Daratumumab (DARA) Subcutaneous (SC) Delivery in Relapsed or Refractory Multiple Myeloma (RRMM): Population Pharmacokinetics (PPK) and Exposure-Response (E-R) Analysis
Authors: Luo Melody , Parasrampuria Dolly A. , Usmani Saad Z. , Mateos Maria-Victoria , Nahi Hareth , Heuck Christoph , Qi Ming , Sun Steven , Clemens Pamela L. , Zhou Honghui , Sun Yu-Nien (Tom) , Xu Steven 
Published: November 2019

Introduction: The intravenous (IV) formulation of human CD38 mAb DARA is approved in many countries as monotherapy or in combination with standard-of-care regimens for treatment of multiple myeloma (MM).
To reduce patient (pt)/provider burden and improve safety, a DARA SC co-formulation (1800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2000 U/mL; Halozyme, Inc.]) was developed. In the phase 3 COLUMBA study, DARA SC was non-inferior to DARA IV (ORR and PK), with a significantly decreased rate of infusion-related reactions and reduced administration time in RRMM. Here, we report the PK of DARA and its relationship with clinical outcomes following DARA SC in MM across pt subgroups, including body weight (wt), vs DARA IV.
Methods: In COLUMBA, DARA SC (1800 mg) and DARA IV (16 mg/kg) were given QW for Cycle (C) 1-2 (C = 28 days), Q2W for C3-6, and Q4W thereafter. DARA SC (15 mL) was given by injection over 3-5 min. The PPK and E-R analyses included data from 3 monotherapy studies (2 phase 1/1b studies [PAVO, MMY1008], and a phase 3 study [COLUMBA; SC and IV arms]).
For PPK, serum concentration-time data were used for nonlinear mixed-effects modeling (NONMEM®; ICON plc, V7.2). First-order conditional estimation with interaction estimation method was used. The DARA IV PPK model with absorption was used to model DARA SC. The effects of covariates on DARA exposure were assessed by subgroup analyses of predicted exposure metrics.
Covariates in the PPK analysis were body wt, age, sex, race, region, baseline CrCl, baseline albumin, alanine aminotransferase, alkaline phosphatase, hepatic dysfunction, and type of MM at baseline (IgG vs non-IgG).
The E-R analysis for ORR was investigated using logistic regression implemented in R. The E-R for safety was explored for selected adverse events (AEs), including overall serious AEs (SAEs), overall ≥grade 3 TEAEs, and neutropenia. Peak DARA concentrations after first dose and overall peak concentrations were investigated for their potential relationship with AEs using logistic regression.
Results: The PPK analysis was based on 5,159 PK samples from 742 pts (DARA SC, n = 487; DARA IV, n = 255). Based on PK data, the recommended DARA SC (1800 mg) dose provided similar or slightly higher trough concentrations (Ctrough) throughout the dosing schedule vs DARA IV (16 mg/kg) with lower maximum concentrations (Cmax) and smaller peak-to-trough fluctuations. The geometric mean ratio for DARA SC/IV Ctrough over time was consistently slightly >1 throughout the treatment period. The mean peak-to-trough ratio at C3D1 was 1.2 vs 1.7 for DARA SC vs IV (Figure 1A). A subgroup analysis on predicted C3D1 Ctrough for DARA SC monotherapy exposure showed no clinically relevant effects for any covariates tested (Figure 1B). Results were consistent across body wt subgroups.
In COLUMBA, efficacy and PK co-primary endpoints were met, demonstrating non-inferiority of DARA SC to DARA IV. ORR was 44% for DARA SC and 39% for DARA IV. Consistent efficacy was also observed for DARA SC vs DARA IV in all body wt subgroups, with ORRs in the high body wt group (>85 kg) of 47.0% (95% CI, 34.6-59.7%) vs 32.8% (95% CI, 21.3-46.0%), respectively.
In the E-R analysis, DARA SC produced higher C3D1 Ctrough in both responders and nonresponders. No relationship was observed between exposure and safety endpoints (SAEs, ≥grade 3 TEAEs, and neutropenia). DARA SC showed slightly higher concentrations at lower body wts than DARA IV (Figure 1C), but the rate of SAEs and ≥grade 3 TEAEs was comparable between groups.
Conclusions: Compared to DARA IV, DARA SC consistently showed similar/higher trough levels over time with lower peak concentrations and lower peak-to-trough fluctuations. Ctrough exceeded threshold needed for 99% target saturation. This favorable PK property for DARA SC resulted in comparable efficacy and safety profiles vs DARA IV. Generally, consistent concentrations of exposure were observed across body wts, with no apparent relationship between exposure and safety endpoints. Similar efficacy (ORR) was observed across body wt subgroups with the DARA SC flat dose, supporting the use of this regimen for pts with MM. Results were consistent across subgroups, therefore, no dose adjustment is recommended.

Disclosures
Luo: Janssen: Employment, Equity Ownership. Parasrampuria:Janssen: Employment, Equity Ownership. Usmani:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau. Mateos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Heuck:Janssen: Employment. Qi:Janssen: Employment. Sun:Johnson & Johnson: Equity Ownership; Janssen: Employment. Clemens:Janssen: Employment, Equity Ownership. Zhou:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Xu:Janssen: Employment, Equity Ownership.

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.