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Outcomes of Trastuzumab–Deruxtecan Therapy in Patients With HER2+ Breast Cancer and Active Brain Metastases
TAKE-HOME MESSAGE
- This prospective single-arm phase II trial involved 15 patients with HER2-positive metastatic breast cancer with active brain metastasis not requiring immediate local therapy. Eligible patients had received prior trastuzumab and pertuzumab therapy. After enrollment, they received trastuzumab-deruxtecan. After a median of 26.5 months of follow-up and with all patients off study treatment, the median progression-free survival duration was 21 months, and the median overall survival duration was not reached. No new safety signals were reported.
- Brain metastasis is a devastating complication of HER2-positive breast cancer, and systemic treatments that address HER2-related brain metastasis are urgently needed. The TUXEDO-1 trial previously reported a 73.7% intracranial response rate, and the current analysis shows impressive progression-free survival and overall survival outcomes in patients with historically poor outcomes. Trastuzumab-deruxtecan should be considered an important treatment option for patients with HER2-positive breast cancer with active brain metastasis.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Brain metastases (BM) are a devastating complication of HER2-positive metastatic breast cancer (BC) and treatment strategies providing optimized local and systemic disease control are urgently required. The antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) over trastuzumab emtansine but data regarding intracranial activity is limited. In the primary outcome analysis of TUXEDO-1, a high intracranial response rate (RR) was reported with T-DXd. Here, we report final PFS and OS results.
PATIENTS AND METHODS
TUXEDO-1 accrued adult patients with HER2-positive BC and active BM (newly diagnosed or progressing) without indication for immediate local therapy. The primary endpoint was intracranial RR; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analysed in the per-protocol population.
RESULTS
At 26.5 months median follow-up, median PFS was 21 months (95% CI 13.3-n.r.) and median OS was not reached (95% CI 22.2-n.r.). With longer follow-up, no new safety signals were observed. The most common grade 3 adverse event was fatigue (20%). Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL was maintained over the treatment period.
DISCUSSION
T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive BC BM in line with results from the pivotal trials. These results support the concept of ADCs as systemic therapy for active BM.
Additional Info
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FINAL outcome ANALYSIS FROM THE PHASE II TUXEDO-1 TRIAL OF TRASTUZUMAB-DERUXTECAN IN HER2-positive breast cancer PATIENTS WITH active brain metastases
Neuro-oncology 2024 Jul 04;[EPub Ahead of Print], R Bartsch, AS Berghoff, J Furtner, M Marhold, ES Bergen, S Roider-Schur, MJ Mair, AM Starzer, H Forstner, B Rottenmanner, MB Aretin, K Dieckmann, Z Bago-Horvath, H Haslacher, G Widhalm, A Ilhan-Mutlu, C Minichsdorfer, T Fuereder, T Szekeres, L Oehler, B Gruenberger, G Pfeiler, C Singer, A Weltermann, L Berchtold, M PreusserFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Approximately 20% to 40% of patients with breast cancer (BC) will develop brain metastases (BMs) during the course of their disease, an occurrence that has significant impacts on morbidity and mortality. The development of BMs in patients with HER2-positive tumors is associated with a better prognosis than in those with other subtypes of BC, yet it remains an area of high unmet need. Although there have been considerable advances in local therapies such as surgery, stereotactic radiosurgery, and whole-brain radiation therapy, these interventions are associated with side effects that can have a considerable impact on quality of life. Such effects include neurocognitive decline, the development of radiation necrosis, and interruptions in the management of systemic disease.
The therapeutic paradigm is changing owing to a better understanding of the blood–brain barrier and the availability of improved systemic therapy options. Specifically, the HER2-selective tyrosine kinase inhibitor tucatinib in combination with capecitabine and trastuzumab has demonstrated an overall survival benefit in patients with BC and BMs and is the preferred treatment approach. In addition, accumulating data on agents such as antibody–drug conjugates (which have traditionally not been thought to have central nervous system penetration) offer the promise of additional therapeutic options.
One such therapy, trastuzumab deruxtecan, was evaluated in the TUXEDO-1 trial, which notably included patients with active BMs (newly diagnosed or progressing) without indication for immediate local therapy. The trial previously reported a very high intracranial response rate of 73.3% in the population of patients with active BM. The current report, which presents the results of the final outcome analysis, details a median progression-free survival duration of 21 months; however, the median overall survival duration was not reached. This is encouraging efficacy data for this patient population.
The DESTINY-Breast12 (NCT04739761) is an ongoing phase III study that will enroll up to 250 participants with BCBM, including selected patients with active central nervous system disease. This will provide more information on intracranial responses and overall outcomes in patients treated with trastuzumab deruxtecan.