In SOLTI-1805 TOT-HER3 study, conducted among patients with operable hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer, a HER3-directed antibody-drug conjugate, patritumab deruxtecan (HER3-DXd) increased immune infiltration, suppressed proliferation, and switched tumours to a less proliferative phenotype. It showed clinical and biological activity independently of baseline ERBB3 mRNA and HER3 protein levels.
These results encouraged investigation of HER3-DXd as potential neoadjuvant treatment in the ongoing SOLTI VALENTINE study. Findings from the TOT-HER3 study are published by Prof. Aleix Prat of the Medical Oncology Department, Hospital Clínic Barcelona, and Translational Genomics and Targeted Therapies in Solid Tumours, August Pi Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona in Barcelona, Spain, and colleagues on 19 May 2023 in the Annals of Oncology.
HER3 is an ERBB receptor expressed at higher levels in luminal than in basal mammary cells. It has been associated with poor prognosis in many tumour types, making it a compelling molecular target for the development of anticancer therapies. HER3-DXd is a first-in-class 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, selective, tetrapeptide-based cleavable linker.
Results from a phase I/II study in patients diagnosed with heavily pre-treated metastatic breast cancer demonstrated that treatment with HER3-DXd was associated with durable responses across breast cancer subtypes and a wide range of HER2 and HER3 membrane expression levels.
The authors wrote in the background that window-of-opportunity studies use paired biopsies to evaluate novel compounds in several clinical scenarios. These studies may help identify biomarkers to improve patient selection, provide a molecular landscape absent of acquired mutations associated with resistance in treatment-naïve patients, and allow for the evaluations of in vivo changes within the tumour microenvironment after drug exposure.
The CelTIL score combines information on tumour cellularity and stromal TILs. CelTIL score measured early after the start of neoadjuvant treatment is a practical and easily assessable surrogate biomarker of response to neoadjuvant therapy, with a demonstrated independent predictive value of pathological complete response rate across all breast cancer subtypes.
The SOLTI-1805 TOT-HER3, a window-of-opportunity study was designed to assess the biological activity, measured by CelTIL score, of a single dose of neoadjuvant HER3-DXd in patients with primary operable early breast cancer. In the article published in the Annals of Oncology, the study team reports the results from part A of the study, which evaluated HER3-DXd in HR-positive, HER2-negative breast cancer.
Patients with previously untreated HR-positive, HER2-negative tumours 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.
In total, 77 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 62 patients evaluable for clinical response, an overall response rate of 45.2% was observed, 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 mRNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumour phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity.
A more pronounced immune infiltration was observed among patients experiencing a complete or partial clinical response after one dose of HER3-DXd than in those experiencing stable disease. Subgroup analyses revealed that non-luminal tumour subtype or high baseline PAM50 risk of recurrence (ROR) score was associated with greater CelTIL response than luminal tumours or medium/low ROR scores.
Treatment-emergent adverse events were observed in 96% of patients, of which 14% were grade ≥3. Most common were nausea, fatigue, alopecia, diarrhoea, vomiting, abdominal pain, and neutrophil count decrease.
The authors concluded that the SOLTI TOT-HER3 window-of-opportunity study testing one dose of HER3-DXd found no correlation between ERBB3 mRNA or HER3 immunohistochemistry expression and change in CelTIL score. However, the changes in the tumour microenvironment and promising clinical response rates that were observed may translate into increased response rates in the neoadjuvant setting and improved long-term outcomes. In addition, the safety profile was tolerable and consistent with previously reported results.
Overall, these findings support further study of HER3-DXd in high-risk early breast cancer and provide additional evidence for the role of CelTIL score as an early biomarker of response in the pre-operative setting. The VALENTINE study has been launched to further investigate these findings.
The TOT-HER3 study was sponsored by SOLTI Breast Cancer Research Group and supported by Daiichi Sankyo, Inc.
Reference
Oliveira M, Falato C, Cejalvo JM, et al. 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. Annals of Oncology; Published online 19 May 2023. doi: https://doi.org/10.1016/j.annonc.2023.05.004