Phase 1 study results of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer (mCRPC).

5017 Background: Human kallikrein 2 (encoded by the KLK2 gene and hereafter referred to as KLK2) is a novel target expressed on PC cells with limited normal tissue expression. Pasritamig is a first-in-class T-cell-redirecting bispecific antibody that simultaneously binds KLK2 on PC cells and CD3 receptor complexes on T cells. We report dose escalation and expansion results from a first-in-human study (NCT04898634) evaluating pasritamig in pts with mCRPC. Methods: Pasritamig target doses (TDs) were escalated from 0.5-2000 mg SC and 150-900 mg IV QW-Q6W, with various step-up (SU) dosing schedules. Pre-medication with dexamethasone (16 mg) was required in SU and 1 st TD. The primary objective was to determine the safety and RP2D. Secondary objectives included preliminary assessment of antitumor activity. Results: As of October 7, 2024, 174 pts (median [range] age 69 [36-89] years) had received ≥1 pasritamig dose (Table). Pts had a median of 4 prior therapies (range 1-13; 99.4% ARPI, 78.2% taxane chemotherapy, 17.2% lutetium Lu 177 vipivotide tetraxetan). There were no pasritamig-related deaths. One pt experienced a DLT of transient Gr 3 ALT/AST elevation after 50 mg SU2 SC administration. While most pts reported ≥1 TRAE (82.2% overall; 68.1% IV; 92.2% SC), these were mostly low grade, with only 9.2% of pts (6.9% IV; 10.8% SC) experiencing a Gr ≥3 TRAE. In the RP2D safety population (n=45; 3.5 mg [Day 1], 18 mg [Day 8], 300 mg Q3W or Q6W IV), the most common TRAEs were infusion-related reactions (22.2%; Gr 1/2), fatigue (15.6%; Gr 1/2), and CRS (8.9%; all Gr 1, no tocilizumab was administered), no TRAEs led to treatment discontinuation, no ICANS was observed, and 2 serious TRAEs (Gr 1 CRS) were reported. In the RP2D efficacy population (n=33; 3.5 mg [Day 1], 18 mg [Day 8], 300 mg Q6W IV), PSA50 was 42.4% (14/33) and median rPFS was 6.77 (95% CI 2.89, NE) months with 39.4% of pts ongoing (13/33). ORR in the 85 pts with measurable disease was 16.1% (n=5/31) in pts with lymph node +/- bone and 3.7% (n=2/54) in pts with visceral disease, with a median DOR of 11.27 (95% CI 3.58, NE) months. Conclusions: Pasritamig was very well tolerated (<10% of pts experienced CRS [all Gr1] at the RP2D) with promising antitumor activity, demonstrating proof of concept for KLK2 as a target amenable to T-cell redirection. These results address an unmet need for a targeted T-cell based therapy that is safe to administer in an outpatient setting with clinically meaningful benefit in mCRPC. Phase 3 trials are planned. Clinical trial information: NCT04898634 . TotalN=174 SCn=102 IVn=72 RP2Dn=45 a TRAEs leading to treatment discontinuation, n (%) 1 (0.6) 1 (1.0) 0 0 Gr ≥3 TRAEs, n (%) 16 (9.2) 11 (10.8) 5 (6.9) 2 (4.4) CRS, n (%) 43 (24.7) 31 (30.4) 12 (16.7) 4 (8.9) Gr 1 37 (21.3) 28 (27.5) 9 (12.5) 4 (8.9) Gr 2 6 (3.4) 3 (2.9) 3 (4.2) 0 Radiographic PFS, months, median (95% CI) 4.40 (3.35, 6.47) 4.07 (2.79, 4.93) 5.88 (3.15, NE) 6.77 (2.89, NE) b a RP2D safety pop.=TD 300 mg Q3W/Q6W. b RP2D efficacy pop.=TD 300 mg Q6W (n=33).