Original Research Article (Pfizer): First-in-Human Study of PF-06647020 (Cofetuzumab Pelidotin), an Antibody-Drug Conjugate Targeting Protein Tyrosine Kinase 7 (PTK7), in Advanced Solid Tumors

In the downloadable original research article sponsored by Pfizer, the digital tissue analysis was performed using the Flagship Biosciences proprietary Image Analysis platform. The article was published in the Journal: Clinical Cancer Research online first on June 3, 2021; DOI: 10.1158/1078-0432.CCR-20-3757.

Translational Relevance:

The transmembrane protein tyrosine kinase 7 (PTK7), involved in Wnt signaling, is overexpressed in multiple tumor types, including advanced non-small-cell lung cancer (NSCLC), ovarian cancer (OvCa), and triple-negative breast cancer (TNBC). Also expressed in tumor-initiating cells (TICs) or cancer stem cells, PTK7 is a tumorassociated target for elimination of cancer cells and TICs. PF-06647020 (cofetuzumab pelidotin) is a humanized, anti-PTK7 antibody─drug conjugate (ADC), designed to deliver an auristatin microtubule inhibitor payload (Aur0101) into target cells. It was shown to induce prolonged tumor regression in patient-derived, tumor xenograft preclinical models. In this first-in-human, dose-finding study, PF-06647020 administered every 2 or 3 weeks demonstrated a tolerable safety profile and preliminary clinical activity in previously treated patients with locally advanced/metastatic, PTK7-positive NSCLC, TNBC, and platinum-resistant OvCa, suggesting the feasibility of this PTK7-targeting approach. Further clinical investigations are ongoing to assess the therapeutic potential of PF06647020/cofetuzumab pelidotin in advanced, PTK7-positive cancers.

Abstract

Purpose: We investigated safety, tolerability, pharmacokinetics, and antitumor activity of the protein tyrosine kinase 7 (PTK7)-targeted, auristatin-based antibody–drug conjugate (ADC) PF-06647020/cofetuzumab pelidotin (NCT02222922).

Experimental Design: Patients received PF-06647020 IV every 3 weeks (Q3W) at 0.2–3.7 mg/kg or Q2W at 2.1–3.2 mg/kg, in sequential dose-escalation, following a modified toxicity probability interval method. In dose expansion, pretreated patients with advanced, platinum-resistant ovarian cancer (OvCa), non-small-cell lung cancer (NSCLC) or triple-negative breast cancer (TNBC) received PF-06647020 2.8 mg/kg Q3W.

Results: The most common, treatment-related adverse events (TRAEs) for PF06647020 administered Q3W were nausea, alopecia, fatigue, headache, neutropenia, and vomiting (45%-25%); 25% of patients had grade ≥ 3 neutropenia. Two patients experienced dose-limiting toxicities (DLTs, grade 3 headache and fatigue) at the highest Q3W dose evaluated. The recommended phase 2 dose was 2.8 mg/kg Q3W. The overall safety profile observed with PF-06647020 administered Q2W was similar to that of the Q3W regimen. Systemic exposure for the ADC and total antibody generally increased in a dose-proportional manner. Antitumor activity was observed in treated patients with overall objective response rates of 27% in OvCa (n = 63), 19% in NSCLC (n = 31) and 21% in TNBC (n = 29). Responders tended to have moderate or high PTK7 tumor expression by immunohistochemistry.

Conclusions: This PTK7-targeted ADC demonstrated therapeutic activity in previously treated patients with OvCa, NSCLC, and TNBC at a dose range of 2.1-3.2 mg/kg, supporting further clinical evaluation to refine dose, schedule, and predictive tissue biomarker testing in patients with advanced malignancies.

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