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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

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Summary

Background PF-06650808 is a novel anti-Notch3 antibodydrug 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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Correspondence to Lee S. Rosen.

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Conflict of interest

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.

Research involving human participants

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

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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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