Safety Concerns About Other Therapies Prompt FDA to Put a Hold on Three Opdivo Combo Trials

The U.S. Food and Drug Administration has ordered Bristol-Myers Squibb to put a hold on three clinical trials evaluating Opdivo (nivolumab) in combination with immunomodulatory drugs as a treatment for multiple myeloma.

Myeloma patients’ deaths in trials of Keytruda (pembrolizumab)-based combinations prompted the FDA crackdown on studies of immune checkpoint inhibitors targeting the PD-1 or PD-L1 proteins in combination with other drugs.

There have been no reports of safety concerns in the Opdivo trials. Opdivo researchers are working with regulators in further assessing trial data to see if there is a risk.

Patients in the Opdivo trials can continue taking their combo treatments if researchers believe they are benefiting from them, but the trials will stop recruiting additional participants.

The partial clinical hold will affect one Phase 1 study: CheckMate-039 (NCT01592370). It is assessing the safety of Opdivo and Darzalex (daratumumab) in relapsed or refractory myeloma patients, some of whom also receive Pomalyst (pomalidomide) and dexamethasone.

A Phase 2 trial (NCT02612779) is also on hold. It includes myeloma patients who failed to respond to treatment or whose disease relapsed before receiving Revlimid (lenalidomide). These patients are being treated with a combination of Opdivo and Empliciti (elotuzumab) or Empliciti, Pomalyst and dexamethasone.

The FDA ordered a hold on a Phase 3 trial as well. CheckMate-602 (NCT02726581) is evaluating Opdivo, Empliciti, Pomalyst, and dexamethasone as a treatment for relapsed or refractory myeloma.

Other Opdivo trials are not affected.

The FDA’s concern about Opdivo started when Merck reported unexplained deaths among patients treated with a combination of Keytruda and immunomodulatory drugs, including Pomalyst and Revlimid.

This prompted the agency to shut down one Keytruda trial and place several others on partial hold in July 2017. Later the agency issued a statement saying that the Keytruda trials might not be the only ones affected by safety concerns.

It said other studies of PD-1 or PD-L1 inhibitors, in combination with immunomodulatory and anticancer drugs for myeloma, would be scrutinized and possibly placed on hold.

Bristol-Myers Squibb was the first to be notified that its checkpoint trials would be put on hold. Celgene, which had been testing Imfinzi (durvalumab) in similar combinations, was next. One Celgene study was suspended and five placed on partial hold.

The FDA also warned doctors against prescribing Keytruda in combination with any immunomodulatory drugs, including Revlimid and Pomalyst, as a treatment for myeloma.

The hold on checkpoint inhibitor combinations comes as the FDA halted a trial of Cellectis‘ CAR T-cell therapy because of the death of the first patient.

The combination of these events has cast a spotlight on the unknown risks of cancer immunotherapy.