DOI: 10.1158/1078-0432.ccr-23-2978 ISSN: 1078-0432

A phase 1 study of acapatamab, a half-life extended, PSMA-targeting bispecific T-cell engager for metastatic castration-resistant prostate cancer

Tanya Dorff, Lisa G. Horvath, Karen Autio, Alice Bernard-Tessier, Matthew B. Rettig, Jean-Pascal Machiels, Mehmet A. Bilen, Martijn P. Lolkema, Nabil Adra, Sylvie Rottey, Richard Greil, Nobuaki Matsubara, Daniel S.W. Tan, Alvin Wong, Hiroji Uemura, Charlotte Lemech, Johannes Meran, Youfei Yu, Mukul Minocha, Mason McComb, Hweixian Leong. Penny, Vinita Gupta, Xuguang Hu, Gabor Jurida, Hosein Kouros-Mehr, Margit M. Janát-Amsbury, Tobias Eggert, Ben Tran
  • Cancer Research
  • Oncology


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 mg–0.9 mg in dose exploration (7 dose levels) and 0.3 mg (recommended phase 2 dose) in dose expansion intravenously Q2W. 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 responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (RECIST 1.1). Median PSA progression-free survival (PFS) was 3.3 months (95% CI, 3.0–4.9), radiographic PFS per PCWG3 was 3.7 months (95% CI, 2.0–5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24h 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.

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