FOR46 Shows Early Antitumor Activity in Metastatic Castration-Resistant Prostate Cancer

Pipeline Report: July 2022

The CD46-targeted antibody-drug conjugate FOR46 demonstrated encouraging evidence of antitumor activity in patients with metastatic castration-resistant prostate cancer with a safety profile that proved to be similar to other monomethyl auristatin E–based ADCs, according to data from a phase 1a/1b trial.

Rahul Aggarwal, MD

Rahul Aggarwal, MD

The CD46-targeted antibody-drug conjugate (ADC) FOR46 demonstrated encouraging evidence of antitumor activity in patients with metastatic castration-resistant prostate cancer (CRPC) with a safety profile that proved to be similar to other monomethyl auristatin E (MMAE)–based ADCs, according to data from a phase 1a/1b trial (NCT03575819).

Findings presented during the 2022 ASCO Annual Meeting showed that 45% of evaluable patients (n = 43) experienced a prostate-specific antigen (PSA) decline of at least 50% (PSA50), with a median duration of PSA response of at least 16 weeks (range, 6-48+). Notably, 4 of 8 evaluable patients who received prior docetaxel the castration-sensitive setting had PSA50.

Additionally, among 21 evaluable patients, tumor regression was observed in 48% of patients. A total of 4 patients achieved confirmed partial responses with the ADC, and the median duration of response was longer than 14 weeks (range, 9-31+).

“As with PSA response, there was not a clear relationship with [response and] CD46 expression. However, a dose-response relationship does begin to emerge with these data,” lead study author Rahul Aggarwal, MD, a medical oncologist in the Division of Hematology/Oncology and an associate professor of Medicine at the University of California San Francisco, said in a presentation of the data.

CD46 is highly expressed in prostate cancer, and it is enriched following androgen receptor blockade. FOR46 targets CD46 and carries a MMAE payload. In preclinical studies, the agent has demonstrated potent in vitro and in vivo activity.

The first-in-human, dose-escalation and -expansion, phase 1 study investigated FOR46 in patients with progressive metastatic CRPC per PCWG3 criteria. To be eligible for enrollment, patients were required to have received prior treatment with at least 1 androgen signaling inhibitor like abiraterone acetate (Zytiga) or enzalutamide (Xtandi).

Patients could not have received prior taxane for the treatment of metastatic disease although this was permitted for the treatment of castration-sensitive disease. Notably, CD46 expression by immunohistochemistry was not required.

In the dose-expansion portion of the trial, patients needed to have an available CRPC tissue sample and no histologic evidence of small-cell neuroendocrine prostate cancer.

Study participants received intravenous FOR46 on day 1 of every 21-day cycle. Dose levels ranged from 0.1 mg/kg. the starting dose level, to 3.0 mg/kg. The trial established 2.7 mg/kg to be the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the agent.

Safety and tolerability served as primary end points of the trial, as well as determining the MTD and/or the RP2D. Secondary end points included characterizing the pharmacokinetics and efficacy of the agent, including PSA50 and objective response rate. Evaluating the potential relationships between CD46 expression and the measures of antitumor activity was an exploratory end point.

Among enrolled patients (n = 43), the median age was 68 years (range, 42-81), and 36 patients were White. The median PSA at baseline was 64.5 ng/mL (range, 0.2-1626). Additionally, 60.5% of patients had measurable disease per RECIST v1.1 criteria. At the time of enrollment, types of disease progression included PSA (62.8%), node only (7%), bone with or without nodal disease (53.5%), visceral with or without other sites (16.3%), and symptomatic progression (2.3%).

The median number of prior lines of therapy received was 5 (range, 2-10). Prior androgen deprivation treatment were medical (90.7%), including leuprolide (Lupron; 88.3%) and other luteinizing hormone-releasing hormone or gonadotropin-releasing hormone agents (20.9%), or surgical (9.3%). Prior treatment with an androgen-signaling inhibitor included bicalutamide (Casodex; 60.5%), enzalutamide (74.4%), abiraterone acetate (69.8%), or another unspecified inhibitor (9.3%). Other previously received therapies included sipuleucel-T (Provenge; 37.2%), immune checkpoint inhibitors (20.9%), docetaxel in the castration-sensitive setting (20.9%), or other/investigational options (20.9%).

As of the data cutoff, 7 patients remain on treatment. Thirty-six patients discontinued treatment; 33 did so because of disease progression, 3 due to adverse effects (AEs), and 1 for withdrawal. For patients who received the agent at a dose level of at least 1.2 mg/kg (n = 36), the median duration of treatment was 27.5 weeks (range, 2-131).

Of 12 evaluable tissue samples, 11 tested positive for CD46 expression.

Regarding pharmacokinetics, Aggarwal noted that the minimal dissociation of the free MMAE payload in the serum was consistent with dissociation kinetics of other MMAE-based ADCs.

During the presentation, Aggarwal shared a case of a patient who had baseline target lesions that were 5.7 cm, including lung nodules and peri-rectal soft tissue mass, who received the ADC and experienced a 71% drop in PSA. After cycle 3, the target lesions were 2.5 cm, which translated to a 56% reduction. Moreover, non-target lesions were also noted to have decreased in size.

Regarding safety, the most common treatment-related AEs (TRAEs) of any grade that were experienced with FOR46 included neutropenia (65%), infusion-related reaction (47%), neuropathy (37%), diarrhea (26%), fatigue (26%), nausea (23%), decrease appetite (23%), alopecia (23%), decreased lymphocyte count (19%), constipation (16%), vomiting (14%), and anemia (12%).

Notably, neutropenia was the only grade 3 or 4 TRAE to affect more than 2 patients. Specifically, 19% of patients experienced grade 3 neutropenia, and 35% had grade 4 neutropenia. One patient developed febrile neutropenia.

Dose-dependent absolute neutrophil count nadir for patients with no primary granulocyte colony–stimulating factor (G-CSF) prophylaxis occurred between days 7 and 10 of cycle 1, and the median time to recovery was 8.5 days. For patients with primary G-CSF prophylaxis, no absolute neutrophil count nadir was observed.

“Additional studies [with FOR46], both clinical and preclinical, are underway, including a phase 1/2 combination trial [NCT05011188] with enzalutamide, development of a bispecific T-cell engager, and targeted radioligand therapy using the same antibody backbone,” Aggarwal concluded.


Aggarwal RR, Vuky J, VanderWeele DJ, et al. Phase 1a/1b study of FOR46, an antibody drug conjugate (ADC), targeting CD46 in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 16):3001. doi:10.1200/JCO.2022.40.16_suppl.30

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