Trastuzumab deruxtecan delays cancer growth for people with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer that has progressed following endocrine therapy, according to findings from a new phase III clinical trial.

The research was presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 31-June 4 in Chicago, Illinois.

“These results also represent a potential shift in how we classify and treat metastatic breast cancer, as we may have the opportunity to use trastuzumab deruxtecan earlier in the treatment of HR+ metastatic breast cancer and expand trastuzumab deruxtecan into new metastatic breast cancer patients who previously have not been able to benefit from a targeted medicine post-endocrine therapy,” said Giuseppe Curigliano, MD, PhD, University of Milan and European Institute of Oncology, Milan, Italy

This study included 866 participants with metastatic breast cancer that was either HER2-low (713 participants) or HER2-ultralow (153 participants).

HER2-low cancers have an immunohistochemistry score that indicates the amount of HER2 protein expressed in cancer cells of 1+ or 2+, while HER2-ultralow cancers have a score of greater than 0 but less than 1+.

All study participants had received at least one treatment with endocrine therapy, and nearly all participants (90.4%) had also received targeted therapy with a CDK4/6 inhibitor.

The participants were randomly assigned to receive either trastuzumab deruxtecan (436 participants) or a chemotherapy of their doctor’s choice (430 participants, who received either capecitabine, nab-paclitaxel or paclitaxel).

Key Findings

For those with HER2-low cancer, the median progression-free survival was 13.2 months for those who received trastuzumab deruxtecan vs. 8.1 months for those who received chemotherapy.

Similar results were seen in the small group of patients with HER2-ultralow cancer.

Overall, the patients with HER2-low cancer who received trastuzumab deruxtecan had a 38% lower chance of their cancer growing or spreading compared to those who received chemotherapy. 

For those with HER2-low cancer, the objective response rate (ORR) was 56.5% for those who received trastuzumab deruxtecan vs. 32.3% for those who received chemotherapy.

For those with HER2-ultralow cancer, the ORR more than doubled for those who received trastuzumab deruxtecan compared with those who received chemotherapy (61.8% vs. 26.3%, respectively).

Participants who received trastuzumab deruxtecan were able to receive their treatment for a longer time without experiencing severe side effects, with a median treatment length of 11 months vs. 5.6 months for those who received chemotherapy. 

Serious side effects were more common in the trastuzumab deruxtecan group, with about 41% of participants experiencing a serious side effect vs. about 31% of those who received chemotherapy.

Interstitial lung disease (ILD), a known side effect of trastuzumab deruxtecan that causes inflammation of the lungs, occurred in about 11% of participants receiving the drug, which is consistent with previous research.

ILD was not serious for most participants, however about 5% of the participants discontinued treatment due to ILD and three died from this toxicity.

The most common serious side effect that led to reducing the dose of trastuzumab deruxtecan was nausea (4.4% of participants).

“Antibody-drug conjugates are an exciting and effective part of breast cancer care with a growing role in our treatment paradigms. Trastuzumab deruxtecan, an ADC approved for pre-treated metastatic HER2-positive and HER2-low breast cancer, was evaluated in the DESTINY Breast06 trial as the first therapy for patients with HR+, HER2-low, and HER2-ultralow breast cancer after endocrine therapy. In comparison to standard chemotherapy, trastuzumab deruxtecan significantly improved progression-free survival, with similar results in both HER2-low and HER2-ultralow disease. These data suggest that trastuzumab deruxtecan may become a preferred first-line treatment option for most patients with HR+ metastatic breast cancer after progression on endocrine therapy. It is important to note, however, that trastuzumab deruxtecan resulted in more serious toxicities compared to traditional chemotherapy, and may not be the right choice for every patient.”– Erica L. Mayer, MD, MPH, Dana-Farber Cancer Institute, Boston, Massachusetts

Next Steps

The researchers are planning to continue following the patients to assess overall survival outcomes.

They will also continue to analyse data from other secondary endpoints, including patient-reported outcomes, as well as undertake exploratory translational analyses.

Source: ASCO