in studies evaluating the PD-1 inhibitor pembrolizumab (Keytruda) in combination with immunomodulatory agents for the treatment of patients with multiple myeloma.
The FDA placed a full hold on MEDI4736-MM-002, a phase Ib multicenter, open-label study aiming to establish an appropriate dose and regimen for the combination of durvalumab and lenalidomide (Revlimid) with and without low-dose dexamethasone in patients with newly diagnosed multiple myeloma. No new patients will be enrolled and patients in that trial will discontinue treatment.
Three studies exploring durvalumab in multiple myeloma—MEDI4736-MM-001, MEDI4736-MM-003, and MEDI4736-MM-005—were placed on partial hold. MEDI4736-NHL-001, exploring the drug as a monotherapy in patients with lymphoma or chronic lymphocytic leukemia, and MEDI4736-DLBCL-001, assessing durvalumab in combination with R-CHOP or R2 CHOP, where also given a partial hold. Patients deriving clinical benefit from treatment, as determined by the investigator, can remain on treatment in these 5 studies, but enrollment has stopped for the time being.
Celgene reported in a press release that it has not determined whether the benefits associated with durvalumab exceed the risks but, “the clinical holds allow for additional information to be collected to further understand the risk-benefit profile of the program.”
The FDA made the move based on safety concerns identified in KEYNOTE-183 and KEYNOTE-185, 2 clinical trials evaluating pembrolizumab in combination with dexamethasone and lenalidomide (Revlimid) or pomalidomide (Pomalyst) for the treatment of patients with multiple myeloma.
The agency ordered discontinuation of KEYNOTE-183 and KEYNOTE-185 on July 3, 2017, because interim results showed that pembrolizumab was associated with an increased risk for death.1
Merck, the manufacturer of pembrolizumab, had suspended new enrollment to these trials on June 12, 2017, following the recommendation of an external data monitoring committee.
Patients in both KEYNOTE trials were assigned to 200 mg of pembrolizumab every 3 weeks.
In KEYNOTE-183 (N = 249), there were 29 deaths in the pembrolizumab arm versus 21 deaths in the control arm at a median follow-up of 8.1 months. The hazard ratio (HR) for overall survival (OS) for the pembrolizumab group compared with the control arm was 1.61 (95% CI, 0.91-2.85), translating into a >50% increase in the relative risk of death.
There were 301 patients included in the safety and efficacy analysis in KEYNOTE-185. At a median follow-up of 6.6 months there were 19 deaths in the pembrolizumab group compared with 9 in the control arm (HR for OS, 2.06; 95% CI, 0.93-4.55). The relative risk of death in the pembrolizumab arm was more than double that of the control group.
The safety concerns arising from the KEYNOTE-183 and -185 findings have also resulted in the FDA placing partial clinical holds on 3 trials assessing nivolumab (Opdivo)-based combinations in patients with relapsed/refractory multiple myeloma: the phase III CheckMate-602, phase I CheckMate-039, and phase II CA204142 trials.
CheckMate-602 is an open-label, randomized phase III trial evaluating combinations of nivolumab, elotuzumab (Empliciti), pomalidomide, and dexamethasone for patients with relapsed/refractory multiple myeloma.
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.
CA204142 is assessing the safety and efficacy of elotuzumab in combination with pomalidomide and low-dose dexamethasone versus elotuzumab in combination with nivolumab for patients with multiple myeloma relapsed or refractory to prior treatment with lenalidomide.
FDA Alerts Healthcare Professionals and Oncology Clinical Investigators about Two Clinical Trials on Hold Evaluating KEYTRUDA® (pembrolizumab) in Patients with Multiple Myeloma. https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm. Accessed August 31, 2017.