438TiP - Trastuzumab deruxtecan with pyrotinib in first-line HER2-positive unresectable or metastatic breast cancer: An exploratory, multi-center, single-arm, phase II study (TROPHY, trial in progress)

Background

Targeting human epidermal growth factor receptor 2 (HER2) with small molecule tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) has led to improved survival outcomes for patients with HER2-positive (HER2+) metastatic breast cancer (mBC). Trastuzumab deruxtecan (T-DXd), a HER2-directed ADC, has demonstrated remarkable efficacy in second-line or later treatment of HER2+ mBC (DESTINY-Breast03) and got approval in many countries worldwide. The registrational trial of T-DXd in first-line (1L) HER2+ mBC (DESTINY-Breast09) is on-going. Pyrotinib, an irreversible, pan-HER receptor TKI, has also been approved and is widely used among Chinese HER2+ mBC patients. Preclinical and clinical studies have shown the synergistic effects of HER2 ADCs combined with TKIs. Several HER2 ADCs and TKIs combination explorations are on-going for anticipated improvement in the efficacy. Thus, we conduct the exploratory phase II study to evaluate the efficacy and safety of T-DXd combined with pyrotinib for the 1L treatment of HER2+ mBC in China (TROPHY).

Trial design

Patients with no prior chemotherapy or HER2-targeted therapy in the metastatic setting who have experienced progression with a disease-free interval (DFI) > 6 months from the completion of neoadjuvant or adjuvant treatment to advanced or metastatic diagnosis will be eligible for enrollment. Asymptomatic or treated brain metastases is allowed. The study is comprised of two main parts. The first is a dose finding stage to determine the recommended phase 2 dose (RP2D), followed by a dose expansion stage with 45 patients starting at the RP2D to be enrolled from 8 sites in China. The primary endpoint of the study is investigator-assessed progression free survival (PFS) as per RECIST 1.1. Secondary endpoints include objective response rate (ORR) and duration of response (DOR) as per RECIST 1.1, PFS and overall survival (OS) rates at 12 and 24 months and safety. Efficacy and safety will be summarized with descriptive statistics, while time-to-event endpoints will be analyzed with the Kaplan-Meier method. Enrollment in China is currently underway.

Clinical trial identification

NCT06245824.

Editorial acknowledgement

Legal entity responsible for the study

Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences.

Funding

AstraZeneca.

Disclosure

H. Li: Financial Interests, Institutional, Funding: AstraZeneca, Novartis, Lilly. Z. Song: Financial Interests, Institutional, Funding: Novartis, Roche. B. Xu: Non-Financial Interests, Personal, Advisory Role: AstraZeneca, Novartis; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Novartis. All other authors have declared no conflicts of interest.