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

M. Oliveira, C. Falato, J.M. Cejalvo, M. Margelí Vila, P. Tolosa, F.J. Salvador-Bofill, J. Cruz, M. Arumi, A.M. Luna, J.A. Guerra, M. Vidal, O. Martínez-Sáez, L. Paré, B. González-Farré, E. Sanfeliu, E. Ciruelos, M. Espinosa-Bravo, S. Pernas, Y. Izarzugaza, S. EskerP.-D. Fan, P. Parul, A. Santhanagopal, D. Sellami, G. Villacampa, J.M. Ferrero-Cafiero, T. Pascual, A. Prat

Research output: Contribution to journalArticleResearchpeer-review


Background: Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (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 [= −0.8 × tumor cellularity (in %) + 1.3 × tumor-infiltrating lymphocytes (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 and methods: Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA 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. Results: 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 = 0.003). Among patients assessable 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 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA 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. Conclusions: A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-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.

Original languageEnglish
Pages (from-to)670-680
Number of pages11
JournalAnnals of Oncology
Issue number8
Publication statusPublished - Aug 2023


  • CelTIL score
  • ERBB3
  • HER3
  • HER3-DXd
  • breast cancer
  • patritumab deruxtecan

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