Dose reduction does not limit efficacy of trastuzumab deruxtecan in MBC

Reducing the dose of trastuzumab deruxtecan (T-DXd) does not have any significant effect on real-world (rw) progression-free survival (PFS) or treatment-related toxicities among patients with metastatic breast cancer (MBC), as shown in a Singapore study.

In addition, only 5.7 percent of patients developed interstitial lung disease (ILD), and T-Dxd delivered good control of central nervous system (CNS) disease, with 82 percent achieving CND disease control, according to the researchers.

This study used medical records from the Joint Breast Cancer Registry in Singapore. Using data from these records, the researchers assessed MBC patients treated with T-Dxd from February 2021 to June 2024. They tried to determine whether reducing dose intensity and density would have a negative effect on treatment outcomes.

Eighty-seven patients with MBC (median age 59 years) received T-Dxd. Of these, 32.1 percent were still being treated with T-Dxd at the time of data cutoff. More than half (54 percent) of the participants received an initial relative dose intensity (RDI) of ≥85 percent. [Ann Acad Med Singap 2025;54:458-466]

Patients achieved an overall median rwPFS of 8.1 months, with comparable rwPFS between RDI groups (<85 percent: 9.7 months; ≥85 percent: 8.1 months; p=0.62). In contrast, patients with human epidermal growth receptor (HER) 2-positive MBC had significantly better rwPFS outcomes than those with HER-low disease (8.8 vs 2.5 months; p<0.001).

“The relatively shorter rwPFS compared to PFS observed in contemporary pivotal clinical trials suggests that the cohort in this study consisted of heavily pre-treated patients with poorer general fitness,” the researchers said. “This likely reflects the recent access to T-DXd and the relatively short follow-up period, which may have impacted the observed outcomes.”

Moreover, only 16 percent of patients with CNS involvement had CNS progressive disease on treatment. No significant differences were noted in PFS between those with and without CNS disease, regardless of RDI groups.

ILD developed in five patients (5.7 percent), of whom three (3.4 percent) had grade 3 events. Two patients required high-dose steroids, and none were rechallenged after ILD. No deaths were recorded.

“It is unclear if the lower rates of ILD are related to the lower dose intensity administered among these patients or because of pharmacogenetic differences between real-world and the DESTINY-Breast study populations,” the researchers said.

“Careful monitoring, early recognition, and timely glucocorticoid administration for adverse event management likely contributed to the avoidance of ILD fatalities in our study,” they added.

Ethnicity

The study supports the importance of having a fair and equitable trial allocation, particularly with regard to ethnicity and geographical location.

“Even within the Asian category, there are nuanced differences between different ethnic groups (eg, South Asians, Han Chinese, or Japanese),” the researchers said. “Singapore is a multi-ethnic city-state populated by Chinese, Malays, Indians, and other racial minorities.”

Genetic variations among these groups may result in differences in how patients respond to treatment (eg, drug metabolism or susceptibility to adverse events).

“Therefore, it is crucial for international clinical trials to incorporate a broader representation of Asian populations to better understand drug effects and uncover pharmacogenetic issues on diverse ethnicities during clinical development of novel cancer therapeutics,” the researchers said.