Ajai Chari, MD, Ph.D. – Professor of Medicine, the Director of Clinical Research in the Multiple Myeloma Program, and the Associate Director of Clinical Research, Mt Sinai Cancer Clinical Trials Office speaks about ASH 2020 abstract 290 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)Clinically Relevant Abstract.
Most patients (pts) will develop refractory disease despite enhanced results with current MM therapies, emphasizing the need for novel treatments. GPRC5D is an orphan receptor whose transcript is highly expressed but has generally restricted expression elsewhere in primary MM cells, making it an attractive therapeutic target.
Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to GPRC5D and CD3 via the recruitment and activation of T cells to induce T cell-mediated killing of GPRC5D-expressing MM cells. Talquetamab induced cell killing of primary MM cells in preclinical models and prevented the development and growth of tumors in MM mouse models. Initial findings from a continuing phase 1 dose escalation analysis of Talquetamabab are presented (NCT03399799).
Eligible pts had observable MM and continued with existing therapies or were unable to tolerate them. The key objective is to characterize the protection of talquetamab and to evaluate the recommended dose of phase 2 (RP2D). Increasing doses were evaluated for intravenous (IV) or subcutaneous (SC) talquetamab ± step-up doses. The characterization of pharmacokinetics, pharmacodynamics, and preliminary efficacy are secondary objectives. Per CTCAE, cytokine release syndrome (CRS) per Lee 2014, adverse events (AEs) were classified. The investigator evaluated the response according to IMWG guidelines.
Talquetamab was given 137 pts as of 20 Jul 2020; 102 by IV (0.5-180 μg/kg) and 35 by SC (5-800 μg/kg) dosing. The median age was 64 years (33-80; 31% were around 70) and 22% had stage III ISS disease at the beginning of the study. The median number of previous treatments was 6.
Over a total of 6.5 years (0.9-27) after diagnosis (2-20), 85% were refractory to the last line of treatment, 79% were triple-class refractory, 73% were exposed to penta-drugs, and 31% were refractory to penta-drugs. Selinexor earned 13 (10 percent) pts and 21 (15 percent) had previous BCMA-directed therapy.
All grade AEs were most widely identified as anemia (50 percent), CRS (47 percent), neutropenia (45 percent), and lymphopenia (40 percent ). Lymphopenia (37 percent), anemia (27 percent), and neutropenia were the most common Grade 4 AEs (25 percent ). CRS was mainly grade 1-2 except for 5 pts with CRS grade 3 (approximately 8 percent of pts with CRS) that occurred with IV dosing; with SC dosing, only grade 1-2 CRS was seen. In general, CRS was confined to the first period with a median time of 1 day (1-3) for IV and 2 days (1-5) for SC dosing to begin. In 7 (5 percent) pts (all resolved/resolving; median period of 2 days [1-9]), treatment-related neurotoxicity was reported: 4 had grade 2 events and 3 had grade 3 delirium events (n=1), decreased consciousness level (n=1), or uncertainty (n=1). Neurotoxicity occurring in the sense of CRS occurred in six out of 7 pts, including all 3 Grade 3 cases. Infections were reported in 37% of pts (8% of grades 3-4). Infusion-related (IV; 15%) and injection site (SC; 14%) reactions were grade 1-2 and usually occurred in cycle 1. Two dose-limiting toxicities have been observed: clinically asymptomatic grade 4 increased lipase in pancreatic plasmacytoma setting (7.5 μg/kg IV) and maculopapular rash grade 3 setting (135 μg/kg SC). There was no definition of the maximum tolerated dose (MTD).
Talquetamab’s half-life facilitates weekly IV dosing. After the first IV dose (1.5-60 μg/kg), exposure increased in an approximately dose-proportional fashion. At a similar dose, SC dosing resulted in lower Cmax with trough levels comparable with IV dosing. Comparable increases in activation of T cells and cytokines (e.g., IL-10, IL-2R alpha, IL-6) resulted from IV and SC doses of talquetamab. With step-up dosing, cytokine production was modulated while T cell activation was maintained.
For IV doses of 20 to 180 μg/kg, the overall response rate (ORR) was 78 percent (14/18; 2 awaiting confirmation); 6/6 responded to the 60 μg/kg IV dose. The ORR was 67% (8/12) for SC doses of 135-405 μg/kg; 3/4 responded to the 405 μg/kg SC dose. Responses were observed beginning at 1.0 μg/kg, were rapid at a median of 1 month (0.2-3) and durable with a median not reached at 36/46 (4 pts with 15+ months of response; 23+ months longest). Data at higher doses are immature and will be revised at the meeting with the findings.
GPRC5D is a novel target for MM, and promoting clinical activity with manageable protection was observed with talquetamab in heavily pretreated pts with RRMM in the first clinical report of this first-in-class agent. There has been no concept of an MTD and dose escalation continues, with the study reaching RP2D. Monotherapy development and combination therapies are facilitated by promoting clinical activity.