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A supplemental biologics license application has been submitted to the FDA for a new subcutaneous formulation of daratumumab (Darzalex) for the treatment of patients with multiple myeloma.
A supplemental biologics license application (sBLA) has been submitted to the FDA for a new subcutaneous formulation of daratumumab (Darzalex) for the treatment of patients with multiple myeloma.
The sBLA is based on findings from the phase III COLUMBA (MMY3012) study, which demonstrated noninferiority in terms of efficacy compared with the intravenous (IV) formulation of the CD38-targeted monoclonal antibody. Data also demonstrated that the subcutaneous version led to a reduction in treatment burden when compared with the standard version.
The application also includes results from the ongoing, phase II PLEIADES (MMY2040) trial (NCT03412565).
“This submission represents our commitment to develop innovative treatment options for people living with multiple myeloma,” Craig Tendler, MD, vice president, Clinical Development and Global Medical Affairs, Oncology, Research & Development, Janssen, the manufacturer of daratumumab, said in a press release. “The Darzalex subcutaneous formulation showed noninferiority to the existing IV formulation, both as a monotherapy and in combination with common background therapies, while administered with a considerably shorter infusion time. We look forward to working closely with the FDA in their review of the data supporting this regulatory application.”
The subcutaneous formulation of daratumumab is co-formulated with recombinant human hyaluronidase PH20.
In the phase III COLUMBA study, 522 patients with relapsed/refractory multiple myeloma were randomized to receive daratumumab IV (n = 259) or subcutaneously (n = 263). Treatment in the subcutaneous group was given at a flat dose of 1800 mg while the IV formulation was given at 16 mg/kg. Treatment in both arms was given weekly in the first 2 cycles followed by every 2 weeks for cycles 3 to 6 and every 4 weeks from cycle 7 until disease progression.
Patient characteristics were similar between the two arms, but some variation was observed seen for cytogenetic risk levels. Overall, more patients in the subcutaneous arm had high-risk cytogenetics (26%) compared with the intravenous group (17%). The median age in the intravenous group was 68 years versus 65 years in the subcutaneous arm. Approximately one-third of patients in each arm had International Staging System stage III disease, and the median number of prior therapies was 4 in each arm.
The median duration of treatment was approximately 5 months, with a median of 6 completed cycles of treatment. The median duration of infusion was consistently 5 minutes at each visit in the subcutaneous group. However, in the IV arm, the first infusion lasted 7 hours, the second infusion was 4.3 hours, and subsequent infusions lasted a median of 3.4 hours.
Results showed that the objective response rate (ORR) was 41.1% with subcutaneous daratumumab versus 37.1% with the intravenous formulation, which met the criteria for noninferiority (relative risk [RR], 1.11; 95% CI, 0.89-1.37; P <.0001). Pharmacokinetic analyses also reached noninferiority for Ctrough. Additionally, the median duration per infusion dropped from >3 hours per infusion in the IV arm to 5 minutes with the subcutaneous version.
In the subcutaneous arm, the ORR consisted of a complete response (CR) or better rate of 1.9% and a rate of very good partial response (VGPR) or better of 19%. The rate of CR or better was 2.7% in the IV group and the VGPR or better rate was 17.0%. For Ctrough, the ratio of geometric means for the subcutaneous to IV formulation was 107.93% (90% CI, 95.74%-121.67%), which met the requirements for noninferiority.
Additionally, outcomes by median body weight to determine the potential impact of using a flat dose in the subcutaneous group compared with a body weight-based dose in the IV arm were analyzed. The median body weight in the IV group was 73.0 kg versus 72.4 kg in the subcutaneous arm. Overall, weight did not appear to impact the efficacy data. The RR favored noninferiority between the 2 doses for those with a body weight ≥85 (RR, 1.34; 95% CI, 0.86-2.12) and for those with a weight ≤65 (RR, 1.15; 95% CI, 0.81-1.63).
At a median follow-up of 7.46 months, the median progression-free survival was 6.1 months with IV daratumumab versus 5.6 months with the subcutaneous formulation (HR, 0.99; 95% CI, 0.78-1.26; P = .9258). The 6-month overall survival rate was 83.0% versus 87.5% for the IV and subcutaneous formulations, respectively (HR, 0.90; 95% CI, 0.59-1.35; P = .6032).
Regarding safety, there were significantly fewer infusion-related reactions (IRR) events in the subcutaneous group versus the IV arm (12.7% vs 34.5%; odds ratio, 0.28; 95% CI, 0.18-0.44; P <.0001). The median time to onset of IRR was 1.5 hours in the IV group versus 3.6 hours for the subcutaneous arm.
With the exception of IRR, which primarily occurred with the first dose, the safety profile was similar between the formulations. The rate of grade 3/4 neutropenia was higher in the subcutaneous group, at 13% versus 8%. The rates of any grade chills (11% vs 5%) and dyspnea (12% vs 6%) were lower in the subcutaneous group versus intravenous, likely due to a reduction IRRs.
Patients were more satisfied with the subcutaneous formulation compared with intravenous, according to treatment satisfaction questionnaires. There was at least a mean difference of 5.9 points between groups, with a score near 90 for the subcutaneous arm during cycle 10 compared with a score just below 80 in the IV arm.
The IV version of daratumumab is currently approved across a number of indications for patients with multiple myeloma.
In the nonrandomized, open-label, parallel assignment, phase II PLEIADES study, 240 adults with either newly diagnosed or relapsed/refractory multiple myeloma are enrolled. Those with newly diagnosed disease were treated with 1800 mg of subcutaneous daratumumab in combination with either bortezomib (Velcade), lenalidomide (Revlimid) and dexamethasone (D-VRd) or bortezomib, melphalan, and prednisone (D-VMP). Patients with relapsed/refractory disease were treated with 1800 mg of subcutaneous daratumumab plus lenalidomide/dexamethasone (D-Rd).
The primary endpoint for the D-VMP and D-Rd cohorts was ORR, and the primary endpoint for the D-VRd cohort was VGPR or better rate. An additional cohort of patients with relapsed/refractory multiple myeloma treated with daratumumab plus carfilzomib and dexamethasone was subsequently added to the study.