A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer

Abstract

Purpose: Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC).

Patients and methods: Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed.

Results: In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion.

Conclusions: Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.

Figure 1.

Prostate-specific antigen response with acapatamab in dose expansion Figure 1A. Best (unconfirmed) PSA response after treatment initiation, shown as percentage change from baseline for each of the 54 patients with post-baseline PSA measurements. Figure 1B. Prostate-specific antigen response 12 weeks after acapatamab initiation shown as percentage change from baseline for patients (n = 23) in the PSA response evaluable set in dose expansion. The PSA response evaluable set included all subjects that enrolled and received at least one dose of acapatamab, had measurable (>0) baseline PSA levels and had the opportunity to be followed for at least 9 weeks starting from study day 1 and included patients who discontinued treatment prior to the 9-week time point as long as the data cut-off date was at least 9 weeks after cycle 1 day 1 of acapatamab treatment.

Figure 2.

Association of baseline tumor volume with prostate-specific antigen response and pharmacodynamics associated with acapatamab therapy Figure 2. Panel A: Higher baseline tumor PSMA expression was associated with PSA50 responses. Panels 2B, 2C, and 2D: Acapatamab induces T-cell activation in patients and higher levels of T cell differentiation in responders. Panel A shows the baseline PSMA maximum standardized uptake value (SUVmax) and baseline tumor volume as measured by PSMA-PET/CT and FDG-PET/CT in patients with and without a PSA50 response. Number of patients assessed by PSMA-PET/CT = 45; < PSA50 = 34; > PSA50 = 11; the number of patients assessed by FDG-PET/CT = 41; < PSA50 = 31; > PSA50 = 10. Patients in Panel B, C, and D received a 3-day eIV infusion of 0.09 mg acapatamab in week 1, followed by 0.3 mg of IV acapatamab (target dose), administered over 1h every 2 weeks starting in week 2. Panel B shows the changes from baseline in the percentage of activated (CD69+) CD4+ T cells and CD8+ T cells (n = 62). The blue line represents mean ± standard error. Grey lines represent data from individual patients. Panel C shows cytokine induction following acapatamab infusion within the first infusion period (n = 63). Data are shown as fold change from baseline. Blue lines represent mean ± standard error. Grey lines represent data from individual patients. Panel D shows the ratio of change in the number of different T cell subsets by PSA50 response from baseline at cycle 2, day 1 prior to next acapatamab infusion (< PSA50, n = 11; > PSA50, n = 26) for flow cytometry analysis. Changes in T cell numbers are shown relative to baseline. Abbreviations: C: cycle; CM: central memory; D: day; EM: effector memory; HR: hour; pre: pre-acapatamab infusion; PSA: prostate-specific antigen; TEMRA: effector memory T cells re-expressing CD45RA