Subcutaneous Daratumumab Found Noninferior to IV Formulation in Multiple Myeloma

Maria-Victoria Mateos, MD, PhD

A subcutaneous formulation of daratumumab showed similar efficacy to the original intravenous formulation of daratumumab (Darzalex) in the phase III COLUMBA trial of patients with relapsed/refractory multiple myeloma. The subcutaneous flat-dose of daratumumab also showed a reduction in the treatment burden, according to results presented at the 2019 ASCO Annual Meeting.

The objective response rate (ORR) was 41.1% with subcutaneous daratumumab compared with 37.1% with the intravenous formulation, meeting the criteria for noninferiority (relative risk [RR], 1.11; 95% CI, 0.89-1.37;P<.0001). Pharmacokinetic analyses also reached noninferiority for Ctrough. Moreover, the median duration per infusion dropped from at least 3 hours per infusion in the intravenous group to just 5 minutes in the subcutaneous arm.

Janssen, the company developing the anti-CD38 monoclonal antibody, plans to submit an application to the FDA for the subcutaneous formulation, which consists of daratumumab plus the recombinant human hyaluronidase PH20. The company plans to complete the submission later this year.

&ldquo;The daratumumab subcutaneous [formulation] was noninferior to intravenous, based on ORR and maximum concentration evaluated at cycle 3 day 1,&rdquo; COLUMBA primary investigator Maria-Victoria Mateos, MD, PhD, director of the Myeloma Unit at University Hospital of Salamanca-IBSA, said during a presentation of the results at ASCO. &ldquo;Daratumumab subcutaneously has a reduced treatment burden, due a considerably shorter administration duration, and patients treated with daratumumab subcutaneously reported higher satisfaction with therapy.&rdquo;

The phase III COLUMBA study randomized 522 patients with relapsed/refractory multiple myeloma to receive daratumumab intravenously (n = 259) or subcutaneously (n = 263). Treatment in the subcutaneous group was given at a flat dose of 1800 mg while the intravenous 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, with some variation 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 compared with 65 years in the subcutaneous arm. Almost a third of patients in each group had ISS stage III disease, and the median number of prior therapies was 4 in both arms.

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. In the intravenous arm, the first infusion lasted 7 hours, the second infusion was 4.3 hours, and subsequent infusions lasted a median of 3.4 hours.

The ORR in the subcutaneous arm consisted of a complete remission (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 in the intravenous group was 2.7% and the VGPR or better rate was 17.0%. For Ctrough, the ratio of geometric means for the subcutaneous to intravenous formulation was 107.93% (90% CI, 95.74%-121.67%), which met the requirements for noninferiority.

The investigators analyzed 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 intravenous arm. The median body weight in the intravenous group was 73.0 kg compared with 72.4 kg in the subcutaneous arm. Overall, weight did not appear to impact the efficacy findings, Mateos noted. The RR favored noninferiority between the two doses for those with a body weight &ge;85 (RR, 1.34; 95% CI, 0.86-2.12) and for those with a weight &le;65 (RR, 1.34; 95% CI, 0.86-2.12).

At the median follow-up of 7.46 months, the median progression-free survival was 6.1 months with intravenous 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 intravenous and subcutaneous formulations, respectively (HR, 0.90; 95% CI, 0.59-1.35;&nbsp;P= .6032).

There were significantly fewer infusion-related reactions (IRR) events in the subcutaneous group compared with the intravenous arm (12.7% vs 34.5%; odds ratio, 0.28; 95% CI, 0.18-0.44;P<.0001). Median time to onset of IRR was 1.5 hours in the intravenous group compared with 3.6 hours for the subcutaneous arm.

&ldquo;In both arms, most infusion-related reactions were grade 1 and 2, and only a few patients developed grade 3 reactions,&rdquo; said Mateos. &ldquo;Injection site reactions occurred in 7% of daratumumab subcutaneous [treated] patients, and all were grade 1 or 2.&rdquo;

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% compared with 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, Mateos said.

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 the groups, with a score near 90 for the subcutaneous arm during cycle 10 compared with a score just below 80 in the intravenous arm.

The intravenous version of daratumumab is currently approved across a number of indications for patients with multiple myeloma. Based on findings from the study, Mateos noted that a flat dose of subcutaneous daratumumab should also enter clinical practice.

&ldquo;Our ambition in multiple myeloma has always focused on improving outcomes, but also experience for patients, and we are therefore incredibly pleased to see these results which confirm the potential for a new, and shorter, route of administration,&rdquo; Patrick Laroche, MD, Europe, Middle East and Africa Haematology Therapeutic Area Lead, Janssen-Cilag France, said in a statement. &ldquo;We look forward to submitting these data for regulatory review in coming months, to extend the reach of daratumumab to patients who could benefit from this novel formulation.&rdquo;

Reference:

Mateos M-V, Nahi H, Leggier W, et al. Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA.J Clin Oncol.2019;37 (suppl; abstr 8005).