Jan van de Winkel, PhD
Single-agent daratumumab (Darzalex) for the treatment of patients with relapsed/refractory multiple myeloma previously treated with a proteasome inhibitor and an immunomodulatory agent (IMiD) has received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP).
CHMP’s review of the CD38-targeted antibody was conducted under the EMA’s accelerated assessment program, with a final decision expected from the European Commission (EC) within 60 to 90 days. An accelerated approval from the EC would be conditional based on results from ongoing phase III studies.
The positive opinion was primarily based on data from the phase II SIRIUS MMY2002 study, in which daratumumab demonstrated a 65% 1-year overall survival (OS) rate and a 29.2% objective response rate (ORR) in heavily pretreated patients with myeloma.1
Additional data were reviewed from 4 other studies, including the phase I/II GEN501 study, in which the ORR with single-agent daratumumab was 36%, median progression-free survival (PFS) was 5.6 months (95% CI, 4.2-8.1), and the 1-year OS rate was 77% (95% CI, 58-88) in pretreated patients with relapsed/refractory myeloma.2
"We are very pleased to receive the positive opinion from the CHMP for the use of Darzalex as monotherapy in patients with relapsed and refractory multiple myeloma. The CHMP opinion brings Genmab and its partner Janssen one step closer toward offering a fundamentally new treatment option to patients with multiple myeloma in Europe, and we look forward to the decision of the European Commission,” Jan van de Winkel, PhD, CEO of Genmab said in a statement.
In the MMY2002 study, 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. Data from the 106 patients who received the 16 mg/kg dose were used to support the approval.
Patients in the trial had received a median of 5 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 IMiDs.
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 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 (AEs) 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 AEs that were not deemed to be associated with daratumumab.
The GEN501 study contained two parts. In the first, 32 patients were treated with daratumumab at various doses, in order to find a recommended dose and schedule. In the second phase of the trial, 72 patients received daratumumab at either 8 mg/kg (n = 30) or 16 mg/kg (n = 42). In each group, patients had received a median of 4 prior therapies.
The median follow-up was 16.9 months in the 8-mg/kg group and 10.2 months in the 16-mg/kg arm. Patients who received daratumumab at 16 mg/kg experienced an ORR of 36%, which included 2 CRs and 2 VGPRs.
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 1-year PFS rate of 65% (95% CI, 28-86).
In this trial, the most frequently occurring all-grade AEs with daratumumab were fatigue, allergic rhinitis, and pyrexia. Grade 3/4 AEs occurred in 26% of patients in the 16-mg/kg arm of the study and in 53% of those treated with the 8 mg/kg dose. Serious AEs occurred in 40% and 33% of patients in the 8- and 16-mg/kg arms, respectively. IRRs occurred in 71% of patients.
Daratumumab is a fully human monoclonal antibody that binds to glycoprotein CD38. Once bound, the antibody interacts with natural killer cells by mimicking the normal interaction between CD38 and CD31. This interaction elicits antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity resulting in antitumor activity.
The FDA granted daratumumab an accelerated approval in November 2015 as a monotherapy for patients with multiple myeloma following at least 3 prior therapies. The indication is specifically for patients following progression on a proteasome inhibitor and an IMiD or for those who are double refractory to a proteasome inhibitor and an IMiD. A full indication for daratumumab is contingent on the results of ongoing confirmatory studies.
Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial [published online January 6, 2016]. Lancet. doi: 10.1016/S0140-6736(15)01120-4.
Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373(13):1207-1219.