Patritumab deruxtecan in untreated hormone receptor-positive/HER2-negative early breast cancer: final results from part A of the window-of-opportunity SOLTI TOT-HER3 pre-operative study

Abstract

Patritumab deruxtecan (HER3-DXd) is a HER3-directed antibody-drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score [ = -.8 × tumor cellularity (in %) + 1.3 × TILs (in %)], and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer. Patients with previously untreated hormone receptor (HR)-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 mRNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score. Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, -3.8 to 12.7; P=.003). Among patients evaluable for clinical response (n=62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 vs +1.9). Change in CelTIL score was independent of baseline ERBB3 mRNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease. A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in HR-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.