Summary
Background PF-06650808 is a novel anti-Notch3 antibody–drug conjugate (ADC) able to deliver an auristatin-based cytotoxic payload to target cells. In this first-in-human, dose-finding, phase I study (NCT02129205), we investigated safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-agent PF-06650808 in 40 patients with advanced breast cancer (BC) and other solid tumors unselected for Notch3 expression. Primary endpoint was dose-limiting toxicity (DLT). PF-06650808 was administered intravenously every 3 weeks at a starting dose of 0.2 mg/kg, escalated up to 6.4 mg/kg following the modified continual reassessment method. An additional dose level, 2.0 mg/kg, was evaluated in patients with advanced, estrogen receptor-positive (ER+) BC. Results The majority of patients had advanced BC (60%) and almost all (90%) had received ≥3 prior lines of anticancer therapy. Treatment with PF-06650808 was generally well tolerated at dose levels ≤2.0 mg/kg with no DLTs. The maximum tolerated dose (MTD) was estimated to be 2.4 mg/kg. The most common treatment-related AEs in all patients were fatigue (40.0%), decreased appetite (37.5%), nausea (35.0%), alopecia (32.5%), abdominal pain (25.0%), pruritus (25.0%), and vomiting (25.0%). Five patients achieved a partial response (PR), including 2 unconfirmed PRs; 4 of the responders had ER+/PR+/HER2− BC. Sixteen (51.6%) patients achieved stable disease, including 8 (57.1%) of 14 patients with ER+ BC. Tumor samples from all responders tested positive for NOTCH3 expression in a retrospective, exploratory analysis. Conclusions The anti-Notch3 ADC PF-06650808 has demonstrated a manageable safety profile and early signs of antitumor activity in patients with advanced BC.
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Acknowledgments
The authors thank the patients and their families/caregivers, and the investigators, research nurses, study coordinators, and operations staff who contributed to this study; J. S. Holland, D. Rassam, and R. Li for their support during manuscript development; and X. Sun, X. Wang, and their team for statistical programming support in the data analyses. This study was supported by Pfizer. Medical writing support was provided by S. Mariani, MD PhD, of Engage Scientific Solutions and was funded by Pfizer.
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L. S. Rosen and A. W. Tolcher received research funding from Pfizer. R. Wesolowski served on an advisory board for Pfizer. R. Baffa, K-H. Liao, S. Y. Hua, B. L. Gibson, and S. Pirie-Shepherd were employees of Pfizer during the conduct of this study.
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Rosen, L.S., Wesolowski, R., Baffa, R. et al. A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody–drug conjugate, in patients with breast cancer and other advanced solid tumors. Invest New Drugs 38, 120–130 (2020). https://doi.org/10.1007/s10637-019-00754-y
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DOI: https://doi.org/10.1007/s10637-019-00754-y