Phase 1a/1b study of FOR46, an antibody drug conjugate (ADC), targeting CD46 in metastatic castration-resistant prostate cancer (mCRPC).

3001 Background: FOR46, a fully human antibody (ab) conjugated to monomethyl auristatin E (MMAE), targets a tumor selective epitope of CD46, which is highly expressed in mCRPC and treatment-emergent small cell neuroendocrine cancer (t-SCNC). CD46 is enriched in tumor cells upon treatment with androgen signaling inhibitors (ASI). Following dose escalation (Phase 1a), dose expansion was undertaken in 2 cohorts (Phase 1b): 1) Pts with de novo or t-SCNC and 2) pts with mCRPC without a t-SCNC component. Pts with adenocarcinoma enrolled in dose escalation and expansion are included in this analysis. Methods: Eligible pts had mCRPC, with progression on at least 1 ASI, with no prior chemotherapy for CRPC. Phase 1a pts received FOR46 0.1-3.0 mg/kg IV Q3 weeks (wks). The primary objectives in phase 1a were to assess adverse effects (AEs) and select the phase 1b dose; and in phase 1b to assess efficacy. For phase 1b, tumor biopsy in the CRPC setting for assignment to the 2 cohorts was required. CD46 expression was not required for inclusion in the expansion cohort, but was evaluated using a non-epitope specific CD46 polyclonal ab. Histology and CD46 expression were centrally reviewed. Results: Thirty-three pts were enrolled in phase 1a and 10 in phase 1b (including 6 treated in ph1a at the expansion dose or higher). Overall, 36 pts were treated at doses > 1.2 mg/kg. Following excess toxicity in pts with body mass indices > 30 (3 of 3 with Gr 4 neutropenia and 1 of 3 with Gr 3 fatigue at 2.4 mg/kg), further dosing was calculated using adjusted body weight (AJBW) rather than actual weight, allowing escalation to 3.0 mg/kg. The 2.7 mg/kg dose by AJBW was determined to be the MTD and phase 1b dose. The most common AEs at the 2.7 mg/kg dose were neutropenia (77% Gr 3 or 4), infusion reactions (37%, all < Gr 2), fatigue (31%, all < Gr 2) and peripheral neuropathy (24%, all < Gr 2)). Fourteen of 31 evaluable pts (45.2%) at > 1.2 mg/kg achieved a PSA50 response with 10 (32.3%) confirmed. Five pts were not evaluable for PSA response; 3 had no post-baseline PSA and 2 had baseline PSA < 1 ng/mL. The median duration of confirmed PSA50 response is >16 wks (range 6-48+ wks, with 4 ongoing at 12, 24, 25 and 48 wks). 18 pts had measurable lesions; 8 of 18 (44.4%) had tumor regression, with 4 (22.2%) confirmed partial responses (PR). The median duration of response is > 14 wks (range 9 -31+ weeks with 2 ongoing at 13 and 31 wks). Eight pts were evaluable for CD46 expression with a median H-score of 245 (range 0-300). Two pts with PRs had H-scores of 15 and 300; 4 with confirmed PSA50 had H-scores of 10, 15, 40 and 300. Conclusions: FOR46, a novel ADC targeting CD46, demonstrates clinical activity in mCRPC pts, with an acceptable safety profile, similar to other MMAE-containing ADCs. FOR46 merits further investigation in pts with mCRPC, alone and in combination with agents that enhance CD46 expression. Clinical trial information: NCT03575819.