FDA Halts Imfinzi Combination Trials After Unexplained Keytruda-related Deaths

The U.S. Food and Drug Administration (FDA) suspended a Phase 1 clinical trial testing a combination of AstraZeneca‘s Imfinzi (durvalumab) with an immunomodulatory and an anti-cancer therapy for multiple myeloma.

The agency also placed a partial hold on five additional trials testing similar Imfinzi combinations in myeloma and other blood cancers.

The move was not based on safety issues identified in these clinical trials, but stemmed from safety concerns noted in studies of Keytruda (pembrolizumab) — a drug with a similar mechanism of action — given in combinations with immunomodulatory and chemotherapeutic drugs.

Imfinzi is a so-called checkpoint inhibitor immunotherapy that targets the PD-L1 molecule, while Keytruda’s checkpoint strategy is to block PD-1 — the receptor to which PD-L1 is binding.

The clinical trial that the FDA suspended was a Phase 1b open-label that intended to find the optimal dosing and administration schedule for Imfinzi in combination with Revlimid (lenalidomide) in newly diagnosed myeloma patients. Some patients also received low-dose dexamethasone. Patients in this trial will have to stop the treatment, and new patients will not be recruited.

Patients currently receiving treatment in the five studies placed on a partial hold (NCT02616640, NCT02807454, NCT03000452, NCT02733042, and NCT03000452) may continue treatment if clinical investigators judge they are benefitting from the treatment.

Three of these trials — one Phase 1 and two Phase 2 — include myeloma patients.

The Phase 1 study (NCT02616640) is testing Imfinzi in combination with Pomalyst (pomalidomide) and low dose dexamethasone in relapsed or refractory myeloma. One Phase 2 study (NCT02807454) combined Imfinzi with Darzalex (daratumumab) in the same type of patients.

The second Phase 2 study (NCT03000452) also is testing the Imfinzi and Darzalex combo, but in myeloma patients who have progressed while treated with Darzalex.

In July, the FDA shut down one Keytruda clinical trial and placed several others on partial hold after an external Data Monitoring Committee flagged unexplained deaths among myeloma patients treated with Keytruda in combination with other drugs, including Pomalyst and Revlimid.

A month later, the FDA followed up with a statement in which they explained that Merck’s Keytruda trials were not their only focus once the safety issue had been discovered. Other studies of PD-1 or PD-L1 inhibitors in combination with immunomodulatory drugs also would be scrutinized.

Just ahead of Celgene, Bristol Myers Squibb also was notified that three of their Opdivo (nivolumab) combination trials were ordered to pause.

While Celgene underscored that researchers have not observed similar safety issues in the Imfinzi trials, the clinical hold will allow scientists to gather more data to better understand if there is an undetected risk with these combinations.

The FDAs’ decision to end or halt further recruitment in several trials act as a reminder that manipulations of the immune system to fight cancer might hold unknown risks.

Other Celgene trials are not affected by the FDA’s decision.