In a Japanese-U.S. phase I/II trial (U31402-A-J101) reported in the Journal of Clinical Oncology, Ian E. Krop, MD, PhD, and colleagues found that the HER3-targeted antibody-drug conjugate patritumab deruxtecan (HER3-DXd) produced durable responses in previously treated patients with HER3-expressing metastatic breast cancer.'

Ian E. Krop, MD, PhD

Study Details

In the multicenter trial, 182 patients enrolled between December 2016 and August 2021 received HER3-DXd at doses of 1.6 to 8.0 mg/kg every 3 weeks or two dose regimens recommended for expansion during the dose-escalation, dose-finding, and dose-expansion phases of the study.  Approximately 78% of patients enrolled were from Japan.

Patients had received a median of five prior therapies for advanced disease. Efficacy results were reported according to clinical disease subtypes: hormone receptor–positive, HER2-negative (n = 113), triple-negative (n = 53), HER2-positive (n = 14), and unknown subtype (n = 2).

Efficacy Outcomes

Dose-limiting toxicities identified during dose selection were decreased platelet count and elevated aminotransferases. During the dose-finding phase, fixed-dose HER3-DXd regimens of 4.8 mg/kg and 6.4 mg/kg once every 3 weeks were selected for dose expansion. Among 182 patients, 146 received the dose-expansion regimens of 4.8 mg/kg (n = 48) or 6.4 mg/kg (n = 98).

Among 113 patients with hormone receptor–positive, HER2-negative disease (81% with HER3-high and 19% with HER3-low expression): objective response rate (all partial responses) was 30.1% (95% confidence interval [CI] = 21.8%–39.4%); median duration of response was 7.2 months (95% CI = 5.3 months to not evaluable); the disease control rate was 80.5%; median progression-free survival was 7.4 months (95% CI = 4.7–8.4 months), with a 6-month rate of 53.5%; and median overall survival was 14.6 months (95% CI = 11.3–19.5 months). Objective responses were observed in both patients with HER3-high and HER3-low expression.   

Among 53 patents with triple-negative disease (all with HER3-high expression): objective response rate (all partial responses) was 22.6% (95% CI = 12.3%–36.2%); median response duration was 5.9 months (95% CI = 3.0–8.4 months); the disease control rate was 79.2%; median progression-free survival was 5.5 months (95% CI = 3.9–6.8), with a 6-momth rate of 38.2%; and median overall survival was 14.6 months (95% CI = 11.2–17.2 months).

Among 14 patients with HER2-positive disease (all with HER3-high expression): objective response rate (all partial responses) was 42.9% (95% CI = 17.7%–71.1%); median response duration was 8.3 months (95% CI = 2.8–26.4 months); the disease control rate was 92.9%; median progression-free survival was 11.0 months (95% CI = 4.4–16.4 months), with a 6-month rate of 51.6%; and median overall survival was 19.5 months (95% CI = 12.2 months to not evaluable).

Adverse Events

Among all 182 patients, grade ≥ 3 adverse events occurred in 71%; the most common grade 3 or 4 events were decreased neutrophil count (40%), decreased platelet count (31%), and anemia (19%). Serious adverse events occurred in 33% of patients.

Adverse events led to treatment discontinuation in 9.9%. Treatment-related interstitial lung disease occurred in 12 patients (7%). Adverse events led to death in seven patients (3.8%), with one death due to neutropenic sepsis considered related to treatment.

The investigators concluded, “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.”

Dr. Krop, of Yale Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Daiichi Sankyo, Inc. For full disclosures of the study authors, visit ascopubs.org.