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

Abstract

Purpose: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study.

Methods: Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received HER3-DXd 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.

Results: One hundred eighty-two enrolled patients received ≥1 dose of HER3-DXd. Patients had a median of five previous therapies for advanced disease. Efficacy results are reported across clinical subtypes: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer (n = 113; objective response rate [ORR], 30.1%; median progression-free survival [mPFS], 7.4 months), triple-negative breast cancer (n = 53; ORR, 22.6%; mPFS, 5.5 months), and HER2-positive breast cancer (n = 14; ORR, 42.9%; 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, GI and hematologic 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.

Conclusion: HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.

Trial registration: ClinicalTrials.gov NCT02980341.

FIG 1.

Kaplan-Meier plots for (A) PFS and (B) OS by breast cancer clinical subtype. HER2+, human epidermal growth factor receptor 2–positive; HER2–, HER2-negative; HR+, hormone receptor–positive; OS, overall survival; PFS, progression-free survival; TNBC, triple-negative breast cancer.

FIG 2.

Best percentage change from baseline in tumor size in patients with HR+/HER2– breast cancer, TNBC, or HER2+ breast cancer. Best percent change from baseline in sum of diameters based on blinded independent central review for all target lesions identified is represented by patient. The patients who have available data for both the baseline and postbaseline tumor assessment visit are included in the analysis. ^aPatients with TNBC and HER2+ were all HER3-high. HER2+, human epidermal growth factor receptor 2–positive; HER2–, HER2-negative; HER3, human epidermal growth factor receptor 3; HR+, hormone receptor–positive; TNBC, triple-negative breast cancer.

FIG 3.

Pretreatment HER3 membrane expression by (A) BOR and (B) over time in patients with HR+/HER2– breast cancer. Overall percentage of HER3 membrane positivity was centrally assessed by HER3 immunohistochemistry. ^aHER3 positivity from patients in the dose-expansion cohorts. ^bOn-treatment biopsy specimen collected at cycle 2 day 3 or cycle 3 day 3. BOR, best overall response; EOT, end of treatment ; HER2–, human epidermal growth factor receptor 2–negative; HER3, human epidermal growth factor receptor 3; HR+, hormone receptor–positive; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease.