RP2R dose selection of Tal + Tec for the treatment of EMD patients in the RedirecTT-1 study.

Abstract

7524 Background: Talquetamab (Tal, anti-GPRC5D) and Teclistamab (Tec, anti-BCMA) are first-in-class bispecific antibodies approved as monotherapies for triple-class exposed relapsed/refractory multiple myeloma (RRMM). Extramedullary disease (EMD) is an aggressive MM subtype with poor outcomes and high unmet need. RedirecTT-1 (NCT04586426) is a Phase 1b/2 dose escalation/expansion study evaluating Tal + Tec in RRMM patients (pts) including EMD. We present data supporting selection of the recommended Phase 2 regimen (RP2R) for treatment of EMD pts, based on efficacy, safety, and exposure-response (E-R) analyses from Phase 1. Phase 2 allowed switching to a Q4W regimen after cycle 6 or cycle 4 if the response was ≥VGPR. Methods: Phase 1 evaluated 6 dose regimens of Tal (0.2–0.4 mg/kg QW, 0.8 mg/kg Q2W, 0.8 mg/kg Q4W) + Tec (0.75-1.5 mg/kg QW, 1.5-3 mg/kg Q2W, 3 mg/kg Q4W). Responses were investigator-assessed per IMWG criteria. CRS and ICANS were graded by ASTCT criteria; all other adverse events were graded by CTCAE v5.0. Model-based E-R analyses for efficacy were conducted with reported efficacy endpoints (ORR, ≥VGPR, ≥CR). First cycle PK metrics (C avgC1 , C troughC1 ) were used due to time-varying clearance of Tal and Tec. Results: At the clinical cutoff for this analysis (18 March 2025), Phase 1 enrolled 114 pts (38 EMD) with a median follow-up of 31.6 months. EMD pts treated with QW regimens of Tal 0.2-0.4 mg/kg + Tec 0.75-1.5 mg/kg (n=13), which comprised of multiple dose levels (1-9 pts per cohort), achieved an ORR of 33-100% (≥CR, 0-22.2%). EMD pts treated with the Q2W regimen using Tal 0.8 mg/kg and Tec 1.5 mg/kg (n=4) achieved an ORR of 50% (≥CR, 25%), while EMD pts treated with the Q2W regimen including Tal 0.8 mg/kg + Tec 3.0 mg/kg (RP2R, n=18) demonstrated high and deep response rates (ORR, 61.1%, ≥CR, 44.4%) with a manageable safety profile. EMD pts treated with the Q4W regimen of Tal 0.8 mg/kg + Tec 3.0 mg/kg (n=3) achieved an ORR of 100%, where 2 achieved ≥VGPR, but none achieved ≥CR. The RP2R generally provided higher and deeper responses in EMD pts compared to non-RP2R regimens. The efficacy E-R analysis for EMD pts showed a positive E-R relationship between exposure (C avgC1 and C troughC1 ) and ≥CR. Pts with exposures above the median for both Tal and Tec showed higher CR rates. At RP2R, C avgC1 and C trC1 exceeded median exposures across all Phase 1 dose regimens for both antibodies. The overall safety profile of Tal + Tec at the RP2R was manageable and consistent with each agent as monotherapy, while enabling deeper and more durable responses than observed across non-RP2R regimens. Conclusions: The totality of efficacy, safety and E-R analyses support advancement of a Tal + Tec regimen for further clinical development in RRMM pts with EMD who have received a PI, an IMiD, and an anti-CD38 mAb, and offers flexibility of switching to Q4W for responders. Clinical trial information: NCT04586426 .