In an exploratory analysis of the DESTINY-Breast03 study, consistent systemic disease control and efficacy benefit were observed with trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer (mBC) with and without brain metastases. Median progression-free survival (PFS) was numerically longer with T-DXd than with T-DM1 for patients with brain metastases (15.0 versus 3.0 months) and estimated to be numerically longer for patients without brain metastases (not reached, NR versus 7.1 months). A higher proportion of patients randomly assigned to T-DXd exhibited confirmed systemic objective response relative to those randomly assigned to T-DM1, including in patients with baseline brain metastases.
T-DXd treatment was associated with substantial intracranial response (65.7% versus 34.3% patients) and reduction in CNS disease. Intracranial progression disease (PD) was observed in fewer patients randomised to T-DXd compared with T-DM1 (0% versus 20.0% patients). For patients with brain metastases at baseline, those randomised to T-DXd experienced fewer PD events versus T-DM1 (48.8% versus 69.2%) according to Dr. Sara A. Hurvitz of the Division of Hematology and Oncology, Fred Hutchinson Cancer Center in Seattle, WA, US, and colleagues who published the findings on 24 April 2024 in the ESMO Open.
Several anti-HER2 therapies have been investigated for the treatment of brain metastases in patients with HER2-positive mBC. Before DESTINY-Breast03, T-DM1 was the standard-of-care treatment for patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane. T-DXd has previously demonstrated systemic efficacy in patients with brain metastases in a subgroup analysis of DESTINYBreast01. Intracranial efficacy of T-DXd has also been reported in both preclinical and clinical studies.
In the phase III DESTINY-Breast03 study, T-DXd demonstrated a clinically meaningful and statistically significant improvement in PFS versus T-DM1 in patients with HER2positive mBC: NR (95% confidence interval [CI] 18.5 months-not estimable [NE]) versus 6.8 months (95% CI 5.6-8.2 months); hazard ratio (HR) 0.284 (95% CI 0.217-0.373, p < 0.0001). The 12-month PFS was 75.8% for T-DXd (95% CI 69.8% to 80.7%) versus 34.1% (95% CI 27.7% to 40.5%) for T-DM1.
Based on the strength of DESTINY-Breast03 efficacy and safety data, the US Food and Drug Administration approved T-DXd for the treatment of patients with unresectable or advanced HER2-positive breast cancer who have received prior anti-HER2 therapy in the metastatic setting or in the adjuvant/neoadjuvant setting and have progressed within 6 months. In the latest article published in the ESMO Open, the study investigators report subgroup analyses for patients from DESTINY-Breast03 with and without brain metastases at baseline.
DESTINY-Breast03 is a randomized, multicentre, open-label, phase III study. Patients were randomly assigned 1:1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic brain metastases were eligible. Lesions were measured as per modified RECIST v1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR.
As of 21 May 2021, 43 of 261 patients randomised to T-DXd and 39 of 263 patients randomised to T-DM1 had brain metastases at baseline, as per investigator assessment. Among patients with baseline brain metastases, 20 of 43 in the T-DXd arm and 19 of 39 in the T-DM1 arm had not received prior local treatment for brain metastases.
For patients with brain metastases, median PFS was 15.0 months (95% CI 12.5-22.2 months) for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; HR 0.25 (95% CI 0.13-0.45). For patients without brain metastases, median PFS was NR (95% CI 22.4 months-NE) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without brain metastases, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1.
The authors concluded that this exploratory analysis shows that T-DXd provides meaningful efficacy benefit for patients with HER2-positive mBC either with or without clinically inactive/ asymptomatic brain metastases in the second-line setting. These findings also further support the continued investigation of T-DXd in patients with brain metastases, including active brain metastases, a population for whom treatment options are currently limited.
In an accompanied editorial article, Drs. Sarah Sammons and Nancy U. Lin of the Dana-Farber Cancer Institute, Dana-Farber Brigham Cancer Center, and Harvard Medical School in Boston, MA, US wrote that T-DXd and tucatinib/capecitabine/trastuzumab are both excellent options for patients with brain metastases. They favour T-DXd in the second line for patients with extracranial progression who have stable brain metastases with low brain metastasis velocity, or those with small asymptomatic/untreated lesions. They prefer tucatinib/ capecitabine/trastuzumab for patients with previously treated, but progressive lesions and those with high brain metastasis velocity due to a paucity of data for T-DXd in this population relative to the much larger published experience with tucatinib to date. However, they would favour T-DXd over other systemic options in patients who have progressed on a tucatinib-based regimen.
The editorialists underlined that exploratory analysis of the DESTINYBreast03 study suggests that T-DXd is the premier antibody drug conjugate for the treatment of patients with HER2-positive breast cancer brain metastases. The analysis underscores the pressing need to investigate T-DXd in patients with HER2-low expressing brain metastases, active HER2-positive brain metastases across other solid tumours, and leptomeningeal disease as the next crucial steps, as well as a move towards default inclusion of patients with brain metastases into clinical trials of antibody drug conjugates across the board.
This study was sponsored and designed by Daiichi Sankyo in collaboration with AstraZeneca.
References
- Hurvitz SA, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial. ESMO Open; Published online 24 April 2024. DOI: https://doi.org/10.1016/j.esmoop.2024.102924
- Sammons S, Lin NU. Antibody–drug conjugates are active in patients with HER2-positive breast cancer brain metastases: where do we go from here? ESMO Open; Published online 24 April 2024. DOI: https://doi.org/10.1016/j.esmoop.2024.102990