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.
Lee S Rosen, Robert Wesolowski, Raffaele Baffa, Kai-Hsin Liao, Steven Y Hua, Brenda L Gibson, Steven Pirie-Shepherd, Anthony W Tolcher
Author Information
Lee S Rosen: David Geffen School of Medicine, Division of Hematology-Oncology, University of California Los Angeles Medical Center, 2020 Santa Monica Blvd., Ste. 600, Santa Monica, CA, 90404, USA. LRosen@mednet.ucla.edu.
Robert Wesolowski: Ohio State University Comprehensive Cancer Center, 320 West 10th Ave., Columbus, OH, 43210, USA.
Raffaele Baffa: Pfizer, 10724 Science Center Drive, San Diego, CA, 92121, USA.
Kai-Hsin Liao: Pfizer, 10724 Science Center Drive, San Diego, CA, 92121, USA.
Steven Y Hua: Pfizer, 10724 Science Center Drive, San Diego, CA, 92121, USA.
Brenda L Gibson: Pfizer, 10724 Science Center Drive, San Diego, CA, 92121, USA.
Steven Pirie-Shepherd: Pfizer, 10724 Science Center Drive, San Diego, CA, 92121, USA.
Anthony W Tolcher: START Center for Cancer Care, 4383 Medical Dr., San Antonio, TX, 78229, USA.
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.
