Novel ADC Shows Promise of Targeting CD46 in mCRPC

Image Credit: © Alexey Novikov [stock.adove.com]

FOR46 (FG-3246), an immune-modulating antibody-drug conjugate targeting CD46, had a manageable safety profile and elicited promising preliminary activity in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings from a phase 1 trial (NCT03575819) published in the Journal of Clinical Oncology.¹

The median radiographic progression-free survival was 8.7 months (range, 0.1-33.9)among the 40 patients in the efficacy evaluable population. Among the 25 RECIST-evaluable patients, the confirmed objective response rate was 20% (n = 5) and the median duration of response was 7.5 months. The investigators also observed that among patients achieving a response, the on-treatment frequency of circulating effector CD8⁺ T cells was significantly higher.

The safety population comprised all 56 patients treated with at least 1 dose of FOR46. Dose-limiting toxicities consisted of neutropenia (n = 4), febrile neutropenia (n = 1), and fatigue (n = 1). Based on these, 2.7 mg/kg using adjusted body weight dosing was determined to be the maximum tolerated dose. Across all dose levels, the most frequently occurring grade 3 or higher adverse events were neutropenia (59%), leukopenia (27%), lymphopenia (7%), anemia (7%), and fatigue (5%). One patient experienced grade 3 febrile neutropenia and there were no treatment-related deaths.

“Encouraging anticancer activity and acceptable tolerability was observed in an unselected mCRPC patient population. A randomized study is planned with integration of [⁸⁹Zr]DFO-YS5 PET as a potential predictive biomarker of response,” the study authors wrote.

Study Design and Patient Characteristics

Overall, this first-in-human, dose escalation/expansion phase 1 study enrolled 56 patients who had progressive mCRPC after receiving at least 1 prior androgen signaling inhibitor. Patients were enrolled between February 2019 and April 2022 at 6 sites in the United States.

The median age of the 56 patients was 69 years (range, 42-81), 86% of patients were White, 9% were Black, 4% were Asian/Pacific Islander, and 2% were Native American. Patients had an ECOG performance status of 0 (46%) or 1 (54%). At study entry, the median PSA was 37.5 ng/mL (range, 0.02-1626.6), the median LDH was 198 U/L (range, 98-466), the median hemoglobin level was 12.4 g/dL (range, 8.3-14.8), and the median alkaline phosphatase level was 96 U/L (range, 43-557).

The median number of prior lines of systemic therapy was 5 (range, 2-14). Prior androgen signaling inhibitors received included abiraterone acetate (Zytiga; 66%), enzalutamide (Xtandi; 71%), apalutamide (Erleada; 14%), and darolutamide (Nubeqa; 2%). One-fourth (25%) of patients had previously been treated with docetaxel for castration-sensitive disease. The types of progression at study enrollment included PSA (64%), node only (no osseous metastases; 11%), bone with and without nodal involvement (64%), visceral with and without other sites (23%), and symptomatic progression (2%).

In this dose escalation/expansion study, the starting dose was 0.1 mg/kg of FOR46 administered intravenously every 3 weeks. The highest dose administered in dose escalation was 3.0 mg/kg. Through their evaluation of dose-limiting toxicities, the researchers determined 2.7 mg/kg using adjusted body weight dosing once every three weeks to be the maximum tolerated dose.This dose was used in the dose expansion phase.

“The study presents the first-ever clinical results targeting the cancer-specific epitope of CD46 in any tumor type, and provides a foundation for further clinical investigation of CD46-targeting therapies. This approach could be extended to other CD46-expressing solid malignancies,” JCO Associate Editor Andrea Necchi, MD, wrote in a commentary published alongside the article.

Reference

Aggarwal RR, Vuky J, VanderWeele D, et al. Phase I, First-in-Human Study of FOR46 (FG-3246), an Immune-Modulating Antibody-Drug Conjugate Targeting CD46, in Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. March 26, 2025. doi:10.1200/JCO-24-01989