TY - JOUR
T1 - 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
AU - Aggarwal, Rahul R.
AU - Vuky, Jacqueline
AU - Vanderweele, David
AU - Rettig, Matthew
AU - Heath, Elisabeth I.
AU - Quigley, David
AU - Huang, Jiaoti
AU - Chumber, Arun
AU - Cheung, Alexander
AU - Foye, Adam
AU - Leung, Stanley
AU - Abbey, Jill
AU - Dorr, Andrew
AU - Nasoff, Marc
AU - Hunter, John
AU - Wang, Steven
AU - Flavell, Robert R.
AU - Fong, Lawrence
AU - Liu, Bin
AU - Small, Eric J.
N1 - Publisher Copyright:
© 2025 American Society of Clinical Oncology.
PY - 2025/5/20
Y1 - 2025/5/20
N2 - PURPOSEFOR46, 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 METHODSThis 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.RESULTSFifty-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.CONCLUSIONFOR46 demonstrated encouraging preliminary clinical activity with a manageable safety profile. Targeting CD46 elicited an immune priming effect that was associated with clinical outcomes.
AB - PURPOSEFOR46, 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 METHODSThis 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.RESULTSFifty-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.CONCLUSIONFOR46 demonstrated encouraging preliminary clinical activity with a manageable safety profile. Targeting CD46 elicited an immune priming effect that was associated with clinical outcomes.
UR - http://www.scopus.com/inward/record.url?scp=105002424485&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=105002424485&partnerID=8YFLogxK
U2 - 10.1200/JCO-24-01989
DO - 10.1200/JCO-24-01989
M3 - Article
C2 - 40138611
AN - SCOPUS:105002424485
SN - 0732-183X
VL - 43
SP - 1824
EP - 1834
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 15
ER -
