A large prospective phase 3b/4 trial has found that trastuzumab deruxtecan (T-DXd) demonstrates substantial intracranial activity in patients with HER2-positive advanced breast cancer and brain metastases. The DESTINY-Breast12 study, published in December 2024 in Nature Medicine, provides the most robust evidence to date supporting the use of T-DXd in this challenging patient population.
The international, multicenter, open-label, single-arm study was designed to evaluate the efficacy and safety of T-DXd in two cohorts - patients with baseline brain metastases (BMs) and those without BMs. The trial was sponsored by AstraZeneca and Daiichi Sankyo as part of their global development and commercialization collaboration for T-DXd.
A total of 504 patients were enrolled across 78 sites between June 2021 and February 2024. The study included 263 patients with baseline BMs (157 with stable BMs and 106 with active BMs) and 241 patients without baseline BMs. Eligible patients had HER2-positive advanced or metastatic breast cancer, disease progression on one or more prior anti-HER2 regimens, and no more than two prior therapy regimens in the metastatic setting. Patients were required to be tucatinib-naive and have an ECOG performance status of 0 or 1. Those with known or suspected leptomeningeal metastases were excluded.
The primary endpoint for the BMs cohort was progression-free survival (PFS), while objective response rate (ORR) was the primary endpoint for the non-BMs cohort. Key secondary endpoints included overall survival (OS), central nervous system (CNS) PFS, CNS ORR, and safety.
In the BMs cohort, the 12-month PFS rate was 61.6% (95% CI: 54.9-67.6). The 12-month CNS PFS rate was 58.9% (95% CI: 51.9-65.3). Among patients with measurable CNS disease at baseline (n=138), the confirmed CNS ORR was 71.7% (95% CI: 64.2-79.3). Notably, CNS ORR was 79.2% in patients with stable BMs and 62.3% in those with active BMs.
For patients without baseline BMs, the confirmed ORR was 62.7% (95% CI: 56.5-68.8). The 12-month PFS rate in this cohort was 72.1% (95% CI: 65.4-77.8). Importantly, only 4 patients (1.7%) developed new symptomatic CNS metastases during the study period.
The safety profile was consistent with previous studies of T-DXd. Grade 3 or higher adverse events occurred in 51% of patients with BMs and 49% of those without BMs. Interstitial lung disease/pneumonitis of any grade was reported in 16% and 13% of patients with and without BMs, respectively. There were 9 fatal cases of ILD/pneumonitis across both cohorts.
The authors concluded that these results demonstrate substantial and durable overall and intracranial activity for T-DXd in patients with HER2-positive metastatic breast cancer, regardless of the presence of stable or active baseline brain metastases. They note that the intracranial efficacy observed in this large prospective cohort builds upon previous smaller studies and retrospective analyses suggesting CNS activity with T-DXd.
Several limitations of the study were acknowledged. The open-label, single-arm design precludes direct comparisons to other treatments. The follow-up duration was relatively short at a median of 15-16 months. Patients with leptomeningeal disease were excluded. Additionally, the study population underrepresented Black and Asian patients.
Despite these limitations, DESTINY-Breast12 represents the largest prospective evaluation of T-DXd in patients with HER2-positive breast cancer and brain metastases to date. The results have potentially significant clinical implications, supporting the use of T-DXd in patients with stable or active brain metastases who have received prior HER2-directed therapy.
Currently, the combination of tucatinib, trastuzumab and capecitabine is considered the preferred systemic therapy for previously treated patients with HER2-positive metastatic breast cancer and active brain metastases. The authors note that without a direct comparison between T-DXd and this regimen, treatment selection should be individualized based on efficacy and toxicity considerations.
The robust intracranial activity observed with T-DXd is particularly noteworthy given historical challenges in treating breast cancer brain metastases. The blood-brain barrier has often limited the CNS penetration and efficacy of systemic therapies. These results suggest T-DXd may overcome this barrier to a meaningful degree.
Moving forward, additional research is warranted to further define the role of T-DXd in treating HER2-positive breast cancer brain metastases. Ongoing studies are evaluating T-DXd in earlier lines of therapy and in combination with other agents. Studies in HER2-low breast cancer and other HER2-positive solid tumors with CNS involvement are also underway.
In conclusion, the DESTINY-Breast12 trial provides compelling evidence supporting T-DXd as an effective treatment option for patients with HER2-positive metastatic breast cancer and brain metastases. These results may expand the therapeutic armamentarium for this challenging patient population, potentially impacting clinical practice and treatment guidelines. However, clinicians should carefully weigh the efficacy benefits against the risk of serious adverse events, particularly ILD/pneumonitis, when considering T-DXd for individual patients.
References
Harbeck N, Ciruelos E, Jerusalem G, et al. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial [published correction appears in Nat Med. 2024 Dec;30(12):3780. doi: 10.1038/s41591-024-03349-0.]. Nat Med. 2024;30(12):3717-3727. doi:10.1038/s41591-024-03261-7
