DESTINY-Breast12 is the largest prospective study reporting intracranial activity of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer (mBC) and baseline brain metastases. This phase IIIb\/IV study was designed to collect data from settings that resemble real-world clinical practice, to provide a detailed understanding of trastuzumab deruxtecan outcomes in patients previously treated with HER2-targeted agents.<\/p>\n
Trastuzumab deruxtecan showed substantial and durable overall and intracranial clinical activity in patients with HER2-positive mBC, including a large cohort with stable and active baseline brain metastases. No new safety signals were identified. Interstitial lung disease\/pneumonitis remains an important safety risk of trastuzumab deruxtecan. The study primary results were reported at the ESMO Congress 2024 along with a simultaneous publication by Prof. Nadia Harbeck of the LMU University Hospital in Munich, Germany and colleagues on 13 September 2024 in the Nature Medicine<\/em>.<\/p>\n Half patients with HER2-positive advanced\/mBC develop brain metastases, which are associated with a poorer prognosis. Local therapy including surgical resection, stereotactic radiosurgery, stereotactic radiotherapy and\/or whole-brain radiation therapy is recommended; however, central nervous system (CNS) progression typically occurs within 6-12\u2009months of treatment, and no extracranial benefit is conferred.<\/p>\n The authors wrote in the background that trastuzumab-based therapy has long been the mainstay of systemic therapy for patients with HER2-positive mBC, and several additional HER2-directed therapies have been investigated for the treatment of HER2-positive mBC with brain metastases, including tucatinib. Despite this, a large proportion of patients receiving treatment, including those with an initial response, eventually experience disease progression, commonly in the CNS.<\/p>\n Promising preliminary evidence of trastuzumab deruxtecan intracranial efficacy was reported in a retrospective, exploratory pooled analysis of DESTINY-Breast01, 02 and 03. Encouraging intracranial responses in patients with active (untreated or previously treated and progressing) brain metastases were also reported in the phase Ib\/II DESTINY-Breast07 study, in the ongoing five-cohort phase II DEBBRAH study, in a multicentre retrospective medical chart review ROSET\u2011BM study, in the prospective single-arm single-centre phase II TUXEDO\u20111 study and in a retrospective cohort analysis of heavily pretreated patients with brain metastases.<\/p>\n A total of 504 patients were treated in DESTINY-Breast12 study across 78 sites between June 2021 and February 2024; 263 patients had baseline brain metastases, and 241 patients had no baseline brain metastases. All patients have been treated with one or more prior anti-HER2\u2013based regimens and received trastuzumab deruxtecan 5.4\u2009mg per kg.<\/p>\n Primary endpoints were progression-free survival (PFS) in brain metastases cohort and objective response rate (ORR) per RECIST v1.1 in non-brain metastases cohort. Additional endpoints included CNS PFS, ORR, time to second progression, CNS ORR in brain metastases cohort, incidence of new symptomatic CNS metastases in non-brain metastases cohort, time to progression, duration of response, overall survival and safety in both cohorts. No formal hypothesis testing was conducted for this single-arm, open-label study.<\/p>\n In the brain metastases cohort, 12-month PFS was 61.6% (95% confidence interval [CI] 54.9\u201367.6), and 12-month CNS PFS was 58.9% (95% CI 51.9\u201365.3). In the non-brain metastases cohort, ORR was 62.7% (95% CI 56.5\u201368.8).<\/p>\n Grade 3 or higher adverse events occurred in 51% in brain metastases cohort and 49% in non-brain metastases cohort of patients. Investigator-reported interstitial lung disease\/pneumonitis occurred in 16% (grade \u22653 in 3%) of patients with brain metastases and 13% (grade \u22653 in 1%) of patients without brain metastases.<\/p>\n The authors commented that the results of the DESTINY-Breast12 study indicate the CNS efficacy of trastuzumab deruxtecan in a large, prospective patient cohort. Without a direct comparison between trastuzumab deruxtecan and the tucatinib, trastuzumab and capecitabine regimen, treatment selection for previously treated patients with HER2-positive mBC and brain metastases should be balanced between efficacy and toxicity considerations on an individual basis.<\/p>\n The study was sponsored by AstraZeneca and Daiichi Sankyo.<\/p>\nReferences<\/h3>\n