HOLD OF IMMUNOTHERAPY TRIALS IN HEMATOLOGY

Because of safety concerns, the US Food and Drug Administration has placed full or partial holds on clinical trials of three immunotherapies — pembrolizumab (Keytruda, Merck), nivolumab (Opdivo, BMS), and durvalumab (Imfinzi, AstraZeneca) — that are being used experimentally in combination with other drugs for the treatment of multiple myeloma and other blood cancers.

In the case of pembrolizumab, there was an increased risk for death associated with its use in combination with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) for the treatment of patients with multiple myeloma compared with controls who did not receive pembrolizumab.

On September 1, the FDA issued a statement about the mortality risk associated with pembrolizumab in multiple myeloma, as reported by Medscape Medical News. The statement was a follow-up to an FDA action in early July that halted the conduct of two clinical trials (KEYNOTE-183 and KEYNOTE-185) exploring the use of pembrolizumab in this setting, both of which showed an increased death risk.

Last week, the FDA expanded the trial restrictions to rival immunotherapies, nivolumab and durvalumab, according to statements from the drugmakers.

With regard to nivolumab, the agency placed a partial hold on three clinical trials testing the agent in combination with other medicines for multiple myeloma — because of the risks seen in similarly designed studies involving pembrolizumab, according to Bristol-Myers Squibb.  Both pembrolizumab and nivolumab are programmed cell death (PD)-1 inhibitors.

Patients with relapsed multiple myeloma in the trials who experienced clinical benefit will be allowed to continue treatment, but no new patients will be enrolled at this time, the company said.

Then, after the announcement from Bristol-Myers Squibb, AstraZeneca and Celgene said that the FDA had placed a partial hold on five trials testing durvalumab in combination with Celgene drugs and a full hold on one other study, according to a Reuters report.

Again, the actions were based on safety concerns from the pembrolizumab trials.

Most of the affected combination studies were for multiple myeloma. However, one of the trials under partial hold is evaluating durvalumab in patients with lymphoma or chronic lymphocytic leukemia. Durvalumab is a PD ligand 1 inhibitor.

The FDA's actions and concerns do not apply to the approved, on-label indications of these immunotherapies.