ABSTRACT

Background: Objective response rates in the DESTINY-Breast01/02/03 trials, which evaluated trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC), were 62%/70%/79%, respectively.

Patients and methods: This exploratory pooled analysis investigated associations between best confirmed response to T-DXd and baseline characteristics/long-term outcomes in patients who received T-DXd 5.4 mg/kg in DESTINYBreast01/ 02/03. Endpoints included best confirmed response per (blinded) independent central review [(B)ICR] using RECIST v1.1, progression-free survival (PFS) by (B)ICR, overall survival (OS), safety, and biomarker analyses of expression levels/alterations of genes relevant to HER2-positive mBC or T-DXd activity.

Results: A total of 834 patients who received T-DXd in DESTINY-Breast01/02/03 were assessable for response; 125 (15.0%) experienced complete response (CR), 477 (57.2%) experienced partial response (PR), and 232 (27.8%) were considered non-responders (stable disease/progressive disease). The median number of prior regimens in the metastatic setting was two for patients with CR versus three for patients with PR and non-responders; visceral disease and baseline brain or bone metastases were less frequently observed in patients with CR. The 24-month PFS rates in patients with CR, PR, and no response, respectively, were 77.8%, 46.3%, and 20.6%, and 36-month OS rates were 88.6%, 54.0%, and 35.9%. Rates of serious adverse events, T-DXd discontinuation, and interstitial lung disease/pneumonitis were numerically lower in patients with CR. In exploratory biomarker analyses, responders had tumors with numerically higher HER2 plasma copy number, lower ESR1 gene expression and ESR1 mutation frequency, and lower circulating tumor DNA levels at baseline.

Conclusions: Patients with objective response to T-DXd, particularly those with CR, showed prolonged median PFS and OS. These results support T-DXd use across broad patient groups with HER2-positive mBC, including those with lower disease burden. Patients whose disease does not respond to T-DXd represent an unmet medical need, and research into more effective treatment approaches for these patients is warranted.

Key words: metastatic breast cancer, HER2 positive, trastuzumab deruxtecan, pooled analysis