Updated Phase 1 Results from MonumenTAL-1: First-in-Human Study of Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

ABSTRACT

Introduction: Despite recent advances in treatment, patients with multiple myeloma (MM) continue to relapse. G protein-coupled receptor family C group 5 member D (GPRC5D) is a promising target for immunotherapy in patients with MM due to its high expression in malignant plasma cells and limited expression in normal human tissue;unlike other antigens targeted by MM therapies, there is no indication that GPRC5D sheds into the periphery. Talquetamab (JNJ-64407564) is a first-in-class bispecific IgG4 antibody that redirects T cells to kill MM cells by binding to both GPRC5D and CD3 receptors. Here we report updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) from a phase 1 trial in relapsed/refractory MM (RRMM;NCT03399799). Methods: Eligible patients with MM had relapsed or refractory disease or were intolerant to standard therapies;patients previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC;range 5.0-800 µg/kg) weekly or biweekly. Step-up dosing was used as a patient management strategy to minimize the severity of cytokine release syndrome (CRS). The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03 with CRS events graded per Lee et al 2014 criteria. Responses were investigator-assessed per International Myeloma Working Group criteria. Results: As of July 19, 2021, 95 patients have received SC talquetamab. The RP2D was originally identified as a weekly SC dose of 405 µg/kg talquetamab with step-up doses. However, alternative dosing schedules that require less frequent administration continue to be investigated. A biweekly RP2D was also identified as an SC dose of 800 µg/kg talquetamab with step-up doses. 30 patients received the 405 µg/kg weekly dosing schedule (median age 61.5 years [range 46-80];63% male;100% triple-class exposed;80% penta-drug exposed;77% triple-class refractory, 20% penta-drug refractory;30% prior BCMA-directed therapy;median follow-up 7.5 mo [range 0.9-15.2]). 23 patients received the 800 µg/kg biweekly dosing schedule (median age 60.0 years [range 47-84];48% male;96% triple-class exposed;70% penta-drug exposed;65% triple-class refractory, 22% penta-drug refractory;17% prior BCMA-directed therapy;median follow-up 3.7 mo [range 0.0-12.0]). There were no treatment discontinuations due to AEs at either of the RP2Ds. The most common AEs at the 405 µg/kg weekly dose were CRS (73%;1 patient had grade 3 CRS), neutropenia (67%;grade 3/4 60%), and dysgeusia (60%;grade 2 29%);skin-related AEs occurred in 77% (all grade 1/2;nail disorders 30%) of patients, and infections occurred in 37% of patients (1 patient had grade 3 COVID-19 pneumonia). The most common AEs at the 800 µg/kg biweekly dose were CRS (78%;all grade 1/2), dry mouth (44%;all grade 1/2), and neutropenia (44%;grade 3/4 35%);skin-related AEs occurred in 65% of patients (grade 3 13%;nail disorders 17%) and infections occurred in 13% of patients (1 patient had grade 3 pneumococcal sepsis). In 30 response-evaluable patients treated with the 405 µg/kg weekly dose, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR] rate 57%). In 17 response-evaluable patients treated with the 800 µg/kg biweekly dose, the ORR was 71% (≥VGPR rate 53%). Responses were durable and deepened over time in both cohorts (Figure). Median duration of response (DOR) was not reached at either RP2D;the 6-month DOR rate for patients who received the 405 µg/kg weekly dose was 67% [95% CI 41-84]. Serum trough levels of talquetamab were comparable at both RP2Ds. Consistent with the mechanism of action for talquetamab, pharmacodynamic data from cohorts treated at both dose levels showed peripheral T-cell activation and induction of cytokines. Conclusions: These findings indicate that SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data from the 800 µg/kg biweekly cohorts indicate that less frequent, higher doses of SC talquetamab do not have a negative impact on the previously described safety profile. Further investigation of talquetamab as monotherapy (phase 2;NCT04634552) and in combination with other therapies in patients with RRMM is underway. [Formula presented] Disclosures Krishnan MAGENTA Consultancy;BMS Consultancy, Current equity holder in publicly-traded company, Speakers Bureau;JANSSEN Consultancy, Research Funding;City of Hope Cancer Center Current Employment;REGENERON Consultancy;SANOFI Consultancy;GSK Consultancy;Amgen Speakers Bureau. Minnema Celgene Other Travel expenses;Alnylam Consultancy;Cilag Consultancy;BMS Consultancy;Janssen Consultancy;Kite/Gilead Consultancy. Berdeja Lilly, Novartis Research Funding;Abbvie, Acetylon, Amgen Research Funding;Celularity, CRISPR Therapeutics Research Funding;EMD Sorono, Genentech Research Funding;Poseida, Sanofi, Teva Research Funding;Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda Consultancy;GSK, Ichnos Sciences, Incyte Research Funding. Oriol Sanofi Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm Consultancy, Membership on an entity's Board of Directors or advisory committees;Oncopeptides Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk Roche Consultancy;Takeda Consultancy;Cellectis Research Funding;Amgen Consultancy, Research Funding;Janssen Consultancy, Research Funding;BMS/Celgene Consultancy, Honoraria;Novartis /bayer/servier Consultancy. Rodriguez-Otero Clínica Universidad de Navarra Current Employment;Janssen Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene-BMS Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;GSK Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer Consultancy;Sanofi Honoraria, Membership on an entity's Board of Directors or advisory committees;Kite Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen Honoraria;Regeneron Honoraria. Askari Janssen Research Funding. Mateos Sanofi Honoraria, Membership on an entity's Board of Directors or advisory committees;Sea-Gen Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer Honoraria, Membership on an entity's Board of Directors or advisory committees;Regeneron Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene - Bristol Myers Squibb Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda Honoraria, Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies Honoraria, Membership on an entity's Board of Directors or advisory committees;Oncopeptides Honoraria;Bluebird bio Honoraria;AbbVie Honoraria;GSK Honoraria;Oncopeptides Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche Honoraria, Membership on an entity's Board of Directors or advisory committees. Costa BMS Consultancy, Honoraria, Research Funding;Janssen Consultancy, Honoraria, Research Funding;Amgen Consultancy, Honoraria, Research Funding, Speakers Bureau;Karyopharm Consultancy, Honoraria;Pfizer Consultancy, Honoraria;Sanofi Consultancy, Honoraria, Speakers Burea . Verona Janssen Current Employment. Ma Janssen Current Employment, Current holder of individual stocks in a privately-held company. Girgis Janssen Current Employment, Current holder of individual stocks in a privately-held company. Yang Janssen Current Employment. Hilder Janssen Current Employment, Current holder of individual stocks in a privately-held company. Russell Janssen Ended employment in the past 24 months. Goldberg Janssen Current Employment, Current holder of individual stocks in a privately-held company. Chari Shattuck Labs Consultancy, Membership on an entity's Board of Directors or advisory committees;Seattle Genetics Membership on an entity's Board of Directors or advisory committees, Research Funding;Millenium/Takeda Consultancy, Research Funding;Sanofi Genzyme Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Antengene Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda Consultancy, Research Funding;Amgen Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Pharmacyclics Research Funding;Secura Bio Consultancy, Membership on an entity's Board of Directors or advisory committees;Oncopeptides Consultancy, Membership on an entity's Board of Directors or advisory committees;AbbVie Consultancy, Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis Consultancy, Research Funding;Genentech Consultancy, Membership on an entity's Board of Directors or advisorycommittees;Janssen Oncology Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.