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.

Disrupting EGFR–HER2 Transactivation by Pertuzumab in HER2-Positive Cancer: Quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome

“…Even in these cells, the combination of trastuzumab and pertuzumab had no deleterious effect on cell proliferation, and only their further combination with the anti-HER3 antibody patritumab was effective [ 86 ]. Very recently, the antibody–drug conjugate (ADC) of this antibody with deruxtecan, HER3–DXd, was found safe and effective in heavily pretreated patients with diverse HER3-positive tumors; however, the effect was independent of the presence of HER2 on these tumors [ 87 ].…”

Mechanisms of action and resistance to anti-HER2 antibody-drug conjugates in breast cancer

“…BIO-201 is a novel bispecific ADC that targets TROP-2 and HER2 conjugated with a topoisomerase I inhibitor via a cleavable linker. Preclinical data suggest that BIO-201 is effective in different types of cancer co-expressing TROP-2/HER2 or either of the targets [84] .…”

“…It has been evaluated in the U31402-A-J101 phase I/II trial in patients with HER3-expressing metastatic BC. Interestingly, in the subgroup of patients with HER2-positive BC ( n = 14), HER3-DXd was associated with remarkable clinical activity with ORR of 42.9%, DCR of 92.9%, and median PFS of 11.0 months [ 85 ] . Zenocutuzumab is a bispecific antibody targeting HER2 and HER3 simultaneously.…”

Current Status and Future Perspectives of Antibody–Drug Conjugates in Hormone Receptor-Positive Breast Cancer

“…Patritumab deruxtecan (U3-1402; HER3-DXd) is a HER3-directed human IgG1 mAb bonded to deruxtecan through a stable, cleavable linker. This agent has demonstrated antitumor activity in preclinical models with a variable HER3 expression status [77,78]. The results from early phase trials have demonstrated the preliminary efficacy of patritumab deruxtecan in HR+/HER2-negative and triple-negative breast cancers.…”