Subcutaneous (SC) Isatuximab Administration by an On-Body Delivery System (OBDS) in Combination with Pomalidomide-Dexamethasone (Pd) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients: Interim Phase 1b Study Results

Introduction:
SC Isa delivery would optimize convenience of administration. Prior results showed SC Isa administered by syringe pump has efficacy and safety comparable to IV Isa; recommended Phase 2 dose (RP2D) was 1400 mg (IMW21 P-207).
Methods:
This multicenter Phase 1b study evaluated safety, pharmacokinetics (PK), and efficacy of SC vs IV Isa + Pd in RRMM pts after ‚â•2 prior treatment lines. Pts randomized 2:1 to SC1000 mg or IV10 mg/kg and to SC1400 mg or IV. Expansion cohort was later implemented with SC Isa administered at RP2D via OBDS (wearable bolus injector applied to abdomen by healthcare professional). Primary endpoints (EPs) were safety, including injection site reactions (ISRs), and PK. Main secondary EPs were overall response rate (ORR) and progression-free survival (PFS).
Results:
56 pts were randomized and treated: 12 IV, 12 SC1000, 10 SC1400, and 22 OBDS pts. At study entry, ISS stage II–III was: IV 67%, SC1000 33%, SC1400 60%, and OBDS 50%. On 20Jan2022, 33% IV, 25% SC1000, 50% SC1400, and 86% OBDS pts remained on treatment. Due to sequential accrual, median follow-up (FU; in months) was longer in IV (20.6) and SC1000 (23.8) than SC1400 (18.1) and OBDS (6.5) pts. Infusion reactions (IRs) were infrequent (≤10% in each cohort, all Grade [G] 2), only at first IV or SC infusion/injection, with no IRs in OBDS. OBDS local tolerability was very good, with 5 (22.7%) pts experiencing 7 ISR episodes, all G1, out of 305 administrations (2.3%): 5 injection site erythemas, 1 injection site hemorrhage, and 1 injection site induration. Median duration of OBDS injection was 10 min. Lower % of ≥G3 treatment-related adverse events in OBDS (77%) vs other cohorts (≥80%) may be due to shorter FU; most common ≥G3 TEAEs in OBDS pts were neutropenia (77.3%) and anemia (13.6%), however, only 1 (4.5%) pt in this cohort developed febrile neutropenia. None of the pts discontinued Isa due to TEAEs; 3 (1 SC1000, 2 SC1400) pts and 2 (SC1400) pts prematurely discontinued P and d, respectively, due to TEAE. ORR, ≥VGPR, CR, and PR rates were: 66.7%, 50%, 16.7% and 16.7% in IV, 66.7%, 41.7%, 25% and 25% in SC1000, 80%, 40%, 20% and 40% in SC1400, 77.3%, 40.9%, 13.6% and 36.4% in OBDS, and 78.1%, 40.6%, 15.6% and 37.5% in SC1400+OBDS(R2PD); longer FU is needed for OBDS pts. Median PFS (in months) was: IV 22, SC1000 12.5, and SC1400 and OBDS not reached. Mean C of Isa at end of weekly dosing period was higher after Isa OBDS and SC vs IV. Mean CD38 receptor occupancy was: OBDS 78%, SC1400 81%, and IV 76%.
Discussion:
SC Isa administered by OBDS shows a safety profile consistent with IV administration with no IRs and excellent local tolerability. Efficacy in the SC cohorts was comparable to Phase 3 ICARIA results. PK results in OBDS pts were similar to those receiving SC1400. Isa SC administration by OBDS is well tolerated, requires short duration of injection, and provides convenient hands-free option.