Jan van de Winkel, PhD
Daratumumab (Darzalex) significantly improved progression-free survival (PFS) when added to bortezomib (Velcade) and dexamethasone for patients with relapsed or refractory multiple myeloma, according to findings published in The New England Journal of Medicine
“We are pleased that the positive data from the phase III CASTOR study of daratumumab, which was presented earlier this year at the ASCO and EHA meetings, has now been published in the prestigious The New England Journal of Medicine
,” said Jan van de Winkel, PhD, chief executive officer of Genmab, the company manufacturing daratumumab in collaboration with Janssen. “The data from this study formed part of the basis of this month’s submission of the supplemental Biologics License Application to the US Food and Drug Administration and the submission of the variation to the Marketing Authorization to the European Medicines Agency.”
In the study, which included 498 patients who had relapsed or refractory multiple myeloma, the 12-month PFS rate was 60.7% for patients who received the combination of daratumumab, bortezomib, and dexamethasone versus 26.9% in those who received bortezomib and dexamethasone alone. After a median follow-up period of 7.4 months, the median PFS was not reached in the daratumumab group and was 7.2 months in the control group (HR, 0.39; 95% CI, 0.28-0.53; P
<.0001). More patients had partial responses (59.2% vs 29.1%, P
< 0.001) or complete responses (19.2% vs 9.0%, P
= 0.001) with the addition of daratumumab.
The overall response rate (ORR) was also higher with the addition of daratumumab, with an 82.9% ORR in the daratumumab group compared with 63.2% in the control group (P
Patients in the trial received 8 cycles of bortezomib/dexamethasone with or without 16 mg/kg of daratumumab. Bortezomib was administered subcutaneously at 1.3 mg/m2
on days 1, 4, 8, and 11 of each 21-day cycle for a maximum of 8 cycles. Patients received 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles. Patients in the daratumumab group were administered an intravenous infusion of the antibody at 16 mg/kg weekly for the first 3 cycles, on day 1 of cycles 4 to 9, and then every 4 weeks. Treatment was administered until disease progression or unacceptable toxicity.
Patients in the trial had received a median of 2 prior lines of therapy (range, 1–10) and 66% had received prior bortezomib, 76% received prior immunomodulatory drugs (IMiDs), and 48% had received prior proteasome inhibitors and IMiDs. Thirty-three percent were IMiD-refractory and 32% were refractory to last line of prior therapy.
The primary endpoint was PFS and secondary endpoints include time-to-progression (TTP), ORR, overall survival (OS), and safety.
The most common grade 3 or 4 adverse events in patients treated with daratumumab in combination with bortezomib and dexamethasone compared with those who only received bortezomib and dexamethasone were thrombocytopenia (45.3% vs 32.9%), anemia (14.4% vs 16.0%), and neutropenia (12.8% vs 4.2%). Daratumumab-associated infusion-related reactions were reported in 45.3% of patients, were mostly grade 1/2, and occurred predominantly during the first infusion. This is consistent with the previously reported safety profile of daratumumab monotherapy and background bortezomib/dexamethasone therapy.
In November 2015, daratumumab was granted an accelerated approval by the FDA as a monotherapy for patients with multiple myeloma who had undergone 3 or more prior therapies based on data from 2 open-label clinical trials. The CASTOR study served as one of the confirmatory trials required for full approval. Daratumumab is the first CD38–targeted monoclonal antibody approved for multiple myeloma.
In March 2016, Janssen announced that the CASTOR study would be stopped early after meeting its primary endpoint for PFS. Patients in the control arm could then cross over to receive daratumumab. Janssen plans to communicate with the FDA about the potential to file for regulatory approval for a new indication for daratumumab based on the CASTOR data.
Longer patient follow-up is planned to determine the impact of the daratumumab combination on patient survival. A clinical trial that combines daratumumab with another standard therapy for recurrent multiple myeloma is underway.
1. Palumbo A, Chanan-Khan A, Weisel K. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 375:754-766.