First-in-Class Multiple Myeloma Drug Shows Encouraging Clinical Activity, Manageable Safety

Talquetamab is a bispecific antibody that binds to GPRC5D and CD3 to induce T cell-mediated killing of GPRC5D-expressing multiple myeloma cells.

Talquetamab, a first-in-class bispecific antibody, was shown to have positive clinical activity and an acceptable safety profile in the results of a phase 1 dose escalation study of heavily pretreated patients with relapsed or refractory multiple myeloma.

The drug is a bispecific antibody that binds to GPRC5D and CD3 to induce T cell-mediated killing of GPRC5D-expressing multiple myeloma cells. Preclinical models found that it induced the death of multiple myeloma cells and inhibited tumor formation and growth.

In the phase 1 trial, eligible patients have measurable multiple myeloma and progressed on, or could not tolerate, established therapies. Primary objectives are to characterize the safety and to identify a recommended phase 2 dose. As of July 20, 2020, 137 participants had received talquetamab—102 intravenously (IV) and 35 subcutaneously (SQ). The median age was 64 years and 22% had stage 3 disease. The median number of prior therapies was 6 over a median of 6.5 years.

The most frequently reported adverse events (AEs) of all grades were anemia, cytokine release syndrome (CRS), neutropenia, and lymphopenia. The most common grade 3 to 4 AEs were lymphopenia, anemia, and neutropenia. CRS was mostly grade 1 or 2, except for 5 patients in the IV group who had grade 3 CRS. Treatment-related neurotoxicity was reported in 7 patients.

The half-life of talquetamab supports weekly IV dosing, according to the study. Exposure increased in an approximately dose-proportional manner after the first IV dose, and SQ dosing resulted in lower maximum serum concentration with trough levels comparable to IV dosing at a similar dose. Cytokine production was modulated with step-up dosing while T cell activation was maintained.

The overall response rate (ORR) for IV doses of 20 µg/kg to 180 µg/kg was 78%, with 6 out of 6 patients responding at the highest dose. ORR for SQ doses of 135 µg/kg to 405 µg/kg was 67% with 3 out of 4 patients responding at the highest dose. Responses were noted starting at 1 µg/kg, were rapid at a median of 1 month, and were durable with the median not reached in 36 of the 46 patients. Data at higher doses are immature, according to the authors.

Based on these findings, the authors concluded that talquetamab warrants further investigation, with encouraging clinical activity and an acceptable safety profile in heavily pretreated patients. A maximum tolerated dose has not been defined and dose escalation continues. The authors added that their findings support both monotherapy development and combination approaches.

REFERENCE

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 (RRMM). Paper presented at: American Society of Hematology 62nd Annual Meeting & Exposition; December 5-8, 2020. Accessed December 3, 2020.