OAB-025: Talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D)×CD3 bispecific antibody, in relapsed/refractory multiple myeloma (RRMM): Updated results of a phase 1, first-in-human study

Background As patients (pts) with MM continue to relapse, new immunotherapy targets are needed. GPRC5D is an orphan receptor that is expressed on malignant plasma cells in MM. Talquetamab (JNJ-64407564) is a bispecific IgG4 antibody that binds to the novel target, GPRC5D, and to CD3 to redirect T cells to kill MM cells. Updated phase 1 results of talquetamab in pts with RRMM treated at the recommended phase 2 dose (RP2D) are presented here. Methods Eligible pts had RRMM or were intolerant to standard therapies. Talquetamab was given either intravenously (IV; range 0.5–180 µg/kg) or subcutaneously (SC; range 5.0–800 µg/kg) weekly or biweekly. Primary objectives of the study were to identify the RP2D (part 1) and characterize talquetamab safety and tolerability at the RP2D (part 2). Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events v4.03 (cytokine release syndrome [CRS] per Lee 2014). Response was assessed per International Myeloma Working Group criteria. Results As of Feb 8, 2021, 174 pts received talquetamab IV (n=102) or SC (n=72). Across both parts of the study, 28 pts received the RP2D of 405 µg/kg SC weekly, with 10.0 and 60.0 µg/kg step-up doses. Pts treated at the RP2D had a median age of 61.5 years (range 46–80) and received a median of 5.5 prior lines of therapy (range 2–14; 100%/79% triple-class/penta-drug exposed; 71%/18% triple-class/penta-drug refractory; 86% refractory to last line of therapy; 21% had prior B-cell maturation antigen–directed therapy). No dose-limiting toxicities occurred at the RP2D in part 1. Most common AEs at the RP2D were CRS (79%; grade 3 were 4%; median time to onset was day after SC injection), neutropenia (64%; grade 3/4 were 54%), anemia (57%; grade 3/4 were 29%) and dysgeusia (57%; all grade 1/2). Infections were reported in 32% of pts (grade 3/4 were 4%) and neurotoxicity in 7% (no grade 3/4 events). Overall, 75% of pts treated at the RP2D had skin-related AEs (no grade 3/4 events), including 18% with nail disorders. In 24 response-evaluable pts, overall response rate at the RP2D was 63%, with 50% reaching very good partial response or better; 9/17 (53%) evaluable triple-class refractory pts and 3/3 (100%) penta-drug refractory pts responded. The median time to first confirmed response at the RP2D was 1.0 month (range 0.2–3.8). Responses were durable and deepened over time (median follow-up 6.2 month [range 2.7–9.7+] for responders at the RP2D). Talquetamab exposure at the RP2D was maintained over the maximum EC90 target level from an ex vivo cytotoxicity assay, and consistent T cell activation was seen. Conclusions Talquetamab, at the RP2D of 405 µg/kg SC weekly, demonstrated a high clinical response rate and was well-tolerated in pts with RRMM. Based on pharmacokinetic data, other SC dosing strategies are being explored. The promising efficacy, safety profile and convenience of SC dosing support monotherapy development and combination approaches with this novel agent.