Pasotuxizumab, a Bite ^® Immune Therapy for Castration-Resistant Prostate Cancer: Phase I, Dose-Escalation Study Findings

Abstract

Aim: We report results of a first-in-human study of pasotuxizumab, a PSMA bispecific T-cell engager (BiTE®) immune therapy mediating T-cell killing of tumor cells in patients with advanced castration-resistant prostate cancer. Patients & methods: We assessed once-daily subcutaneous (SC) pasotuxizumab. All SC patients developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed. Results: A total of 47 patients received pasotuxizumab (SC: n = 31, 0.5–172 μg/d; cIV: n = 16, 5–80 μg/d). The SC maximum tolerated dose was 172.0 μg/d. A sponsor change stopped the cIV cohort early; maximum tolerated dose was not determined. PSA responders occurred (>50% PSA decline: SC, n = 9; cIV, n = 3), including two long-term responders. Conclusion: Data support pasotuxizumab safety in advanced castration-resistant prostate cancer and represent evidence of BiTE monotherapy efficacy in solid tumors. Clinical trial registration: NCT01723475 (ClinicalTrials.gov)

Bispecific Antibodies in Prostate Cancer Therapy: Current Status and Perspectives

“…Accordingly, in the last decade, several studies reported on this and other PSMA targeting radiolabeled agents that showed clinical activity in CRPC [ 57 , 58 , 59 , 60 ]. In line, a plethora of preclinically characterized therapeutic constructs and almost all bsAbs that underwent clinical evaluation in PC are directed to PSMA [ 61 , 62 , 63 , 64 ].…”

“…Another major drawback of some bsAb constructs is the occurrence of anti-drug antibodies (ADAs) [ 61 , 92 , 93 ], which may not only limit efficacy, but can also cause side effects.…”

“…Low serum half-life requires a cumbersome continuous infusion and comes with higher costs. In a phase I clinical study, Pasotuxizmab was dose-escalated in patients with metastatic CRPC to evaluate maximum tolerated dose (MTD), which was not reached due to premature termination of the trial [ 61 ]. The drug was applied as subcutaneous injection (sc) and intravenous (iv) continuous infusion in 31 and 16 patients, respectively.…”

“…Of particular relevance is the observation that all evaluable patients in the sc group developed ADAs, whereas in the iv group, no ADA development was observed. A >50% PSA reduction was reported in nine of 31 and three of 16 patients receiving sc and iv dosing of Pasotuximab, respectively, including two long-term responders [ 61 ].…”

“…However, the maximum tolerated dose was not reached. Overall, 68.6% of patients showed a PSA decline across all dose cohorts and, similar to sc Pasotuximab application [ 61 ], 34.3% of patients showed PSA reduction greater than 50%. Despite these promising results, immunogenicity of this construct appears to be a problem: of 30 patients assessed for ADA development, six (20.0%) had developed ADAs at high levels that affect drug exposure, despite the drug being applied iv.…”