CD46-targeting ADC shows encouraging clinical activity in mCPRC

The CD46-targeting antibody-drug conjugate (ADC) FG-3246 (formerly FOR46) demonstrated encouraging clinical activity while maintaining a manageable safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC), according to data from a phase 1 trial (NCT03575819).¹

Rahul Aggarwal, MD

“I am excited to see the results from the phase 1 monotherapy study of FG-3246 published in the Journal of Clinical Oncology,” said lead author Rahul Aggarwal, MD, a professor of medicine at the University of California, San Francisco, in a news release on the findings.² “This is the first clinical trial targeting CD46 in patients with prostate cancer, and the totality of the data highlights the promising potential of FG-3246 anti-cancer activity, especially when considering the unselected, heavily pre-treated patient population in the trial. The trial results provide key insights into the potential clinical impact of targeting CD46 in the treatment of mCRPC and support its further development in this disease space with high unmet need.”

In total, the study enrolled 56 patients with mCRPC across both the dose escalation and dose expansion phases. The maximum tolerated dose was determined to be 2.7 mg/kg, using adjusted body weight, every 3 weeks.

According to the authors, “Dose-limiting toxicities included neutropenia (n = 4), febrile neutropenia (n = 1), and fatigue (n = 1).”

Across all dose levels, the most frequently reported grade 3 or higher adverse events were neutropenia (59%), leukopenia (27%), lymphopenia (7%), anemia (7%), and fatigue (5%). Grade 3 febrile neutropenia was also observed in 1 patient. No treatment-related deaths were reported.

A total of 40 patients were evaluable for efficacy, which was defined as patients with adenocarcinoma who received a dose of 1.2 mg/kg or higher. In these patients, the median radiographic progression-free survival (rPFS) was 8.7 months (range, 0.1 to 33.9). A prostate-specific antigen (PSA) decline of at least 50% (PSA50) was observed in 36% of patients (14 of 39). A PSA50 response was also noted among 4 of 8 (50%) patients who received docetaxel in the castrative-sensitive setting.

Additionally, 25 patients were included in the RECIST-evaluable set. Among those patients, the confirmed objective response rate was 20%, with all objective responses observed among patients who received a dose of 2.7 mg/kg or higher. The median duration of response was 7.5 months.

Further, the disease control rate was 80%. The duration of treatment was longer than 24 weeks in 48% (12) of patients.

Immunohistochemistry showed that 12 of 15 (80%) evaluable baseline tumors were positive for CD46 expression. Patients who responded to treatment with FG-3246 were found to have a significantly higher frequency of effector T cells as well as a lower frequency of immunosuppressive myeloid cells.

Overall, the first-in-human, open-label phase 1 trial enrolled 56 patients with mCRPC across 5 clinical trial sites in the US.³ Those enrolled were biomarker unselected and heavily pretreated, with a median of 5 lines of prior therapy.

The dose-escalation phase of the trial included 33 patients who received FG-3246 at doses ranging from 0.1 mg/kg and 3.0 mg/kg intravenously every 3 weeks. The dose-expansion phase included 23 patients, of whom 18 had adenocarcinoma mCRPC (cohort 1) and 5 had neuroendocrine prostate cancer (cohort 2). Patients in the dose-expansion phase received FG-3246 at the dose level of 2.7 mg/kg using adjusted body weight to a maximum of 270 mg for every 3 weeks.

Primary outcome measures included dose-limiting toxicities and disease response.

“We are looking forward to advancing FG-3246 in the clinic and remain on track for initiating the phase 2 monotherapy study by mid-2025 as well as disclosing topline results from the combination trial of FG-3246 and enzalutamide in the second half of 2025,” said Thane Wettig, CEO of FibroGen, in the news release.² “FG-3246 represents a potential first-in-class, non-PSMA approach to treating mCRPC and we, along with the medical community, are excited about the potential for CD46 to become a next generation target in the prostate cancer treatment paradigm.”

REFERENCES

1. 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. 2025:JCO2401989. doi:10.1200/JCO-24-01989

2. FibroGen announces publication of results from phase 1 monotherapy study of FG-3246 in patients with metastatic castration-resistant prostate cancer in the Journal of Clinical Oncology. News release. FibroGen, Inc. March 28, 2025. Accessed April 3, 2025. https://investor.fibrogen.com/news-releases/news-release-details/fibrogen-announces-publication-results-phase-1-monotherapy-study

3. A phase 1 study of FOR46 in patients with metastatic castration-resistant prostate cancer (mCRPC). ClinicalTrials.gov. Last updated February 1, 2024. Accessed April 3, 2025. https://www.clinicaltrials.gov/study/NCT03575819