The FDA has given accelerated approval to the CD38-targeted monoclonal antibody daratumumab as a monotherapy for patients with multiple myeloma following at least 3 prior therapies a full four months ahead of schedule.
Richard Pazdur, MD
The FDA has given accelerated approval to the CD38-targeted monoclonal antibody daratumumab (Darzalex) as a monotherapy for patients with multiple myeloma following at least 3 prior therapies a full four months ahead of schedule.
The approval for daratumumab is based on data from two open-label clinical trials.
“Targeting proteins that are found on the surface of cancer cells has led to the development of important oncology treatments,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, said in a statement. “Darzalex provides another treatment option for patients with multiple myeloma who have become resistant to other therapies.”
In the phase II MMY2002 study1, daratumumab demonstrated a 65% one-year overall survival (OS) rate and a 29.2% objective response rate (ORR). In the phase I/II GEN501 study, the ORR was 36%, median progression-free survival (PFS) was 5.6 months (95% CI, 4.2-8.1), and the one-year OS rate was 77% (95% CI, 58-88). The first 34 patients enrolled received daratumumab at 16 mg/kg (n = 16) or 8 mg/kg (n = 18). After a response evaluation, the 16 mg/kg dose was selected for future study, with an additional 90 patients enrolled at this dose (N = 106).
Patients in the trial had received a median of five prior therapies over a median of 4.8 years following diagnosis. Ninety-six percent of patients were refractory to their last treatment, including proteasome inhibitors and IMiD agents (95%).
Responses to daratumumab consisted of stringent complete responses (sCR; n = 3; 2.8%), very good partial responses (VGPR; n = 10; 9.4%), and partial responses (PR; n = 18; 17%). The median duration of response was 7.4 months. After a median follow-up of 9.4 months, 45.2% of patients remained on therapy. The median progression-free survival (PFS) was 3.7 months (95% CI, 2.8-4.6).
Infusion-related reactions (IRR) predominately occurred during the first infusion and were mostly grade 1/2 (all-grade 42.5%). Grade 3 IRRs were seen in 4.7% of patients; however, no grade 4 events were experienced. No patients discontinued daratumumab as a result of an IRR.
The most common all-grade adverse events were fatigue (39.6%), anemia (33%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), and cough (20.8%). Overall, 4.7% of patients discontinued treatment due to adverse events. These side effects were not deemed to be associated with daratumumab.
In the GEN501 study,2patients who received daratumumab at 16 mg/kg (n = 42) experienced an ORR of 36%, which included 2 CRs and 2 VGPRs. At this dose, the estimated median PFS was 5.6 months (95% CI, 4.2-8.1) and the one-year OS rate was 77% (95% CI, 58-88).
ORR was higher in less heavily pretreated patients, at 56% for those who received 2 or 3 prior lines of therapy compared with 23% in a more heavily pretreated population. The estimated median duration of response in the 8 mg/kg arm was 6.9 months (95% CI, 6.2-10.6). In the 16 mg/kg arm, a median duration of response was not yet reached, with a one-year PFS rate of 65% (95% CI, 28-86).