P-292: Ongoing Phase 1 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC®) Targeting B Cell Maturation Antigen (BCMA) for Relapsed/Refractory Multiple Myeloma (MM)

Introduction: HPN217 is a B Cell Maturation Antigen (BCMA)-targeting tri-specific T cell engager (TCE). HPN217 contains three binding domains including anti-BCMA for MM cell binding, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. HPN217 is under investigation in patients (pts) with heavily pretreated relapsed/refractory MM (RRMM).

Methods: This dose escalation study is evaluating both fixed and step dose regimens to assess the safety/pharmacology and early clinical activity of HPN217. Pts with RRMM who received at least 3 prior therapies including a proteasome inhibitor, immunomodulatory drug, and CD38 targeted therapy are eligible. Prior exposure to BCMA-targeting agent is permitted. Primary objectives include evaluation of safety, tolerability, pharmacokinetics, and determination of the Recommended Phase 2 Dose(s). Secondary objectives include preliminary efficacy. HPN217 is administered IV once weekly or once every 2 weeks. AEs are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS). Clinical activity is assessed per IMWG Response Criteria.

Results: As of 01May2023, 84 pts were treated with HPN217 across 14 dose escalation cohorts and 3 backfill cohorts; dose escalation up to 24 mg is complete; the target dose MTD has not been reached. Further dose/regimen optimization is ongoing in cohorts with doses of 12 mg QW and 24 mg (QW & Q2W).

Across all cohorts, pts received a median (range) of 6 (2-19) prior lines of treatment (70% transplantation, 94% triple-exposed, 76% penta-exposed, 16% BCMA targeted therapy). Median age was 69 (38-85). 34 pts remain on treatment. The most common (≥25%) treatment emergent adverse events (TEAEs) were anemia (45%), fatigue (36%), cough and CRS (30%), diarrhea (27%), and nausea (25%). All CRS events were G1-G2 except one event of G3 CRS at 24 mg. Responses were observed at doses ≥ 2.15 mg.

The 12 mg cohorts (n=19) have completed enrollment and follow-up is ongoing. At the 12 mg dose level, TEAEs reported in ≥25% of pts were fatigue and cough (47%), anemia (42%), hypokalemia (37%), hypophosphatemia (32%) and diarrhea (26%). CRS was reported in 16% of pts (all G1-2). Responses of PR or better have been reported in 11 (58%) pts, including 2 pts treated with prior BCMA CAR-T. Eight pts (42%) reported a best response of VGPR or better. Treatment is ongoing in 9 responders.

Conclusions: Dose escalation of HPN217, a novel half-life extended BCMA-targeting TCE, has been completed; target dose MTD was not reached. The 12 mg QW regimen is well tolerated with a manageable adverse event profile, low rates of CRS (16%) and robust early clinical activity (58% ORR). Evaluation of regimens using 24 mg QW and Q2W is ongoing to inform the choice of an RP2D(s). NCT04184050