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

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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.

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Most cited references 13

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Sunil Verma, David Miles, Luca Gianni … (2012)

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.).

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Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer

Aditya Bardia, Sara A Hurvitz, Sara M Tolaney … (2021)

Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker.

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DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1.

Tetsuo Aida, Yusuke Ogitani, Shingo Arakawa … (2016)

An anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed.