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The FDA approved a Darzalex (daratumumab) triplet for the treatment of relapsed myeloma.
Darzalex (daratumumab) gained FDA approval in combination with Revlimid (lenalidomide) and dexamethasone or Velcade (bortezomib) and dexamethasone to treat patients with relapsed multiple myeloma following at least one prior therapy. The approval is based on findings from the phase 3 POLLUX and CASTOR studies.
In the POLLUX trial, adding Darzalex to Revlimid and dexamethasone reduced the risk of progression or death by 63 percent versus Revlimid and dexamethasone for patients with relapsed/refractory multiple myeloma. In the CASTOR trial, the addition of Darzalex to Velcade and dexamethasone reduced the risk of progression or death by 61 percent compared with the two drugs alone for patients with recurrent or refractory multiple myeloma.
“This is an exciting day for patients with multiple myeloma in the U.S., who will now have the opportunity to receive Darzalex at an earlier point in treatment of their disease," said Jan van de Winkel, Ph.D., CEO, of Genmab. “We believe daratumumab has the potential to become a backbone therapy for multiple myeloma.”
The application was preceded by a breakthrough therapy designation for the same indication, which the CD38-targeted monoclonal antibody received in July 2016. The agent was given an initial accelerated approval as a monotherapy for myeloma after three or more prior therapies in November 2015.
The international, open-label POLLUX trial randomized 569 patients with relapsed/refractory multiple myeloma to Darzalex combined with Revlimid /dexamethasone (286 patients) or Revlimid plus dexamethasone alone (283 patients). Patient characteristics were well balanced between the study arms. The median age across the trial was 65 years and the median number of prior treatment lines for each cohort was one.
At a median follow-up of 13.5 months, the median progression-free survival (PFS) was not yet reached in the Darzalex arm versus 18.4 months with Revlimid /dexamethasone alone. The overall response rate (ORR) was 92.9 percent versus 76.4 percent, respectively. The very good partial response (VGPR) or better rate was 75.8 percent with Darzalex versus 44.2 percent in the control arm. The complete response (CR) rates were 43.1 percent and 19.2 percent, respectively.
The CASTOR study randomized 498 patients with relapsed or refractory multiple myeloma to Velcade and dexamethasone alone (247 patients) or with Darzalex (251 patients). Patients had received a median of two prior lines of therapy. Overall, 66 percent had received prior Velcade, 76 percent received a prior immunomodulatory drug (IMiD) and 48 percent had received prior proteasome inhibitors and IMiD.
The 12-month PFS rate was 60.7 percent with Darzalex, Velcade, and dexamethasone versus 26.9 percent for Velcade and dexamethasone alone. After a median follow-up of 7.4 months, the median PFS was not reached in the Darzalex arm compared with 7.2 months in the control group.
The ORR with the addition of Darzalex was 82.9 percent compared with 63.2 percent in the control group. The VGPR or better rate was 59.2 percent with Darzalex versus 29.1 percent in the control arm. The CR rate was 19.2 percent with Darzalex versus 9.0 percent with the doublet.
In the POLLUX study, the safety profile was consistent with previously report adverse events (AEs) for single-agent Darzalex and the combination of Revlimid and dexamethasone. The most common grade 3/4 AEs were neutropenia (51.9 percent in the Darzalex arm vs 37 percent in the control arm), thrombocytopenia (12.7 percent vs 13.5 percent) and anemia (12.4 percent vs 19.6 percent). Infusion-related reactions associated with Darzalex were reported for 47.7 percent of patients and for the most part, were grade 1/2.
In the CASTOR study, the most common grade 3/4 AEs were thrombocytopenia (45.3 percent in the Darzalex group vs 32.9 percent in the control), anemia (14.4 percent vs 16.0 percent), and neutropenia (12.8 percent vs 4.2 percent). Daratumumab-associated infusion-related reactions were reported in 45.3 percent of patients. These were mostly grade 1/2, and occurred predominantly during the first infusion.
The FDA is also reviewing an application for the combination of Darzalex, Pomalyst (pomalidomide) and dexamethasone in patients with relapsed or refractory multiple myeloma following at least two prior therapies, with a proteasome inhibitor and an IMiD. A decision for this indication is anticipated by June 17, 2017.