Phase III Trial Confirms Subcutaneous Daratumumab Noninferior to Standard in Myeloma

Jan van de Winkel, PhD

Jan van de Winkel, PhD

According to findings from the phase III COLUMBA trial in patients with relapsed/refractory multiple myeloma, a subcutaneous (SC) formulation of daratumumab (Darzalex) was noninferior in terms of inefficacy and pharmacokinetics to the standard intravenous (IV) daratumumab.¹

Among the 263 patients who received SC daratumumab coformulated with recombinant human hyaluronidase PH20, the overall response rate (ORR) was 41.1% versus 37.1% among the 259 patients treated with the IV formulation. In the SC daratumumab arm, the geometric mean of C_troughwas 499 mg/mL compared to 463 mg/mL in the IV arm.

“The lower limit of the 95% CI for the ratio of the two met the specified noninferiority criterion for this coprimary endpoint,” Genmab A/S, which co-develops daratumumab with Janssen Biotech, Inc., reported in a press release.

The SC formulation did not demonstrate new safety signals in these data. The companies plan to report the full results from the trial at an upcoming medical meeting and initiate discussions with regulatory authorities on an approval pathway for SC daratumumab.

“With the data from each of the key clinical studies we learn more about the difference that daratumumab potentially can make to the lives of patients suffering with multiple myeloma. I am particularly excited about the results from this study as it may support a much quicker and far more convenient administration of daratumumab, which would provide an important benefit for many patients and their families,” Jan van de Winkel, PhD, chief executive officer of Genmab, said in a press release.

The open-label phase III COLUMBA trial (NCT03277105) included 522 adult patients with relapsed/refractory multiple myeloma. Patients were randomized to either a dose of 1800 mg of SC daratumumab with rHuPH20 2000 U/mL or 16 mg/kg of IV daratumumab. Both treatments were administered once weekly in cycles 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until unacceptable toxicity, disease progression, or study completion. ORR and maximum trough of daratumumab (C_trough; serum pre dose concentration of daratumumab on cycle 3 Day 1) were the coprimary endpoints.

Daratumumab as an IV formulation is approved in various combination regimens for the treatment of patients with both newly diagnosed and pretreated myeloma. Single-agent IV daratumumab is also approved for patients with heavily pretreated myeloma.

Earlier this month, the FDA approved a split-dosing regimen of daratumumab for patients with multiple myeloma, providing physicians the option to split the first infusion of the CD38-directed monoclonal antibody over 2 consecutive days or complete in a single session.

The approval was based on findings from the phase Ib EQUULEUS (MMY1001) trial, which demonstrated that the pharmacokinetic concentrations of daratumumab at 16 mg/kg were comparable at the end of weekly dosing, regardless of whether it was a split-dose or a single infusion.²Additionally, the safety profiles were similar across both dosing regimens.

References:

1. Genmab Announces Positive Topline Results in Phase III COLUMBA Study of Subcutaneous Daratumumab. Published February 25, 2019. Accessed February 25, 2019. https://bit.ly/2tCig7V.
2. Chari AJ, Martinez-Lopez J, Mateos MV, et al. Daratumumab (DARA) in combination with carfilzomib and dexamethasone (D-Kd) in lenalidomide (Len)-refractory patients (Pts) with relapsed multiple myeloma (MM): Subgroup analysis of MMY1001.J Clin Oncol. 2018;36 (suppl; abstr 8002).