P883: ALNUCTAMAB (ALNUC; BMS-986349; CC-93269), A BCMA × CD3 T-CELL ENGAGER, IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): LATEST RESULTS FROM A PHASE 1 FIRST-IN-HUMAN CLINICAL STUDY
2023-08-01

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: ALNUC, a 2 + 1 T-cell engager (TCE) with bivalent binding to BCMA, has demonstrated clinical activity in pts with RRMM in an open-label phase 1 study (NCT03486067). IV-administered ALNUC exhibited a long duration of response (DOR) but resulted in cytokine release syndrome (CRS) in 76% of treated pts. Subcutaneous (SC) dosing reduced CRS rate and severity, allowing escalation to higher target doses, while showing promising antitumor activity. Aims: To present long-term follow-up data for IV ALNUC and safety and efficacy for SC ALNUC in pts with RRMM treated in the phase 1 study. Methods: Pts had ≥3 prior lines of therapy (LOTs), including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 therapy. IV ALNUC was administered at target doses of 0.15–10 mg with both fixed and step-up dosing as previously reported (Costa LJ et al. Blood 2019). SC ALNUC was given on 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 mg) on C1D8 and thereafter. Safety and tolerability were primary objectives. Data cutoff was Nov 9, 2022. Results: In total, 70 pts had received IV ALNUC. Overall response rate (ORR) was 39% (27/70) with median DOR of 33.6 mo (95% CI, 10.6–NA). Median PFS was 3.1 mo (95% CI, 1.9–5.5). CRS was reported in 53 (76%) pts, with grade (G) ≥3 in 5 (7%) pts. Of 73 pts treated with SC ALNUC in dose escalation (target dose: 10 mg, 6; 15 mg, 4; 30 mg, 6; 60 mg, 7) and dose expansion (target dose: 10 mg, 19; 30 mg, 21; 60 mg, 10), median age was 64 y; 42% were female. Pts had a median of 4 prior regimens; 93% were refractory to last LOT, 100%/63% had triple-class exposed/refractory MM, and 66%/26% had penta-drug exposed/refractory MM. Median follow-up was 4.3 mo (range, 0.5–16.0); 39 (53%) pts were continuing treatment at data cutoff. Any-G/G3–4 treatment-emergent adverse events (TEAEs) occurred in 99%/79% of SC pts; most common were CRS (56%/0%), neutropenia (49%/42%), infections (47%/10%), anemia (41%/25%), and thrombocytopenia (33%/14%). All CRS events were G1 (44%; 32/73) or G2 (12%; 9/73); 35 (48%) pts received ≥1 concomitant medication for CRS, including tocilizumab (30%; 22/73) and/or corticosteroids (15%; 11/73). Median time to CRS was 3 d (range, 1–20); median duration was 2 d (range, 1–11). Two pts had G1 neurotoxicity suspected related to SC ALNUC. One pt discontinued treatment due to a TEAE (G3 metastatic colon cancer not suspected related to treatment); 1 treatment-related death (cerebral hemorrhage) occurred at the 60-mg target dose. Preliminary PK analysis of SC ALNUC estimated ~61% bioavailability with 15-d T1⁄2. Observed trough concentrations at the 30-mg target dose exceeded levels predicted for efficacy by C2D1. Hallmark pharmacodynamic effects of TCEs were observed with both SC and IV ALNUC. In 55 efficacy-evaluable pts treated with SC ALNUC, ORR was 53% across all doses and 65% at the 30-mg target dose (Figure). Among 29 pts who achieved a response, 16 of 20 pts with evaluable minimal residual disease (MRD) samples were MRD-negative (80%; 10-5 sensitivity by flow cytometry) at C2D1 or C4D1. Median time to response was 1.0 mo (95% CI, 0.7–1.3); 25 responses (86%) were ongoing. Summary/Conclusion: IV ALNUC continued to demonstrate durable responses in heavily pretreated pts with RRMM. SC administration improved the safety profile vs IV ALNUC, with CRS limited to low-grade, short-lived events. SC ALNUC exhibited promising dose-dependent antitumor activity and a high proportion of responders achieved MRD negativity. The phase 1 study is ongoing.E-Mail Address: Keywords: Subcutaneous, B-cell maturation antigen, Bispecific, Cytokine release syndrome