An article with results from the U31402-A-J101 study is the first comprehensive analysis of patritumab deruxtecan in patients with advanced breast cancer and demonstrates clinically meaningful antitumour activity in a heavily pretreated patient population with advanced breast cancer across a range of HER3 (HER3-high and HER3-low) expression. Durable antitumour activity was seen across clinical subtypes, and antitumour activity was also observed in patients with hormone receptor (HR)-positive disease who had HER2-low or HER2-zero protein expression.
A manageable and acceptable safety profile was observed in this population with adverse prognostic features. The findings are published by Dr. Ian E. Krop of the Yale Cancer Center in New Haven, CT, US, and colleagues on 6 October 2023 in the JCO.
The authors wrote in the background that HER3 is highly expressed in breast cancer and other solid tumours, and high expression is associated with poor prognoses. Currently, no HER3-directed treatments have been approved for the treatment of any cancer. Patritumab deruxtecan is a novel, first-in-class, HER3-directed antibody drug conjugate (ADC).
In HER3-expressing xenograft models, patritumab deruxtecan demonstrated antitumour responses across a range of baseline HER3 expression levels that were sustained over time. In vitro studies have shown that patritumab deruxtecan inhibits the proliferation of chemotherapy-resistant breast cancer cell lines with upregulated baseline HER3 expression.
In U31402-A-J101, the study team assessed the safety and efficacy of patritumab deruxtecan in patients with HER3-expressing advanced breast cancer. Efficacy and translational findings based on clinical subtypes (HR-positive/HER2-negative, triple-negative breast cancer [TNBC], and HER2-positive breast cancer) along with safety results by dose for all enroled patients are reported in the article published in the JCO.
Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received patritumab deruxtecan 1.6-8.0 mg/kg intravenously once every 3 weeks or one of two alternative dosing regimens. In the dose-escalation part, the primary objectives were to determine the maximum tolerated dose and recommended dose for expansion (RDE). The safety and efficacy of the RDE were assessed during dose expansion.
A total of 182 enroled patients received at least 1 dose of patritumab deruxtecan. Patients had a median of five previous therapies for advanced disease. Most patients had visceral metastases, and 11.5% of patients had brain metastases at baseline. Efficacy results are reported across clinical subtypes: 113 patients with HR-positive/HER2-negative breast cancer had objective response rate (ORR) of 30.1% and median progression-free survival (mPFS) 7.4 months, 53 patients with TNBC had ORR of 22.6% and mPFS 5.5 months, and 14 patients with HER2-positive breast cancer had ORR of 42.9% and mPFS 11.0 months. Objective responses were observed in cancers with HER3-high and HER3-low membrane expression.
Dose-limiting toxicities observed during dose selection were decreased platelet count and elevated aminotransferases. In dose expansion, gastrointestinal and haematologic toxicities were the most common treatment-emergent adverse events (TEAEs) observed. Grade ≥3 TEAEs were observed in 71.4% of patients, and 9.9% discontinued treatment because of TEAEs. Three grade 3 and one grade 5 treatment-related interstitial lung disease events occurred.
The authors commented that the results of the U31402-A-J101 study highlight the therapeutic reach that patritumab deruxtecan may extend across the treatment landscape for metastatic breast cancer. Multiple phase II studies are ongoing to further evaluate patritumab deruxtecan 5.6 mg/kg in the metastatic setting and explore potential biomarkers associated with response (ICARUS-Breast, BRE-354).
Studies have suggested that one potential mechanism of resistance to current HER2-targeted ADCs is decreased HER2 expression, raising the possibility that such cancers may remain sensitive to HER3-directed agents after progression. As a result, the phase II BRE-354 study will evaluate patritumab deruxtecan as a treatment option for HER2-positive breast cancer that has progressed on trastuzumab deruxtecan.
Studies are also ongoing to evaluate patritumab deruxtecan in earlier lines of treatment. Both the window-of-opportunity SOLTI TOT-HER3 study and the phase II SOLTI-2103 VALENTINE study are investigating the efficacy of neoadjuvant patritumab deruxtecan and its biological effects on the tumour microenvironment.
The study results were presented in part at the 2018 ASCO Annual Meeting, 2018 San Antonio Breast Cancer Symposium, 2019 ESMO Breast Cancer, 2020 San Antonio Breast Cancer Symposium, and the 2022 ASCO Annual Meeting.
Reference
Krop IE, Masuda N, Mukohara T, et al. Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3–Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3–Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial. JCO; Published online 6 October 2023. DOI: 10.1200/JCO.23.00882