Promising Antitumor Activity After One ADC Dose in Breast Cancer

BERLIN — A novel antibody drug conjugate (ADC) targeting HER3 (ERBB3) increases antitumor activity in patients with early-stage hormone receptor (HR)-positive/HER2-negative breast cancer after just one dose, according to the results of an early phase study.

The analysis revealed that patritumab deruxtecan (HER3-DXd, Daiichi Sankyo) was associated with a significant increase in tumor cellularity and tumor-infiltrating lymphocyte (CelTIL) scores and demonstrated an overall response rate of 45% in patients with untreated, early-stage disease.

Aleix Prat, MD, PhD, head of the Medical Oncology Department of Hospital Clínic Barcelona, Spain, presented findings from the SOLTI TOT-HER3 trial at the European Society for Medical Oncology (ESMO) Breast Cancer Congress 2022 on May 3.

Patritumab deruxtecan recently received Breakthrough Therapy Designation from the US Food and Drug Administration to treat metastatic or locally advanced EGFR-mutated non-small cell lung cancer with disease progression on or after prior treatment.

In breast cancer, patritumab deruxtecan has also demonstrated antitumor activity and an acceptable safety profile in heavily pretreated patients with metastatic disease and varying levels of HER3 protein expression.

In addition, interim results from the SOLTI TOT-HER3 trial in 30 patients with early-stage HR-positive/HER2-negative breast cancer reported biologic and clinical activity from a single dose of the drug.

The latest data from the SOLTI TOT-HER3 trial included 78 pre- and postmenopausal women with untreated primary operable HR-positive/HER2-negative breast cancer with Ki67 expression of 10% or more.

The patients were stratified based on their pretreatment ERBB3 mRNA tumor expression into high, medium, low, and ultralow levels, and were given a single dose of HER3-DXd.

A biopsy was performed on day 21. CelTIL scores, considered correlates of pathological complete response, were calculated to determine the variation in disease activity between pre- and posttreatment samples.

Of the 78 patients enrolled, 77 were available for the efficacy analysis and 78 for safety assessment. The average patient age was 53 years, 99% were White, and 56% were premenopausal. Median tumor size was 2.1 cm and average Ki67 expression was 27%. More than half of women had cT2 disease, and 71% had no nodal involvement.

About 1 in 5 patients had high, medium, and low ERBB3 mRNA expression whereas 14% had ultralow expression.

At day 21, patients demonstrated an overall response rate of 45% to one dose of the novel ADC, which included 28 responders and 34 nonresponders.

Overall, CelTIL scores increased after a single dose of the ADC. The mean difference between pre- and posttreatment CelTIL scores was 6.8 across the cohort. Patients who responded to the therapy drove this increase, with a mean difference of 15.2 among responders vs 2.9 among nonresponders.

Further analysis showed that the changes in CelTIL scores were independent of both baseline ERBB3 mRNA and HER3 expression.

Interestingly, patritumab deruxtecan appeared to induce changes in the expression of immune-related genes, including suppression of Ki67 expression.

Adverse events of any grade were reported by 95% of patients, with 14% reporting grade 3 or higher events, which included neutropenia and diarrhea.

"The safety profile was consistent with that previously reported for the drug," Prat noted.

Rebecca Dent, MD, MSc, senior consultant and head of the Medical Oncology Department, National Cancer Center, Singapore, commented that the study brings up "some really critical biological questions," particularly regarding whether preclinical observations that ADCs increase immune cell infiltration translate into clinical practice. She was not associated with the research.

Dent wondered, for instance, whether the ADC was indeed driving the observed increased tumor infiltration in the group of patients who demonstrated notable changes in CelTIL scores.

"I'm hoping we'll see some greater interrogation of those patients in the future," said Dent.

The study was sponsored by SOLTI Cancer Research Group and supported by Daiichi Sankyo.

Prat declares relationships with Pfizer, Lilly, Novartis, Roche, Amgen, PUMA, Nanostring Technologies, Seattle Genetics, Daiichi Sankyo, AstraZeneca, Guardant Health, Foundation Medicine, Oncolytics Biotech, and Reveal Genetics. Dent declared relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.

European Society for Medical Oncology (ESMO) Breast Cancer Congress 2022: Abstract LBA3. Presented May 3, 2022.

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