Paper Details

ABSTRACT

Introduction: Etentamig is being developed as a next generation differentiated B-cell maturation antigen (BCMA) x CD3 bispecific T-cell engager, optimized for convenient monthly (Q4W) dosing from the start, and composed of a bivalent BCMA-binding domain with high avidity, and a low-affinity CD3 binding domain potentially reducing cytokine release syndrome (CRS) and infection rates.

Long-term results from 2 phase 1 studies of intravenous (IV) etentamig in heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM) demonstrated high efficacy with 66% objective response rate (ORR), and a favorable safety profile, including low rates of CRS (30% [Grade [G] 1: 26%; G2: 4%; no G3+) and G3/4 infections (23%), making etentamig an appealing treatment option for pts and healthcare practitioners across treatment settings. Beyond the optimized Q4W dosing, subcutaneous (SC) delivery of etentamig could further simplify treatment and ease administration, potentially improving access for pts. In this 2-part trial (NCT06223516), we examine an SC formulation of etentamig, and report on the SC dose comparable with the IV dose of etentamig along with its safety and efficacy.

Methods: This phase 1 study evaluated etentamig SC Q4W in adult pts with RRMM who have received 3–5 prior lines of therapy (pLoT); and with triple class exposure (TCE), including a proteasome inhibitor, an anti-CD38 monoclonal antibody, and an immunomodulatory drug. Prior anti-BCMA exposure to an antibody-drug conjugate or CAR-T was allowed. In the Part 1 dose finding portion of the study, pts received 1 assigned dose (Cohort 1 or Cohort 2) SC etentamig on Cycle (C) 1 Day (D) 1 without step-up dose (SUD). In the Part 2 dose expansion cohort, pts received 1 SUD on C1D1, followed by full SC dose on C1D4 and Q4W thereafter. Primary objectives were safety, tolerability and pharmacokinetics (PK) of etentamig in pts with RRMM after SC administration, and to determine a SC dose that provides exposures comparable to that observed with IV administration of etentamig. Primary endpoints for both Parts 1 and 2 were rates of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), and PK parameters; secondary endpoints include anti-myeloma activity of etentamig.

Results: At data cutoff, 60 pts received at least 1 dose SC etentamig (Part 1: dose finding Cohort 1 [n=20] and Cohort 2 [n=15]; Part 2: expansion cohort [n=25]); 34 (57%) were male; median age (range) was 73 (46–90) years; and median pLoT was 4; in Part 2, 47% were TCE refractory. Thirty-three (55%) pts remained on treatment; progressive disease (28%) was the most common reason for treatment discontinuation. The median (range) duration of follow up for the overall population was 5.3 (1–18) months with 2.0 (1–5) months for the Part 2 expansion cohort. Preliminary ORR was 59% overall, and 58% in Part 2. In the overall population, any treatment-emergent G3/4 adverse events occurred in 75% of pts, with ≥G3 infections occurring  in 9 (15%) pts. In Part 1, without SUD, the CRS rate with SC etentamig was 40% (G1 34%; G2 6%; no G3+). In Part 2, the CRS incidence was reduced by half to 20% (all G1), without the occurrence of ICANS following the adoption of 1 SUD. Overall, median (range) time to CRS onset was 25.8 (5.9–107.9) hours, and median (range) time to resolution was 11.4 (1.1–111.3) hours. In all pts (N=60), neutropenia and thrombocytopenia occurred in 16 (27%; G3/4: 17%) and 13 (22%; G3/4: 5%) pts, respectively; injection site reaction occurred in 1 pt (which was G1). No treatment-related deaths were observed. Available SC PK data demonstrated systemic exposures comparable to those observed with IV administration of etentamig. Additional data will be presented at the meeting.

Conclusions: In pts with RRMM, SC etentamig with SUD leads to robust responses and a very promising safety profile—with low rates of CRS and G3/4 infections, and no ICANS—while maintaining PK exposures comparable to those achieved with IV administration. In addition to its very favorable safety profile and Q4W dosing, SC delivery further enhances etentamig’s convenience profile, potentially improving pt accessibility and quality of life over time.