A Phase I/Ib Trial Of Pd 0332991 (Palbociclib) And T-Dm1 In Her2-Positive Advanced Breast Cancer After Trastuzumab And Taxane Therapy

Cyclin-dependent kinase 4 and 6 complex (CDK4/6), a therapeutic target of HER2 resistance, is deregulated by cyclin D1 but CDK4/6 inhibition reverses cyclin-mediated HER2 resistance. This phase I/Ib trial of palbociclib and T-DM1 in previously treated HER2-positive breast cancer patients demonstrated a 33% overall response rate and median progression-free survival of 26 weeks, confirming HER2 resistance reversal.Background: Preclinical breast cancer models with acquired HER2 resistance exhibit decreased proliferation with CDK4/6 inhibition in tumors with intact Rb and low p16 levels. Adding cytotoxic agents like T-DM1 enhances the inhibitory CDK4/6 cytostatic effect. Patients and Methods: A phase I/Ib 3+3 dose escalation/expansion trial of palbociclib and T-DM1 identified 150 mg on days 5 to 18 as the palbociclib maximal tolerated dose combined with day 1 intravenous T-DM1 in 21-day treatment cycles. Patients were previously treated with trastuzumab and a taxane with no limitation on prior therapy lines, including prior pertuzumab, lapitinib, neratinib, and T-DM1. Median age was 54 years and twothirds were estrogen receptor positive. Primary objectives included maximum tolerated dose as determined by doselimiting toxicity, and secondary end points of safety, toxicity, response rate, response duration, and progression-free survival. Results: From May 2014 to August 2018, 18 total patients were treated. The median number of cycles was 6.5 (1-22). A maximum tolerated dose was not reached. The most common G3 toxicity of more than 10% incidence was hematologic. Overall response rate (complete response + partial response) was 33% (95% confidence interval, 13%-59%). Median duration of response in responders was not reached and median-progression free survival was 6 months (95% confidence interval, 2.5-11.6). Conclusions: The combination of day 1 T-DM1 and days 5 to 18 palbociclib is safe, tolerable, and active in previously treated HER2-positive relapsed patients. Observed hematologic toxicity is manageable. The trial response rate confirms that a CDK 4/6 inhibitor can resensitize HER2-resistant breast cancer. (C) 2021 Published by Elsevier Inc.