Talquetamab at RP2D Elicits High Clinical Response Rate in Relapsed/Refractory Multiple Myeloma

Jesus G. Berdeja, MD

Talquetamab (GPRC5D), when delivered at the recommended phase 2 dose (RP2D) of 405 µg/kg weekly, induced a high clinical response rate with favorable tolerabilty in patients with relapsed/refractory multiple myeloma, according to updated data from an analysis of the phase 1 MonumentTAL-1 trial (NCT03399799), which were presented during the 2021 ASCO Annual Meeting.

The agent yielded an overall response rate of 70%, when given at the RP2D, with a median time to first confirmed response of 1 month (range, 0.2-3.8). Moreover, 65.2% of patients (n = 15/23) with triple-refractory disease responded to treatment, as did 83.3% of those (n = 5/6) with penta-refractory disease.

“Talquetamab is an off-the-shelf T cell-redirecting agent that requires limited steroid use and has a manageable safety profile,” Jesus G. Berdeja, MD, lead study author and director of myeloma research at Sarah Cannon Cancer Institute, said in a presentation on the data. Talquetamab is a first-in-class antibody that binds to CD3 and GPRC5D to redirect T cells to kill multiple myeloma cells.

Eligible patients with relapsed/refractory disease received talquetamab intravenously (IV, range, 0.5-180 µg/kg) or subcutaneously (SC; range, 5.0-800 µg/kg). Primary objectives of part 1 of the trial was identification of the RP2D whereas safety and tolerability were the objectives of part 2.

In the trial, 184 patients received talquetamab, 102 patients by IV and 82 patients by SC. In patients who received the drug SC there were 6 dose levels tested from 5 µg/kg to 800 µg/kg.

A maximum tolerated dose was not reached and Berdeja noted that safety, efficacy, pharmacokinetic, and pharmacodynamic data supported a weekly SC dose of 405 µg/kg as the RP2D. In the updated analysis, the RP2D of 405 µg/kg was administered SC once weekly to 30 patients with a median follow-up of 6.3 months (range, 1.4-12.0).

In the SC group (n = 82), the median age was 63.0 years (range, 42-80) and in the RP2D group (n = 30) the median age was 61.5 years (range, 46-80). Twenty-two patients (27%) were over 70 years of age in the SC group compared with 7 (23%) in the RP2D group. Twenty patients (24%) in the SC group received prior B-cell maturation antigen (BCMA) therapy compared with 8 (27%) patients in the RP2D group.

In the SC group, 76% of patients were triple-class refractory compared with 77% in the RP2D group. In the SC group, 28% of patients were penta-drug refractory compared with 20% in the RP2D group.

Regarding safety, Berdeja reported that talquetamab had a tolerable safety profile at the RP2D dose with no dose-limiting toxicities (DLTs) reported. Cytopenias were confined to patients who received step-up doses and neutropenias resolved within a week. In general, all grade 1-2 neurotoxicities were observed in 4 patients who received SC dosing and 2 patients who received the RP2D. Skin-related adverse effects (AEs) were reported in 67% of patients in the SC group and 77% in the RP2D group, with the majority being grade 1-2. There were no deaths due to AEs at the RP2D reported.

Overall, the most common nonhematologic AE reported was any grade cytokine release syndrome (CRS) with 67% of patients in the SC group reporting. In this group, 1 patient reported grade 3 CRS. In the RP2D group, 73% of patients reported any grade CRS.

“CRS was confined to step-up and first full doses,” Berdeja explained. “Most patients only required 1 dose of tocilizumab [Actemra] as a supportive measure.”

Of 6 evaluable patients across IV and SC cohorts, 4 had MRD-negative complete responses (CR)/sustained CR at 10-6, including 1 patient in the RP2D group. MRD negativity was sustained 7 months post CR in 1 evaluable patient.

Berdeja noted that responses were durable and deepened over time with 81% of responders in the RP2D group continuing on treatment. He said data from the IV cohort were more mature and that at subtherapeutic doses, responses were ongoing at more than 22 months in patients with longer follow-up.

Regarding immunogenicity, 6 of 50 (12%) patients treated with SC talquetamab had low titer antidrug antibodies, which did not appear to affect safety, pharmacokinetics, or efficacy. Pharmacodynamic analysis revealed that post treatment, PD-1-positive T cells were induced in the periphery, indicative of T-cell activation. Further, cytokine induction was consistent at doses greater than 45 µg/kg SC.

“Findings were encouraging and a phase 2 expansion study of talquetamab at the RB2D [NCT04634552] is currently in progress,” Berjeda concluded.

Reference

1. Berdeja JG, Krishnan A, Oriol A, et al. Updated results of a phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) × CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM). J Clin Oncol. 2021;39(suppl 15):8008. doi:10.1200/JCO.2021.39.15_suppl.8008