A single dose of patritumab deruxtecan (HER3-DXd) produced “clinically meaningful” responses in treatment-naïve patients with hormone receptor (HR)-positive, HER2-negative, early breast cancer, according to researchers. 

Response to HER3-DXd was associated with increased immune infiltration and suppression of proliferation, regardless of baseline ERBB3/HER3 levels.

These results, from the TOT-HER3 trial, were presented at ESMO Breast Cancer 2022 by Aleix Prat, MD, PhD, of Hospital Clinic Barcelona in Spain. 

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In part A of the trial (ClinicalTrials.gov Identifier: NCT04610528), Dr Prat and colleagues investigated the biological effects of HER3-DXd in treatment-naïve patients with HR-positive, HER2-negative early breast cancer whose primary tumors measured 1 cm or larger. 

The primary endpoint was the change in CelTIL score after 1 dose of HER3-DXd. The CelTIL score is an early marker of drug activity based on the percentage of tumor cellularity and tumor-infiltrating lymphocytes. 

The study included 77 evaluable patients. Their mean age was 53 years (range, 29-78 years), 56% were premenopausal, 75% had ductal histology, and 23% had lobular histology. Patients had a median tumor size of 2.1 cm, and 71% of tumors were node negative. 

Patients had varying ERBB3 mRNA levels at baseline: ultralow (n=14), low (n=21), medium (n=21), and high (n=21). Fifty patients had high HER3 expression (75%-100%), 10 patients had low HER3 expression (25%-74%), and 1 patient was HER3 negative (<25%).

All patients received a single dose of HER3-DXd (6.4 mg/kg). On day 21, a tumor biopsy was performed for correlative analysis. 

The study’s primary endpoint was met, as there was a significant increase in CelTIL score after treatment, regardless of baseline ERBB3/HER3 levels. The mean difference in the CelTIL score from baseline to day 21 was +6.8, which was statistically significant (P <.001).

A secondary endpoint was overall response rate (ORR), which was 45%. Of the 28 responders, half achieved a complete response, and half had a partial response. 

The ORR correlated with an increase in CelTIL score from baseline. The mean difference from baseline to day 21 was +15.2 among responders (n=28; P <.001) and +2.9 among nonresponders (n=34; P =.135).

Another secondary endpoint was PAM50 subtype switching. About 10% of luminal A tumors changed to normal subtype, and more than 50% of luminal B tumors switched to luminal A. 

Yet another endpoint the researchers assessed was changes in the expression of 67 genes from baseline to day 21. Changes were observed for all 67 genes. Immune-related genes (CD68, CD4, CD8A, and others) were upregulated at day 21, and proliferation-related genes (MELK, MKI67, CCNB1, and others) were downregulated. 

The researchers also observed a decrease in Ki-67 from baseline to day 21, with a mean difference of -8.96 (P <.001).

Treatment-emergent adverse events (TEAEs) were generally grade 1 (91%) or grade 2 (56%) in nature, though 14% of patients had grade 3 or higher TEAEs. 

TEAEs of grade 3 or higher included diarrhea (1%), decreased neutrophil count (8%), and an increase in alanine aminotransferase (3%). There were no interstitial lung disease events and no deaths reported during the study. 

Dr Prat noted that this trial is ongoing and currently recruiting patients with early-stage triple-negative breast cancer for part B.

Disclosures: This research was supported by Daiichi Sankyo. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


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. ESMO Breast Cancer 2022; May 3-5, 2022. Abstract LBA3.