Peter F. Lebowitz, MD, PhD
Adding daratumumab (Darzalex) to standard bortezomib (Velcade) and dexamethasone improved progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma enrolled in the phase III CASTOR (MMY3004) trial, according to Janssen Research & Development, which codevelops the CD38-targeted monoclonal antibody with Genmab.
The significant delay in disease progression (P
<.0001) met the study’s primary endpoint, as measured by an independent data monitoring panel at a preplanned interim analysis. Following the panel’s recommendation, the study has been halted and patients randomized to bortezomib and dexamethasone alone can cross over at progression to receive daratumumab.
“These results suggest daratumumab could potentially be used in combination with standard therapy in patients with relapsed or refractory multiple myeloma,” said Peter F. Lebowitz, MD, PhD, global oncology head, Janssen Research & Development. “We are especially proud that Janssen was involved in the development of two of the medicines in this trial, daratumumab and bortezomib.”
The open-label, international phase III CASTOR trial randomized approximately 490 patients with relapsed/refractory multiply myeloma to daratumumab combined with bortezomib and dexamethasone or bortezomib and dexamethasone alone.
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. Daratumumab was administered as an IV infusion 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.
Full results from the study are being prepared for a peer-reviewed publication and presentation at an upcoming scientific meeting. Janssen also plans to communicate with the FDA about the potential to file for regulatory approval for a new indication for daratumumab based on the data.
Daratumumab was approved by the FDA in November 2015 as a monotherapy for patients with multiple myeloma following at least 3 prior therapies, based on data from 2 open-label clinical trials. The indication for daratumumab is specifically for patients following progression on a proteasome inhibitor and an immunomodulatory agent (IMiD), or for those who are double refractory to a proteasome inhibitor and IMiD.
In the phase II MMY2002 study, 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 PFS was 5.6 months (95% CI, 4.2-8.1), and the 1-year OS rate was 77% (95% CI, 58-88).
In MMY2002 study,1
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 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 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.2
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. Data from the 16 mg/kg arm were analyzed by the FDA for the approval.
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).
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.
The FDA recommended dose and schedule for daratumumab is 16 mg/kg weekly for 8 weeks followed by every 2 weeks for 16 weeks and then once every 4 weeks until disease progression. Additionally, the agency noted that daratumumab interferes with blood bank crossmatching, specifically with indirect antiglobulin tests, warranting extra consideration when pursuing a blood transfusion.
A full approval for daratumumab is contingent on confirmatory studies, which are currently ongoing.
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.
Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol. 2015;33 (suppl; abstr LBA8512).
Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma N Engl J Med. 2015;373:1207-1219.