Combos, FDA

Safety fears spur FDA to pause checkpoint combo studies by Bristol-Myers, Celgene

Two months after the FDA ordered Merck to slam the brakes on three Keytruda combo studies targeting multiple myeloma, alarmed regulators have followed up by posting a stop sign on enrolling any new patients in Bristol-Myers Squibb’s three rival studies concentrating on the same disease with the same combination approaches. And hours later Celgene $CELG added that it is being forced to pause 5 combo studies using AstraZeneca’s Imfinzi while getting slammed with a full hold on one other.

First to be officially frozen in place were Merck’s KEYNOTE-183 and KEYNOTE-185 after researchers spotted a higher risk of death in the drug arms. Those multiple myeloma trials matched Merck’s blockbuster therapy with two drugs from Celgene: Pomalyst and its big drug Revlimid. The FDA also ordered patients taken off of treatment in KEYNOTE-023 Cohort 1, matching Keytruda in combination with lenalidomide and dexamethasone in patients who received prior anti-multiple myeloma treatment with an immunomodulatory (IMiD) treatment (lenalidomide, pomalidomide or thalidomide).

Worried by evidence of safety issues, the FDA followed up Wednesday evening by ordering a halt to enrollment of new patients in Bristol-Myers’ studies marrying Opdivo with the same drugs: CA209602 (CheckMate-602), CA209039 (CheckMate-039) and CA204142 — also multiple myeloma combo studies.

At Celgene the damage is worse, with a full hold forcing researchers drop an early study looking at durvalumab in combination with lenalidomide with and without low-dose dexamethasone in multiple myeloma patients.

Combined, therse companies have hundreds of combo studies underway, but regulators clearly believe that there’s some other threat to patients in these particular combination studies using Celgene’s mainstay therapies. The FDA highlighted that concern just a week ago, carefully spelling out their reasons for suspending the three Merck studies and pointing out they were hunting down and reviewing other, similar PD-(L)1 combos in the clinic.

Bristol-Myers made for a natural first stop in that process, with Celgene getting tagged at virtually the same time.

The latest order from the FDA followed a stunning reversal for Cellectis, which was slammed with a clinical hold on Tuesday after the first patient treated in its debut off-the-shelf CAR-T study died, underscoring the unknown risks that still confront advanced cancer patients signing up for these experimental immuno-oncology trials.

Merck and Bristol-Myers are way out front with checkpoint inhibitors Keytruda and Opdivo as their PD-1 superstars continue to post jaw-dropping results in cancer. Clearly, though, as researchers continue to test the boundaries of what these new therapies can do unexpected safety issues continue to arise, raising questions of just how far developers should take the drugs.

That same kind of safety issue scuttled Juno’s lead drug, which wound up killing three patients last year after the FDA prematurely offered a green light to resume testing of its CAR-T after a brief clinical hold. At this point, regulators appear to be shifting their position from an encouraging signal to floor it, to a more cautious position of studying safety threats before barreling ahead.

For now, safety is still a gray zone in immuno-oncology, as the data continues to pour in.

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Sr. Manager, Regulatory Affairs, CMC
CytomX Therapeutics San Francisco, CA
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Catalytic Data Science Charleston, SC
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Flatiron Health New York City or San Francisco

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