Phase 1 study of pasotuxizumab (BAY 2010112), a PSMA-targeting Bispecific T cell Engager (BiTE) immunotherapy for metastatic castration-resistant prostate cancer (mCRPC).

Abstract

5034 Background: mCRPC has a poor prognosis and immunotherapies are largely ineffective. PSMA is a promising therapeutic target in mCRPC, and pasotuxizumab is a PSMA x CD3 BiTE that mediates tumor cell killing. Methods: NCT01723475 was a first-in-human, multicenter, dose-escalation study in patients (pts) with mCRPC refractory to standard therapy. Pts received pasotuxizumab as a continuous intravenous infusion in cohorts of 3–4 pts. Dose-escalation followed a continuous reassessment methodology design. The primary objective was to determine safety and maximum tolerated dose (MTD); secondary objectives included pharmacokinetics, biomarkers, and tumor response. Results: 16 pts were enrolled into 5 dosing cohorts (5 µg/d, n = 3; 10 µg/d, n = 4; 20 µg/d, n = 3; 40 µg/d, n = 4; 80 µg/d, n = 2). All pts had ≥1 AE of any grade; most common were fever (94%), chills (69%), and fatigue (50%). 13 pts (81%) had ≥1 AE of grade ≥3; most common were decreased lymphocytes and infections (both 44%). No grade 5 AE occurred. A serious AE related to study drug was reported for 1 pt (fatigue, 20 µg/d). No anti-drug antibodies were observed. Recruitment was stopped before MTD was reached to facilitate initiation of a new study sponsored by Amgen. Antitumor activity as indicated by PSA serum level decline was dose dependent, with a mean best PSA change per dosing cohort versus baseline of +0.74% (5 µg/d), –17.9% (10 µg/d), –37.4% (20 µg/d), –42.5% (40 µg/d) and –54.9% (80 µg/d). PSA decreases of ≥50% occurred in 3 pts (n = 1 each in 20 µg/d, 40 µg/d, and 80 µg/d cohorts). One long-term PSA responder was treated for 14 months (40 µg/d) and one for 19.4 months (80 µg/d). The latter pt showed a complete regression of soft-tissue metastases and marked regression of bone metastases as assessed by PSMA-PET/CT, > 90% reduction in PSA and alkaline phosphatase, and a significant and durable improvement in disease related symptoms. Conclusions: Pasotuxizumab had an acceptable safety profile and dose-dependent clinical activity in mCRPC pts. There were two long term responders in the dose escalation. This is the first clinical study showing that a BiTE immunotherapy can be efficacious in solid tumors. Clinical trial information: NCT01723475.

PSMA Theranostics: Review of the Current Status of PSMA-Targeted Imaging and Radioligand Therapy

“…BiTEs are a class of novel antibodies that form a link between T cells and tumor cells, permitting T-cell cytotoxic activity and initiating apoptosis of malignant cells. The PSMA/CD3-bispecific BiTE antibody BAY2010112 (AMG212, MT112) has been found to potently suppress tumor growth in preclinical research and was found to have an acceptable safety profile and dose-dependent clinical activity in a Phase I study of 16 patients [ 79 , 80 ].…”

Immunotherapy in Prostate Cancer

“…PSMA is a frequently highly expressed poorly differentiated and castrate-resistant prostate cancer and is infrequently expressed in other tissues, making it an attractive target for prostate cancer treatment [ 71 , 72 ]. The Phase I trial with pasotuxizumab showed dose-dependent PSA responses, with two long-term responses lasting 14 and 19.4 months [ 73 ].…”

Contribution of Macrophages and T Cells in Skeletal Metastasis

“…In a phase I clinical trial, patients with metastatic castration-resistant prostate cancer were treated with Pasotuxizumab. Besides being well tolerated, one of the patients had a marked regression of bone metastases, as measured by PSMA PET/CT [335].…”