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): Body Weight Subgroup Analysis of Columba
Authors: Mateos Maria-Victoria , Usmani Saad Z. , Grosicki Sebastian , Vorobyev Vladimir I. , Spicka Ivan , Hungria Vania T.M. , Korenkova Sibirina , Bahlis Nizar , Flogegard Max , Bladé Joan , Moreau Philippe , Kaiser Martin F. , Iida Shinsuke , Laubach Jacob P. , Masterson Tara , Lantz Kristen Anne , O'Rourke Lisa , Qin Xiang , Parasrampuria Dolly A. , Heuck Christoph , Qi Ming , Nahi Hareth 
Published: November 2019

Introduction: DARA, a human CD38 monoclonal antibody (mAb), is approved for intravenous (IV; 16 mg/kg) administration as a single agent or in combination with standard-of-care regimens for treatment of multiple myeloma. To reduce patient and provider burden and improve safety, a subcutaneous (SC) co-formulation of DARA (flat dose of 1,800 mg, ~70% bioavailability) with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) was developed. The phase 3, randomized, open-label COLUMBA study (NCT03277105) demonstrated the non-inferiority of DARA SC vs DARA IV in terms of co-primary endpoints (ORR and Ctrough) in pts with RRMM at a median of 7.5 months follow-up. Here, we present a body weight subgroup analysis of COLUMBA, based on data from the primary analysis.
Methods: DARA SC (flat dose of 1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg) were given in 28-day cycles: QW Cycles 1-2, Q2W Cycles 3-6, and Q4W thereafter. DARA SC (15 mL) was given by manual push over 3-5 mins at alternating left/right abdominal sites. Eligible pts (≥18 yrs) with RRMM had ≥3 prior lines of therapy, including a PI and an IMiD, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum DARA Ctrough (pre-dose concentration on Cycle 3 Day 1 [C3D1]). A subgroup analysis was performed by body weight (≤65 kg, >65 to 85 kg, and >85 kg).
Results: In the intent-to-treat (ITT) population, 522 pts were randomized to receive DARA SC (n = 263) or DARA IV (n = 259). Median baseline body weight was 73 kg. Flat dose DARA SC achieved adequate exposure for all body weight subgroups, as maximum Ctrough (C3D1 predose) exceeded the 236 μg/mL threshold previously established in DARA IV studies as necessary for 99% target saturation (Xu XS, et al. Clin Pharmacol Ther, 2017). Across each subgroup, there was considerable overlap in maximum Ctrough for both treatment groups (Figure); however, mean DARA concentrations were 60% higher for pts ≤65 kg and 12% lower for pts >85 kg treated with DARA SC vs IV. Nevertheless, the range of Ctrough across body weights for DARA SC was within the previously observed range (36 to 1764 µg/mL for C3D1 Ctrough) for the approved DARA IV 16 mg/kg.
ORR in the ITT population was 41.1% vs 37.1% for DARA SC vs DARA IV. In the body weight subgroups, ORR was 43.6% vs 38.0%, 37.3% vs 39.0%, and 43.9% vs 32.8% for DARA SC vs IV in the ≤65 kg, >65 to 85 kg, and >85 kg groups, respectively. These data suggest that the slightly lower exposure observed at higher body weights was not clinically relevant.
For both treatment groups, the incidence of grade 3/4 TEAEs, grade 5 TEAEs, serious TEAEs, and IRRs was similar across body weight subgroups. An increased incidence of TEAEs of any grade with decreasing body weight for DARA SC (≤65 kg, 94.6%; >65 to 85 kg, 87.3%; >85 kg, 78.5%) was observed; incidence of any grade TEAEs was similar across body weight subgroups for DARA IV (≤65 kg, 89.1%; >65 to 85 kg, 89.5%; >85 kg, 88.5%). At the preferred term level, an decreased incidence of grade 3/4 thrombocytopenia (≤65 kg, 16.1%; >65 to 85 kg, 14.7%; >85 kg, 9.2%) and grade 3/4 neutropenia (≤65 kg, 20.4%; >65 to 85 kg, 9.8%; >85 kg, 7.7%) with increasing body weight was observed for DARA SC. An increased incidence of grade 3/4 hypertension (≤65 kg, 4.3%; >65 to 85 kg, 5.7%; >85 kg, 9.8%) with increasing body weight was observed for DARA IV. However, the incidence of maximum Grade 3 and 4 TEAEs (DARA SC, 43.0%; DARA IV, 44.6%) and the incidence of Grade 5 TEAEs (6.5% for both) were similar between treatment groups in the lowest body weight subgroup. For subjects ≤65 kg, DARA SC had a lower incidence of serious TEAEs (DARA SC, 23.7%; DARA IV, 30.4%).
Conclusions: In the primary analysis, efficacy and PK co-primary endpoints were met, demonstrating non-inferiority of DARA SC to DARA IV, with similar safety profiles and significant reduction in IRR rates with DARA SC. In this subgroup analysis, ORR in all body weight subgroups was consistent with ORR in the overall population. DARA SC achieved adequate exposure and was well tolerated across all body weight subgroups. The higher concentration of DARA SC in pts ≤65 kg did not have a clinically relevant effect on safety, suggesting no dose individualization is necessary on the basis of weight.

Disclosures
Mateos: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Usmani:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. Vorobyev:Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sanofi: Consultancy. Spicka:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Hungria:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Moreau:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kaiser:Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Iida:Abbvie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Gilead: Research Funding; Astellas: Research Funding; Teijin Pharma: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MSD: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Daichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Masterson:Janssen: Employment, Equity Ownership. Lantz:Janssen: Employment, Equity Ownership. O'Rourke:Janssen: Employment, Equity Ownership. Qin:Janssen: Employment, Equity Ownership. Parasrampuria:Janssen: Employment, Equity Ownership. Heuck:Janssen: Employment. Qi:Janssen: Employment.

OffLabel Disclosure:
This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.