Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

HER3-DXd Induces CelTIL Increase In Early-Stage HR-Positive, HER2-Negative Breast Cancer

A single dose of HER3-targeted antibody–drug conjugate induces a CelTIL response in treatment-naïve early-stage hormone receptor-positive, HER2-negative breast cancer
04 May 2022
Clinical Research;  Immunotherapy
Breast Cancer

Author: By Lynda Williams, medwireNews Reporter 

 

medwireNews: The SOLTI TOT–HER3 window of opportunity study suggests that a single dose of a HER3-directed antibody–drug conjugate might help induce an anticancer response before surgery in early-stage breast cancer patients with hormone receptor-positive, HER2-negative disease regardless of HER3 expression. 

Aleix Prat, from the Hospital Clinic of Barcelona in Spain, presented the findings at the ESMO Breast Cancer 2022 for patritumab deruxtecan (HER3-DXd) in 77 women with a primary operable tumour of at least 1 cm in size, a Ki67 expression of at least 10% (median 21%) and a core needle biopsy evaluable for HER3 mRNA assessment. 

The majority of the patients were premenopausal (56%), and had tumours with ductal histology (75%) and grade 2 (57%), stage cT2 (53%), cN0 (71%) disease.  

There was an approximately even distribution between ultralow, low, medium and high levels of HER3 mRNA between the patients, with a 4.6-fold difference between the lowest and highest expression. Sixty-one patients were assessed for tumour membrane HER3 protein expression using immunohistochemistry, 50 of whom had high expression and just one patient was negative. 

However, there was only a “weak correlation” between mRNA levels and HER3 protein expression measured by immunohistochemistry, said Aleix Prat.  

The patients were given a single dose of HER3-DXd 6.4 mg/kg and underwent biopsy 21 days later to determine the study’s primary endpoint of the CelTIL score, a measure of stromal tumour-infiltrating lymphocytes and tumour cellularity. A CelTIL high score is associated with improved pathological complete response and survival scores across breast cancer subtypes, the presenter explained. 

Overall, there was a significant increase in CelTIL between baseline and 21 days after HER3-DXd treatment among the 77 patients, with a mean difference of 6.8. The overall response rate at this time was 45%, including a complete response in 23%. 

Moreover, the 28 patients who responded to treatment achieved a significant mean CelTIL increase of 15.2 whereas the 34 nonresponders had a nonsignificant mean increase of 2.9. 

Further analysis found there was no significant association between CelTIL score changes and baseline HER3 mRNA or HER3 protein, the presenter commented. 

In addition, PAM50 subtype switching showed that 10% of tumours changed from baseline luminal A to a normal-like subtype and more than 50% of luminal B tumours switched to luminal A. Of the two patients with baseline HER2-enriched disease, one patient switched to luminal A subtype and the second had achieved a complete pathological response at time of surgery. 

The investigator observed that non-luminal tumour subtypes had greater increases in CelTIL score at day 21 than the luminal A or B tumours, and the patients with a high PAM50 risk of relapse had a greater increase in CelTIL score than those with a medium or low relapse risk. 

When the researchers assessed the differential expression of 67 genes between baseline and day 21, there was an increase in the expression of 12 genes, mostly associated with immune response, such as CD68 and CD4, while the remainder were downregulated and mostly related to cell cycle and proliferation, including MKI67 and CCNB1

Similarly, analysis of Ki67 changes in immunohistochemistry from baseline in 53 patients showed a significant decrease in expression by an average of 8.96. 

Among the safety population of 78 patients, most treatment-emergent adverse events (TEAEs) were grade 1 (70%) or 2 (24%), being largely gastrointestinal symptoms and neutropenia. 

Grade 3 or more severe TEAEs occurred in 14%, most commonly neutropenia (8%), elevated alanine transaminase (3%) and diarrhoea (1%), and this safety profile is “consistent” with earlier reports for HER3-DXd, the presenter said. 

Aleix Prat stated that part B of the SOLTI TOT-HER3 study is ongoing and now recruiting patients with early-stage triple-negative breast cancer, as well as trialling a lower 5.6 mg/kg dose of HER3-DXd among hormone receptor-positive, HER2-negative patients. 

In addition, he said that the SOLTI-VALENTINE trial will soon open to investigate neoadjuvant HER3-DXd alone or in combination with endocrine therapy for patients with hormone receptor-positive, HER2-negative disease. 

Invited discussant Rebecca Dent, from the National Cancer Center Singapore, described the “enhanced infiltration of innate and adaptive immune cells” in the clinical setting of the study as “proof of concept”. 

She commented that the impact of HER3-DXd regardless of HER3 measurements may indicate “bystander killing” with the antibody–drug conjugate and that “upregulation of immune-mediated genes suggests potentially even greater ability to modify microenvironment” and thus a “greater impact” on survival outcomes. 

Reference 

Prat A, Falato C, Pare Brunet L, et al. Patritumab deruxtecan (HER3-DXd) in early-stage HR+/HER2- breast cancer: final results of the SOLTI TOT-HER3 window of opportunity trial. Ann Oncol 2022;33(suppl_3):S165–S174. doi:10.1016/annonc/annonc890 

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.