Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response.

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer.

A Cross-Sectional Validation Study of Camry EH101 versus JAMAR Plus Handheld Dynamometers in Colorectal Cancer Patients and Their Correlations with Bioelectrical Impedance and Nutritional Status.

BACKGROUND: Reduced muscle strength (dynapenia) and mass (atrophy) are prognostic factors in oncology. Measuring maximal handgrip strength with dynamometers is feasible but limited by the cost of the reference device (JAMAR). METHODS: A cross-sectional study was conducted on colorectal cancer outpatients treated with chemotherapy or under active surveillance in our center from September 2022 to July 2023. Accuracy, reliability, and concordance were compared for two handheld dynamometers: the JAMAR Plus (the gold-standard device) and the Camry EH101 (a low-cost index device). A simultaneous nutritional diagnosis with GLIM criteria and bioelectrical impedance analysis (BIA) was carried out. RESULTS: A total of 134 participants were included. The median of maximal strength for the JAMAR Plus had a non-significant difference of 1.4 kg from the Camry EH101. The accuracy and reliability of the devices were high. Bland-Altman analysis showed a 0.8 kg bias and -4.1 to 5.6 kg limits of agreement (LoA); a 0.1 kg bias and -5.3 to 5.4 kg LoA in men; a 1.5 kg bias and -2.2 to 5.3 kg LoA in women. In total, 29.85% of the participants were malnourished. Prevalence of dynapenia increased from 3.67% with the JAMAR Plus to 5.14% with the Camry EH101. Both devices had a moderate and significant correlation with BIA-estimated muscle mass. CONCLUSIONS: The Camry EH101 was a cost-effective alternative to JAMAR Plus in our sample.

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.

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.