Abstract
The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (Ctrough). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of Ctrough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the Ctrough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03–185.00%) and 148.02% (90% CI, 113.32–193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105
Highlights
Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor [1,2,3,4] and immunomodulatory [5,6,7] mechanism of action
In the primary analysis of COLUMBA at a median follow-up of 7.5 months, DARA SC was noninferior to DARA IV in terms of the predefined noninferiority criteria evaluating the co-primary endpoints of overall response rate (ORR) and DARA maximum trough concentration (Ctrough; pre-dose on cycle 3 day 1) [23]
In the Japanese-only cohort, mean scores were similar between the DARA SC and DARA IV groups (Supplementary Figs. 3, 4b, and 5b in the Supplementary information). In both the Asian and Japanese-only cohorts, comparable ORRs and maximum Ctroughs were observed for DARA SC 1800-mg flat dose compared to DARA IV 16 mg/kg
Summary
Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor [1,2,3,4] and immunomodulatory [5,6,7] mechanism of action. To reduce the duration of administration of daratumumab, a subcutaneous version of daratumumab (DARA SC) co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc., San Diego, CA, USA) was developed that allows for dosing in 3–5 min [17, 18]. Flat dosing of DARA SC was selected based on population pharmacokinetics (PK) analysis and simulations for daratumumab and published literature that support the use of flat dosing for monoclonal antibodies [18,19,20,21,22]. The phase 1b PAVO study demonstrated that DARA SC 1800-mg flat dose had efficacy and PK comparable with DARA IV and lower rates of infusion-related reactions (IRRs) [17]
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