A Phase I/Ib Trial of PD 0332991 (Palbociclib) and T-DM1 in HER2-Positive Advanced Breast Cancer After Trastuzumab and Taxane Therapy
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Barbara Haley1, Kiran Batra2, Sunati Sahoo3
1Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
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 two-thirds were estrogen receptor positive. Primary objectives included maximum tolerated dose as determined by dose-limiting 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.
Insights
This study shows that combining palbociclib (a CDK4/6 inhibitor) with T-DM1 is safe and effective for HER2-positive breast cancer patients who have relapsed. This combination can resensitize resistant tumors to treatment.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Preclinical models show CDK4/6 inhibitors decrease proliferation in HER2-resistant breast cancer with intact Rb and low p16.
- Cytotoxic agents like T-DM1 enhance the cytostatic effect of CDK4/6 inhibitors.
Purpose of the Study:
- To determine the safety and efficacy of combining palbociclib with T-DM1 in patients with previously treated, relapsed HER2-positive breast cancer.
- To establish the maximal tolerated dose (MTD) of palbociclib when administered with T-DM1.
Main Methods:
- A Phase I/Ib dose escalation/expansion trial was conducted.
- Patients received palbociclib (days 5-18) and T-DM1 (day 1) in 21-day cycles.
- Eligibility included prior treatment with trastuzumab and a taxane, with no limit on prior therapy lines.
Main Results:
- Eighteen patients were treated, with a median of 6.5 cycles.
- A maximum tolerated dose was not reached.
- The overall response rate was 33% (95% CI, 13%-59%), with a median progression-free survival of 6 months.
Conclusions:
- The combination of T-DM1 and palbociclib is safe, tolerable, and active in relapsed HER2-positive breast cancer.
- Hematologic toxicity was manageable.
- The response rate suggests CDK4/6 inhibitors can resensitize HER2-resistant breast cancer.
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