FOR46 โขShows โPromise in Advanced Prostate Cancer, Phase I Trialโค Reports
A first-in-human phase Iโ studyโข indicates the antibody-drug conjugate FOR46 demonstrates encouraging clinical activity and a manageable safety profile in patients with metastatic, castration-resistant prostate cancer (mCRPC) who have progressed following treatment with androgen pathway signaling inhibitors. Theโข findings, recently presented, โsuggest FOR46 warrants further examination.
FOR46 is a fully human antibody linked to the cytotoxic agent monomethyl auristatin E. It specifically targets CD46, a protein overexpressed on mCRPC cells. Preclinical studies demonstratedโค strong activity of FOR46 in models of enzalutamide-resistantโ CRPC.
The phase I trial โenrolled 56 patients, initially receiving a 0.1 mg/kg loading dose of FOR46 intravenously every threeโ weeks.Theโ study’s primaryโ goal was to determine the maximum โฃtolerated dose (MTD).โ Researchers utilized whole blood mass cytometry to analyze โฃthe peripheralโ immune response and assessed CD46 expression in โtumor tissue via central pathology review.
Dose-limiting toxicities observed included โขneutropenia in four โpatients, febrile neutropenia in one, and fatigue in one. The established MTD was 2.7โ mg/kg. Across all doseโ levels,โ the most frequently reported adverse eventsโค (Grade โฅ3) were โขneutropenia (59%), leukopeniaโค (27%), lymphopenia (7%), anemia (7%), and โขfatigue (5%). One instance of grade 3 febrile neutropenia occurred; no treatment-related deaths were reported.
Analysis of an efficacy-evaluableโฃ subgroup-40โฃ patients with adenocarcinoma treated โwith a starting doseโ of โฅ1.2 mg/kg-revealed a median radiographic progression-free survival of 8.7 months (range: 0.1-33.9). Among 39 patients with evaluable data, 36% (14 patients) experiencedโ a โฅ50% reduction in prostate-specific antigen (PSA). The confirmed overall response rate,based on RECIST criteria,was 20% (5 โคof 25 assessable patients),withโ a medianโข duration of response โคof 7.5 months.
Notably,responders exhibited a considerably higher frequency of circulating effector โCD8+-T cells during treatment.Researchers concluded that targeting CD46 withโฃ FOR46 appears to stimulate an โฃimmune response correlated withโค clinical benefit.