SOLTI-1805 TOT-HER3 Study Concept: A Window-of-Opportunity Trial of Patritumab Deruxtecan, a HER3 Directed Antibody Drug Conjugate, in Patients With Early Breast Cancer

Abstract

Background: Preclinical data support a key role for the human epidermal growth factor receptor 3 (HER3) pathway in hormone receptor (HR)-positive breast cancer. Recently, new HER3 directed antibody drug conjugates have shown activity in breast cancer. Given the need to better understand the molecular biology, tumor microenvironment, and mechanisms of drug resistance in breast cancer, we designed this window-of-opportunity study with the HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402). Trial Design: Based on these data, a prospective, multicenter, single-arm, window-of-opportunity study was designed to evaluate the biological effect of patritumab deruxtecan in the treatment of naïve patients with HR-positive/HER2-negative early breast cancer whose primary tumors are ≥1 cm by ultrasound evaluation. Patients will be enrolled in four cohorts according to the mRNA-based ERBB3 expression by central assessment. The primary endpoint is a CelTIL score after one single dose. A translational research plan is also included to provide biological information and to evaluate secondary and exploratory objectives of the study. Trial Registration Number: EudraCT 2019-004964-23; NCT number: NCT04610528.

Keywords: Breast Cancer; CelTIL Score; ERBB3; HER3; HER3-DXd; U3-1402; patritumab deruxtecan.

Conflict of interest statement

SE and PF are employed by Daiichi Sankyo, Inc. AP has declared personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly, and Daiichi Sankyo, travel, accommodations, and expenses paid by Daiichi Sankyo, research funding from Nanostring Technologies, Roche, and Novartis, and consulting/advisory role for Nanostring Technologies, Roche, Novartis, Pfizer, Oncolytics Biotech, Amgen, Lilly, MSD, PUMA, and Daiichi Sankyo, Inc. outside the submitted work. MO reports honoraria and consulting fees from Roche/Genentech, GSK, PUMA Biotechnology, AstraZeneca, Seattle Genetics, and Novartis; travel and accommodation paid by Roche, Pierre-Fabre, Novartis, GP Pharma, Grünenthal, and Eisai; and grant/Research Support (to the Institution) from AstraZeneca, Philips Healthcare, Genentech, Roche, Novartis, Immunomedics, Seattle Genetics, GSK, Boehringer-Ingelheim, PUMA Biotechnology, and Zenith Epigenetics outside the submitted work. EC reports personal fees from Roche, personal fees from Lilly, personal fees from Novartis, and personal fees from Pfizer, during the conduct of the study. SP reports an advisor/consultant role for AstraZeneca, Daiichi-Sankyo, Polyphor, and Roche, and travel and accommodation paid by Novartis. JC reports an advisor/consultant role for Roche, Novartis, Pfyzer, Pharmamar, Lilly, Eisai, and Amgen, and travel and accommodation by Novartis and Pharmamar. FS-B has declared personal honoraria from Pfizer, Novartis, Roche, and Daiichi Sankyo. PV has received honoraria as a Speaker from Nanostring. MM has declared an advisor role or consulting from Novartis, Pfizer, and Roche; research funding from Roche, Eisai, and AstraZeneca; and travel expenses from Roche. OM-S reports an advisor role from Roche; honoraria as a speaker from Eisai; and travel expenses from Novartis. GV reports receiving honoraria for speaker activities from MSD and an advisory role from AstraZeneca. CS has served as a consultant, participated in advisory boards, or received travel grants from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann—La Roche Ltd., Genomic Health, Merck, Sharp and Dhome España S.A., Novartis, Odonate Therapeutics, Pfizer, Philips Healthwork, Pierre Fabre, prIME Oncology, Puma, Synthon, and Sanofi Aventis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Pascual, Oliveira, Ciruelos, Bellet Ezquerra, Saura, Gavilá, Pernas, Muñoz, Vidal, Margelí Vila, Cejalvo, González-Farré, Espinosa-Bravo, Cruz, Salvador-Bofill, Guerra, Luna Barrera, Arumi de Dios, Esker, Fan, Martínez-Sáez, Villacampa, Paré, Ferrero-Cafiero, Villagrasa and Prat.

Figures

Figure 1

TOT-HER3 trial design.

Figure 2

Measurement of ERBB3 expression in breast cancer using the nCounter platform. (A) Box plots of ERBB3 gene expression in breast tumors as classified by hormone receptor and HER2 expression and intrinsic subtype. (B) Unsupervised hierarchical clustering using the 50 PAM50 genes and ERBB3 (rows) and 1,580 tumor samples (columns). Each colored square on the heatmap represents the relative median signature score for each sample with the highest expression being red, the lowest expression being green, and the average expression being black. (C) Pearson correlation between ERBB3, single genes, and PAM50 gene expression signatures evaluated in breast cancer samples.

Figure 3

Comparing ERBB3 expression across datasets (A) Evaluation of ERBB3 cutoff in breast cancer samples from patients with early breast cancer included in IN-HOUSE, METABRIC, and TCGA. (B) Proportion of samples in each immunohistochemistry subtype based on the ERBB3 cohort. Each bar is colored according to the ERBB3 distribution in each cohort. (C) Correlation coefficients of proportions of tumor samples within each quartile based on the IHC subtype between the three datasets. (D) Scatter plots of ERBB3 vs. ESR1 expression for samples from METABRIC, IN-HOUSE, and TCGA cohorts, colored by subtype. The three horizontal lines indicate the cutoffs of each cohort. Discontinued line in each figure represents the regression line. Pearson correlation coefficient (r) with significance (p-value) is presented in each figure.