TIP113 HERTHENA-PanTumor01 (NCT06172478): Expansion of a Global Phase 2 Trial of HER3-DXd in Patients With Advanced/Metastatic HR+/HER2− Breast Cancer

Background

Increased tumor expression of HER3, a member of the HER/EGFR family of receptor tyrosine kinases, is associated with poor clinical outcomes across multiple types of solid tumors; high HER3 membrane expression is reported in various breast cancer subtypes. HER3-DXd, a first-in-class HER3-directed antibody-drug conjugate (ADC), has demonstrated antitumor activity and clinical benefit in patients with advanced breast cancer across tumor baseline HER3 expression levels. The ICARUS-Breast01 trial reported a confirmed objective response rate (ORR) of 53.5% (90% CI, 44.8%-62.1%) in patients with hormone receptor–positive (HR+)/HER2-negative (HER2–) metastatic breast cancer who received prior CDK4/6 inhibitor and chemotherapy. HERTHENA-PanTumor01 is a global, multicohort, open-label, single-arm, phase 2 trial evaluating the efficacy and safety of HER3-DXd in previously treated patients with advanced tumors. This study includes 13 cohorts in total (Figure; 3 cohorts added recently and are currently open for enrollment); this abstract focuses on the newly opened breast cancer cohort.

Methods

We report the addition of an HR+/HER2− breast cancer expansion cohort (n = 90). Key inclusion criteria: locally advanced or metastatic HR+/HER2− disease (immunohistochemistry [IHC] 0/1+ or IHC 2+/ISH negative); ECOG performance status of 0 or 1; only 1 prior line of chemotherapy for metastatic disease; and disease progression during or after combined CDK4/6 inhibitor and endocrine therapy. Key exclusion criteria: prior treatment with an anti-HER3 antibody or with a topoisomerase I inhibitor (alone or as part of ADC therapy); a history of interstitial lung disease (ILD) requiring corticosteroid therapy or current/suspected ILD; and clinically active brain metastases or spinal cord compression. All patients must provide a fresh or archival biopsy sample obtained since progression on or after the most recent cancer therapy. Patients will receive intravenous HER3-DXd 5.6 mg/kg every 3 weeks until radiographic progression, unacceptable adverse events, patient withdrawal, or other reasons for discontinuation. Tumor assessments will occur every 6 weeks (±7 days) for the first 48 weeks, then every 12 weeks (±14 days) until radiographic progression (per investigator), death, loss to follow-up, or withdrawal of consent (discontinuation of study) regardless of initiation of new anticancer therapy. Blood samples will be collected for biomarker, pharmacokinetic, and antidrug antibody analyses during treatment and at study discontinuation. The primary end point in the breast cancer expansion cohort is ORR by investigator per RECIST 1.1. Key secondary end points include assessment of safety and tolerability, duration of response, clinical benefit rate, disease control rate, time to response, progression-free survival, overall survival, pharmacokinetics, and the correlation of HER3 IHC protein expression with efficacy.

Status

Currently recruiting for the BC cohort, with a planned enrollment of 90 patients.