Phase I, First-in-Human Study of FOR46 (FG-3246), an Immune-Modulating Antibody-Drug Conjugate Targeting CD46, in...

Area of Science:

• Oncology
• Immunotherapy
• Pharmacology

Background:

• Metastatic castration-resistant prostate cancer (mCRPC) remains a significant clinical challenge.
• CD46 is overexpressed in mCRPC, making it a potential therapeutic target.
• Existing treatments like androgen signaling inhibitors eventually lead to resistance.

Purpose of the Study:

• To evaluate the safety and preliminary efficacy of FOR46, a novel antibody-drug conjugate, in patients with mCRPC.
• To determine the maximally tolerated dose (MTD) of FOR46 in this patient population.
• To explore the immune response and CD46 expression in relation to FOR46 treatment.

Main Methods:

• A phase I, dose escalation/expansion study (NCT03575819) was conducted in patients with progressive mCRPC.
• FOR46 was administered intravenously every 3 weeks, starting at 0.1 mg/kg.
• Peripheral immune responses were analyzed using mass cytometry, and CD46 expression was assessed in tumor tissue.

Main Results:

• The MTD of FOR46 was determined to be 2.7 mg/kg.
• Common adverse events included neutropenia (59%) and leukopenia (27%). No treatment-related deaths occurred.
• Radiographic progression-free survival was 8.7 months, with a 20% objective response rate and a median duration of response of 7.5 months. Responders showed increased effector CD8+ T cells.

Conclusions:

• FOR46 exhibits encouraging preliminary clinical activity and a manageable safety profile in mCRPC patients.
• Targeting CD46 with FOR46 appears to induce an immune-priming effect associated with clinical benefits.
• Further investigation of FOR46 in mCRPC is warranted.