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Updated: May 20, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Phase I, First-in-Human Study of FOR46 (FG-3246), an Immune-Modulating Antibody-Drug Conjugate Targeting CD46, in
Rahul R Aggarwal1, Jacqueline Vuky2, David VanderWeele3
1San Francisco Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA.
Purpose:
FOR46, a fully human antibody conjugated to monomethyl auristatin E, targets a tumor-selective epitope of CD46, which is overexpressed in metastatic castration-resistant prostate cancer (mCRPC). FOR46 demonstrates potent nonclinical activity in enzalutamide-resistant CRPC models.
Patients And Methods:
This was a phase I, first-in-human, dose escalation/expansion study in patients with progressive mCRPC after treatment with ≥one androgen signaling inhibitors (ClinicalTrials.gov identifier: NCT03575819). The starting dose of FOR46 was 0.1 mg/kg given intravenously every 3 weeks. The primary objective was to determine the maximally tolerated dose (MTD). Whole-blood mass cytometry (cytometry by time of flight) was used to characterize peripheral immune response and CD46 expression in CRPC tissue that underwent central pathology review.
Results:
Fifty-six patients were enrolled. Dose-limiting toxicities included neutropenia (n = 4), febrile neutropenia (n = 1), and fatigue (n = 1). The MTD was 2.7 mg/kg using adjusted body weight. The most common grade ≥3 adverse events across all dose levels were neutropenia (59%), leukopenia (27%), lymphopenia (7%), anemia (7%), and fatigue (5%). One grade 3 febrile neutropenia event was observed. There were no treatment-related deaths. In the efficacy evaluable subset (patients with adenocarcinoma treated with a starting dose ≥1.2 mg/kg, n = 40), the median radiographic progression-free survival was 8.7 months (range, 0.1-33.9). Fourteen of 39 evaluable patients (36%) achieved a PSA50 response. The confirmed objective response rate was 20% (5 of 25 RECIST-evaluable patients). The median duration of response was 7.5 months. Responders had a significantly higher on-treatment frequency of circulating effector CD8+ T cells.
Conclusion:
FOR46 demonstrated encouraging preliminary clinical activity with a manageable safety profile. Targeting CD46 elicited an immune priming effect that was associated with clinical outcomes.
Insights
FOR46, an antibody targeting CD46, shows promising activity in metastatic castration-resistant prostate cancer. This antibody demonstrated clinical benefits and a manageable safety profile in a phase I study.
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.
