Alnuctamab (ALNUC; BMS-986349; CC-93269), a 2+1 B-Cell Maturation Antigen (BCMA) × CD3 T-Cell Engager (TCE), Administered Subcutaneously (SC) in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from a Phase 1 First-in-Human Clinical Study
Authors: Bar Noffar , Mateos Maria Victoria , Ribas Paz , Hansson Markus , Paris Laura , Hofmeister Craig C. , Rodriguez Otero Paula , Bermúdez Maria Aranzazu , Martin Thomas , Santoro Armando , Yee Andrew J. , Creignou Maria , Encinas Rodriguez Cristina , Cerchione Claudio , De La Rubia Javier , Oriol Albert , Waibel Heidi , Besemer Britta , Thompson Ethan , Kiesel Brian , Chen Jinjie , Chung Alexander , Boss Isaac W. , Gaudy Allison , Li Shaoyi , Hsu Kevin , Godwin Colin , Burgess Michael R. , San-Miguel Jesús , Costa Luciano 
Published: December 2023

Introduction :
ALNUC, a 2+1 TCE with bivalent binding to BCMA, is under investigation in a phase 1 trial (NCT03486067) in pts with triple-class exposed RRMM previously treated with ≥ 3 lines of therapy (LOTs). IV-administered ALNUC demonstrated durable responses (median duration of response, 33.6 mo). However, due to a high frequency of cytokine release syndrome (CRS; 76% of pts), including grade ≥ 3 events (7% of pts), the trial pivoted to SC administration of ALNUC. This resulted in a markedly improved safety profile, allowing escalation to higher target doses, while showing promising antitumor activity (Wong SW et al. EHA 2023. Abstract P883). We present updated data for SC ALNUC in pts with RRMM treated in the phase 1 study.
Methods :
Pts with RRMM who had received ≥ 3 LOTs, including an immunomodulatory drug (IMiD ®), a proteasome inhibitor, and an anti-CD38 therapy, were eligible. SC ALNUC was given on day (D) 1, 4, 8, 15, and 22 of cycle 1 (C1), QW in C2-3, Q2W in C4-6, and Q4W in C7 and beyond (28-d cycles). Step-up doses were given on C1D1 (3 mg) and C1D4 (6 mg), and target doses (10, 15, 30, or 60 mg) on C1D8 and thereafter. Target doses of 10, 30, and 60 mg were tested in dose expansion. Safety and tolerability were primary objectives. Secondary objectives included preliminary efficacy and pharmacokinetics. The data cutoff for the results included herein was Apr 3, 2023; updated data will be presented.
Results :
Of 73 pts treated with SC ALNUC in dose escalation (target dose: 10 mg, n = 6; 15 mg, n = 4; 30 mg, n = 6; 60 mg, n = 7) and dose expansion (target dose: 10 mg, n = 19; 30 mg, n = 21; 60 mg, n = 10), median age was 64 y; 58% were male. Pts had median of 4 prior regimens (range, 3-14); 96% were refractory to last LOT, 100%/78% had triple-class/penta-drug exposed MM, and 63%/19% had triple-class/penta-drug refractory MM. Median follow-up was 7.4 mo (range, 0.5-19.9).
All-grade/grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 99%/81% of pts; most common were CRS (56%/0%), neutropenia (55%/45%), anemia (47%/27%), and thrombocytopenia (37%/16%). All-grade/grade ≥ 3 infections occurred in 62%/16% of pts; infections occurring in ≥ 10% of pts were COVID-19 (23%/3%) and upper respiratory tract infections (12%/0%). Infections of special interest included grade 2 cytomegalovirus reactivation in 1 pt (1.3%); there were no grade ≥ 3 infections of special interest. Median time to CRS was 3 d (range, 1-20), with a median duration of 2 d (range, 1-11). CRS was most common after the first step-up dose (40% of pts). Of 887 doses administered at the fourth dose and beyond, the frequency of CRS per dose was &lt; 1%. Two pts had grade 1 neurotoxicity suspected related to SC ALNUC; no grade ≥ 2 neurotoxicity was observed. One pt discontinued treatment due to a TEAE (grade 3 metastatic colon cancer not suspected related to treatment); 1 treatment-related death (cerebral hemorrhage) occurred at the 60-mg target dose.
Overall response rate (ORR) was 54% (39 of 72 efficacy-evaluable pts treated with SC ALNUC) across all doses, with responses deepening over time (Figure). ORR was 63% (27/43) at target doses ≥ 30 mg and 69% (18/26) at the 30-mg target dose. Median time to response was 1.2 mo (range, 0.9-4.0) and 77% (30/39) of responses were ongoing at data cutoff. Among efficacy-evaluable pts, median PFS was 10.1 mo (95% CI, 2.8-16.6) across all dose levels. For the 30-mg target dose, at a median follow up of 9.3 mo, median PFS was not reached (95% CI, 4.7-NA) with a 12-mo PFS of 53% (95% CI, 30-71). Among the 39 pts who achieved a response, 28/28 pts (100%) with evaluable minimal residual disease (MRD) samples were MRD-negative (10 −5 sensitivity by flow cytometry) at C2D1, C4D1, C6D1, or C8D1; of the 18 pts who achieved a response at the 30-mg target dose, 14/14 pts (100%) with available MRD data were MRD-negative.
Preliminary population pharmacokinetic analysis estimated ~60% SC ALNUC bioavailability with a 14-d half-life. Observed trough concentrations at the 30-mg target dose exceeded levels predicted for efficacy by C2D1. Hallmark pharmacodynamic effects of TCEs were observed.
Conclusions :
SC ALNUC continued to demonstrate a safety profile consistent with the drug class and a low rate of severe infections. Across doses, responses were durable and deepened over time, with a high proportion of responders achieving MRD negativity. High antitumor activity was observed at target doses ≥ 30 mg and specifically at the 30-mg target dose. Enrollment in the phase 1 study is ongoing.