September 18, 2024
By Dibash Kumar Das, PhD
The Phase II ICARUS-BREAST01 trial has shown promising efficacy and manageable safety for the novel therapy patritumab deruxtecan (HER3-DXd) in patients with advanced hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. Presented at the ESMO Congress 2024 conference by Barbara Pistilli, MD, these findings provide a potential option for patients who have progressed after multiple lines of therapy.
As a medical oncologist and Chair of the Breast Cancer Unit at Gustave Roussy in France, Pistilli emphasized the significance of these findings for patients who have progressed after multiple lines of therapy, including endocrine therapy (ET), CDK4/6 inhibitors, and chemotherapy.
While therapies like ET and CDK4/6 inhibitors have significantly improved outcomes for patients with HR+/HER2- advanced breast cancer, resistance to these treatments continues to be a major obstacle. Human epidermal growth factor receptor-3 (HER3), a key player in this resistance, is linked to poor prognosis and failure of standard treatments like PI3K/AKT/mTOR inhibitors and ET.
HER3-DXd, an antibody-drug conjugate (ADC) that targets HER3, is designed to overcome these resistance mechanisms. It consists of a monoclonal antibody conjugated to a topoisomerase I inhibitor, delivered directly to cancer cells via a cleavable peptide linker. The ICARUS-BREAST01 study was designed to investigate the clinical potential of HER3-DXd in this challenging context.
The ICARUS-BREAST01 trial (NCT04965766) is an academic, multicenter, single-arm, Phase II study that enrolled adult patients with HR+/HER2- advanced breast cancer who had progressed on CDK4/6 inhibitors and at least one line of chemotherapy. Patients received HER3-DXd at a dose of 5.6 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity occurred.
The primary endpoint was the confirmed objective response rate, as assessed by local investigators, while secondary endpoints included clinical benefit rate (CBR), progression-free survival (PFS), duration of response (DOR), and safety. As of April 16, 2024, 99 patients were enrolled with 19 still receiving treatment. The median age of participants was 57 years and the median duration of prior CDK4/6 inhibitor therapy was 13.7 months. HER3-DXd demonstrated impressive activity in this heavily pretreated population:
• Confirmed objective response rate: 53.5 percent; 95% CI: 43.2-63.6
• Clinical benefit rate: 63.6 percent; 95% CI: 53.4-73.1
• Median progression-free survival: 9.4 months; 95% CI 8.1-13.4
• Median duration of response: 8.7 months; 95% CI: 8.1-12.5
The safety profile of HER3-DXd was largely manageable, with 98 percent of patients experiencing at least one adverse event (AE) and 55.6 percent of patients reporting AEs of grade 3 or higher. The most common treatment-related AEs were nausea (75% with 5% Grade 3) and diarrhea (53% with 1% Grade 3). There were also six cases of interstitial lung disease, five of which were Grade 1 and one with Grade 2. Dose reductions were necessary in 20.2 percent of patients and 12.1 percent discontinued treatment due to AEs.
Discussing HER3-DXd's clinical activity and versatility, Pistilli noted, “HER3-Dxd showed clinically meaningful activity and manageable safety profile in patients with HR+/HER2- advanced breast cancer progressing after two or more lines of therapy, including CDK4/6 inhibitors. Activity of HER3-DXd was observed across a range of tumor HER3 and HER2 membrane expression by IHC.”
On the biomarker analysis, she added, “Although with the limitations of the small sample size, exploratory biomarker analysis suggests that distribution of HER3-DXd in the tumor may play a role in determining a better treatment response and upregulation of genes involved in immune response, particularly interferon alpha and gamma, were significantly enriched in the entire cohort and among responders. Efficacy and safety profile of HER3-DXd make this ADC an optimal candidate for further larger trials in patients with HR+/HER2- advanced breast cancer after failure of CDK4/6 inhibitors.”
Dibash Kumar Das is a contributing writer.