Janssen Halts Clinical Trials of Darzalex with PD-1/PD-L1 Inhibitors Amid Concerns Over Safety, Effectiveness

Janssen has decided to discontinue a Phase 1 trial assessing Darzalex (daratumumab) in combination with JNJ-63723283 — an anti-PD-1 antibody — in multiple myeloma patients, Genmab announced.

The decision is based on recent findings from the Phase 1b/2 LUC2001 trial (NCT03023423) for non-small cell lung cancer, where a combination of Darzalex and a PD-L1 inhibitor — Tecentriq (atezolizumab) — did not show the expected benefit and led to an increased number of deaths, compared with Tecentriq alone. A data monitoring committee recommended termination of the trial.

Janssen and its partners will also discuss ceasing enrollment and dosing in other trials testing a combination of Darzalex and PD-1/PD-L1 inhibitors while the situation is investigated. The company has also informed the proper health authorities of the events.

“While we are disappointed that the studies will be discontinued, Genmab fully supports Janssen’s decision as patient safety is paramount in drug development. We look forward to gaining a better understanding of the data upon further analysis. We are pleased that the development program for daratumumab remains expansive and continues to benefit patients with Multiple Myeloma,” Jan van de Winkel, PhD, CEO of Genmab, said in a press release.

Darzalex is a human anti-CD38 antibody that works by activating the body’s immune system to attack and kill multiple myeloma cells. But research has shown that Darzalex also induces T-cell expansion by reducing immunosuppressive cells, suggesting it could be used for other tumor types.

Since increasing T-cell numbers doesn’t necessarily mean they are active and able to kill tumor cells, researchers have hypothesized that a combination of Darzalex and immune checkpoint inhibitors could improve clinical responses in cancer patients.

The now-discontinued multicenter Phase 1 trial, called MMY2036 (NCT03357952), was testing a combination of Darzalex and JNJ-63723283 — Janssen’s investigational immune checkpoint inhibitor — in refractory or relapsed multiple myeloma patients.

It was designed to include up to 386 myeloma patients who had received at least three prior lines of therapy — including a proteasome inhibitor and an immunomodulatory agent — or who had not responded to either of those therapies.

Patients would be randomized to receive JNJ-63723283 in combination with Darzalex, versus Darzalex alone. Patients would receive Darzalex once a week for eight weeks first, then once every other week for 16 weeks, followed by once every four weeks. JNJ-63723283 would be administered by injection into the vein every other week.

Primary goals of the study were to determine the treatment’s safety in six patients and overall response rate in 80 patients, comprising the first two parts of the study. A third part with 300 patients would measure progression-free survival, which is the time from treatment start until the disease progresses or a patient dies.

LUC2001, the other trial being terminated, was designed to test a combination of Darzalex and Tecentriq in 98 patients with previously treated advanced or metastatic non-small cell lung cancer.

The primary objective of the study was the percentage of patients who responded to the combination, compared with Tecentriq alone. Patients would receive treatment until disease progression or unacceptable toxicity.

But a recent analysis showed no benefit from the combination and suggested an increase in adverse events leading to death, causing the data monitoring committee to recommend termination of the study.

In August 2012, Genmab granted Janssen an exclusive worldwide license to develop, manufacture, and commercialize daratumumab. In 2015, the U.S. Food and Drug Administration approved daratumumab as a treatment for certain myeloma patients, and the therapy has since been marketed as Darzalex.