A Phase 1, First-in-Human Study of Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D (GPRC5D) x CD3 Bispecific Antibody, in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Despite improved outcomes with current MM treatments, most patients (pts) will develop refractory disease, highlighting the need for novel treatments. GPRC5D is an orphan receptor whose transcript is highly expressed in primary MM cells but has generally limited expression elsewhere, making it an attractive therapeutic target.

Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to GPRC5D and CD3 to induce T cell-mediated killing of GPRC5D-expressing MM cells through the recruitment and activation of T cells. In preclinical models, talquetamab induced cell killing of primary MM cells and inhibited tumor formation and growth in MM mouse models. We present initial results from an ongoing phase 1 dose escalation study of talquetamab (NCT03399799).

Eligible pts have measurable MM and progressed on or could not tolerate established therapies. Primary objectives are to characterize the safety of talquetamab and to identify a recommended phase 2 dose (RP2D). Escalating doses of intravenous (IV) or subcutaneous (SC) talquetamab ± step-up doses were assessed. Secondary objectives include characterizing the pharmacokinetics, pharmacodynamics, and preliminary efficacy. Adverse events (AEs) were graded per CTCAE, cytokine release syndrome (CRS) per Lee 2014. Response was assessed by the investigator according to IMWG criteria.

As of 20 Jul 2020, 137 pts had received talquetamab; 102 by IV (0.5 – 180 µg/kg) and 35 by SC (5 – 800 µg/kg) dosing. Median age was 64 years (33 – 80; 31% were ≥70) and 22% had ISS stage III disease at study entry. Median number of prior therapies was 6 
(2 – 20) over a median of 6.5 years (0.9 – 27) since diagnosis, 85% were refractory to last line of therapy, 79% triple-class refractory, 73% penta-drug exposed, and 31% penta-drug refractory. 13 (10%) pts had received selinexor and 21 (15%) had prior BCMA-directed therapy.

Most frequently reported all grade AEs were anemia (50%), CRS (47%), neutropenia (45%), and lymphopenia (40%). Most common grade 3 – 4 AEs were lymphopenia (37%), anemia (27%), and neutropenia (25%). CRS was mostly grade 1 – 2 except for 5 pts with grade 3 CRS (˂8% of pts with CRS) that occurred with IV dosing; only grade 1 – 2 CRS was seen with SC dosing. CRS was generally confined to the first cycle with median time to onset of 1 day (1 – 3) for IV and 2 days (1 – 5) for SC dosing. Treatment-related neurotoxicity was reported in 7 (5%) pts (all resolved/resolving; median duration of 2 days [1 – 9]): 4 had grade 1 – 2 events and 3 had grade 3 events of delirium (n=1), decreased level of consciousness (n=1), or confusion (n=1). Six of 7 pts had neurotoxicity that occurred in the context of CRS, including all 3 grade 3 events. Infections were reported in 37% of pts (8% grade 3 – 4). Infusion related reactions (IV; 15%) and injection site reactions (SC; 14%) were grade 1 – 2 and generally occurred in cycle 1. Two dose-limiting toxicities were observed: clinically asymptomatic grade 4 increased lipase in the setting of a pancreatic plasmacytoma (7.5 µg/kg IV) and grade 3 maculopapular rash (135 µg/kg SC). The maximum tolerated dose (MTD) has not been defined.

The half-life of talquetamab supports weekly IV dosing. Exposure increased in an approximately dose-proportional manner following the first IV dose (1.5 – 60 µg/kg). SC dosing resulted in lower Cmax with trough levels comparable to IV dosing at a similar dose. IV and SC dosing of talquetamab led to comparable increases in T cell activation and cytokines (e.g., IL-10, IL-2Rα, IL-6). Cytokine production was modulated with step-up dosing while T cell activation was maintained.

Overall response rate (ORR) for IV doses of 20 – 180 µg/kg was 78% (14/18; 2 pending confirmation); 6/6 responded at the 60 µg/kg IV dose. ORR for SC doses of 135 – 405 µg/kg was 67% (8/12); 3/4 responded at the 405 µg/kg SC dose. Responses were noted starting at 1.0 µg/kg, were rapid at a median of 1 month (0.2 – 3), and durable with median not reached in 36/46 (4 pts with response 15+ months; longest at 23+ months). Data at higher doses are immature, and results will be updated at the meeting.

GPRC5D is a novel target for MM and in the first clinical report of this first-in-class agent, encouraging clinical activity with manageable safety was observed with talquetamab in heavily pretreated pts with RRMM. A MTD has not been defined and dose escalation continues, with the study nearing a RP2D. The encouraging clinical activity supports monotherapy development and combination approaches.