Phase I/II Trial To Evaluate Dual HER2 Combination Therapy in HR+, HER2+ Breast Cancer

April 29, 2020

The multi-center trial is comprised of 2 phases, with phase I determining the maximum tolerated dose of palbociclib and phase II determining the clinical benefit rate of treatment with anastrozole, palbociclib, trastuzumab, and pertuzumab.

A phase I/II clinical trial presented at the American Association for Cancer Research (AACR) Annual Virtual Meeting 2020, held April 27-28, 2020, will examine the safety and efficacy of dual HER2 therapy in combination with palbociclib (Ibrance) and anastrozole (Arimidex).1

“Treatment with chemotherapy remains the standard of care in those with newly diagnosed metastatic, triple-positive breast cancer,” Krystal P. Cascetta, MD, assistant professor of Medicine, Hematology, and Medical Oncology at the Tisch Cancer Institute at Mount Sinai, said in a poster presentation of the trial at AACR.2

The multicenter trial will consist of 2 phases, with phase I determining the maximum tolerated dose (MTD) of palbociclib and phase II determining the clinical benefit rate (CBR) of treatment with anastrozole, palbociclib, trastuzumab (Herceptin), and pertuzumab (Perjeta). The clinical benefit rate will be assessed among a maximum of 30 patients using a Simon’s II stage design.

In an exploratory analysis, the researchers also aim to examine the potential biomarkers of response to palbociclib, including expression of cyclin D1, cyclin E1, cyclin E2, CDK 2, CDK 4, CDK 6, retinoblastoma, phosphorylated retinoblastoma, and p16. Additionally, the researchers intend to use RNA sequencing to assess for predictors of response and potential mechanisms of resistance.

“Overexpression or overamplification of HER2 occurs in approximately 15% to 20% of breast cancer patients and roughly half of these tumors are hormone receptor positive,” Cascetta said. “The use of aromatase inhibitors in the metastatic setting is well established, while significant improvement in overall has been established with the use of trastuzumab and pertuzumab in HER2 overexpressing tumors.” 

Patients eligible for the trial must be newly diagnosed with stage IV HR-positive, HER2-positive breast cancer. Target accrual is a maximum of 36 patients.

In phase I of the study, patients were administered 1 mg oral anastrozole daily until day 28, 8 mg/kg IV trastuzumab as an initial loading dose followed by 6 mg/kg every 21 days, and 840 mg IV pertuzumab as an initial loading dose followed by 420 mg every 21 days. Dose 1 of oral palbociclib consisted of 100 mg daily until day 21, then 7 days off in a 28-day cycle, while dose 2 consisted of 125 mg daily until day 21, then 7 days off in a 28-day cycle. 

Enrollment to phase I ended in October 2018, with 1 dose escalation to 125 mg palbociclib, at which level 1 dose limiting toxicities were observed. Therefore, the researchers determined the MTD to be 125 mg for phase II of the study. 

Phase II of the study will consist of 1 mg oral anastrozole daily up to day 28, 125 mg oral palbociclib daily until day 21 followed by 7 days off in a 28-day cycle, 8 mg/kg IV trastuzumab as an initial loading dose followed by 6 mg/kg every 21 days, and 840 mg IV pertuzumab as an initial loading dose followed by 420 mg every 21 days. This will continue until patients experience either disease progression or unacceptable toxicity, or patients achieve a complete or partial response, or stable disease.  

“Secondary endpoints include progression-free survival, and safety and tolerability in women with hormone receptor positive, HER2-positive, metastatic breast cancer,” said Cascetta.

Enrollment to phase II began in February 2019. Further, 39% of planned patients have been enrolled as of January 2020. 

References:

1. AACR. CT262 - Multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab in HR-positive, HER2-positive metastatic breast cancer. AACR website. Published April 27, 2020. abstractsonline.com/pp8/#!/9045/presentation/10704. Accessed April 28, 2020.

2. AACR. CT262 - Multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab in HR-positive, HER2-positive metastatic breast cancer. AACR website. Published April 27, 2020. aacr20.onlineeventpro.freeman.com/posters/24211342/Multicenter-phase-III-trial-of-anastrozole-palbociclib-trastuzumab-and-pertuzumab-in-HR-positive-HER2-positive-metastatic-breast-cancer. Accessed April 28, 2020.