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.
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.
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 months of treatment, and no extracranial benefit is conferred.
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.
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‑BM study, in the prospective single-arm single-centre phase II TUXEDO‑1 study and in a retrospective cohort analysis of heavily pretreated patients with brain metastases.
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–based regimens and received trastuzumab deruxtecan 5.4 mg per kg.
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.
In the brain metastases cohort, 12-month PFS was 61.6% (95% confidence interval [CI] 54.9–67.6), and 12-month CNS PFS was 58.9% (95% CI 51.9–65.3). In the non-brain metastases cohort, ORR was 62.7% (95% CI 56.5–68.8).
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 ≥3 in 3%) of patients with brain metastases and 13% (grade ≥3 in 1%) of patients without brain metastases.
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.
The study was sponsored by AstraZeneca and Daiichi Sankyo.
References
- Harbeck N, Ciruelos E, Jerusalem G, et al. & the DESTINY-Breast12 study group. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nature Medicine; Published online 13 September 2024. DOI: https://doi.org/10.1038/s41591-024-03261-7
- LBA18 - Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) with or without brain metastases (BM): DESTINYBreast-12 primary results. Annals of Oncology 2024;35(Suppl 2):S1211-S1212.