FDA Lifts Holds on 2 Nivolumab Myeloma Trials

The FDA has lifted partial clinical holds placed on the phase I CheckMate-039 and phase II CA204142 trials exploring nivolumab-based regimens in patients with relapsed/refractory multiple myeloma.

The agency placed the partial holds on the studies in October, along with a third study, the phase III CheckMate-602 trial, also examining a nivolumab combination in myeloma. The partial hold on the phase III study remains in place, according to Bristol-Myers Squibb (BMS), the developer of the PD-1 inhibitor nivolumab (Opdivo).

According to BMS, the holds were lifted and patient enrollment has resumed in the phase I and II trials following an agreement between the company and the FDA on amendments to the study protocols.

The FDA placed the holds based on safety concerns identified in 2 clinical trials evaluating pembrolizumab (Keytruda), another anti—PD-1 agent, 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. 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.

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 (Empliciti) 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.

CheckMate-602 is an open-label, randomized trial evaluating combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone for patients with relapsed/refractory multiple myeloma.

In a press release, BMS reported that the company is in ongoing communications with the FDA to determine the next steps for the CheckMate-602 trial. Under the partial clinical hold, enrollment of new patients in the trial has been halted; however, previously enrolled patients experiencing a clinical benefit with the nivolumab-based experimental regimen are allowed to continue treatment.

Nivolumab has FDA-approved indications for melanoma, non—small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colorectal cancer, and hepatocellular carcinoma.