Human epidermal growth factor receptor 2-positive (HER2+) breast cancer comprises 15-20% of all breast cancer cases. Up to 50% of patients with HER2+ advanced/metastatic breast cancer (mBC) develop brain metastases (BMs), which significantly worsen prognosis. Local therapies (surgery, radiosurgery, radiotherapy) are recommended for BMs, but CNS progression often occurs within 6-12 months, with no extracranial benefit. Whole-brain radiation therapy (WBRT), while recommended for multiple BMs, causes cognitive decline, a significant concern given that some patients with HER2+ breast cancer and BMs can survive for several years. Therefore, additional systemic treatment options are needed. Trastuzumab-based therapy has been a mainstay for HER2+ mBC, but many patients eventually progress, often in the CNS. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), targets HER2 and shows promising preliminary evidence of intracranial efficacy in smaller retrospective studies. This phase 3b/4 study, DESTINY-Breast12, is the largest prospective study of T-DXd in HER2+ mBC patients with BMs, evaluating efficacy and safety in patients with and without baseline BMs.

Several HER2-directed therapies, including tucatinib, have been investigated for HER2+ mBC with BMs. However, a significant proportion of patients, even with initial responses, eventually experience disease progression, often in the CNS. Retrospective analyses of T-DXd in smaller cohorts of HER2+ mBC patients with stable or active BMs showed encouraging intracranial objective response rates (ORR) and CNS progression-free survival (CNS PFS). These promising results, seen across multiple smaller studies (DESTINY-Breast01, 02, 03, DESTINY-Breast07, DEBBRAH, ROSET-BM, TUXEDO-1), motivated the current large-scale prospective trial.

This prospective, open-label, single-arm, multicenter, international phase 3b/4 study enrolled 504 patients with pathologically confirmed HER2+ advanced or metastatic breast cancer, categorized into two cohorts: those with baseline brain metastases (BMs) and those without. Patients were eligible if they were ≥18 years old, had disease progression on one or more prior anti-HER2-based regimens (tucatinib-naive), received no more than two prior regimens in the metastatic setting, and had an ECOG PS score of 0 or 1. Patients with leptomeningeal metastases were excluded. Stable BMs were defined as radiographically stable for ≥4 weeks; active BMs included untreated BMs or those progressing since local CNS therapy without immediate retreatment indication. Patients received T-DXd intravenously every 3 weeks at 5.4 mg/kg until RECIST 1.1-defined disease progression outside the CNS, unacceptable toxicity, or withdrawal of consent. Tumor assessments were performed using CT or MRI every 6 weeks. For patients with baseline BMs, brain imaging (MRI or CT) was performed at the same frequency. The primary endpoint for the BMs cohort was PFS; for the non-BMs cohort, it was ORR. Secondary endpoints included CNS PFS, OS, ORR, PFS2, time to progression, CNS ORR, DOR, and safety. Response and progression were assessed by independent central review (ICR) per RECIST 1.1. Safety data were collected using the MedDRA and CTCAE 5.0.

A total of 504 patients were enrolled (263 with baseline BMs, 241 without). In the BMs cohort, the 12-month overall PFS was 61.6% (95% CI: 54.9–67.6), and the 12-month CNS PFS was 58.9% (95% CI: 51.9–65.3). The overall confirmed ORR was 51.7% (95% CI: 45.7–57.8). In the post-hoc analysis of patients with measurable disease at baseline, the confirmed ORR was 64.1% (95% CI: 57.5-70.8). CNS ORR was 71.7% overall, with higher rates in patients with stable BMs (79.2%) compared to those with active BMs (62.3%). In the non-BMs cohort, the confirmed ORR was 62.7% (95% CI: 56.5–68.8), with a confirmed ORR of 68.4% in patients with measurable disease. Grade 3 or higher adverse events occurred in 51% of patients in the BMs cohort and 49% in the non-BMs cohort. Interstitial lung disease/pneumonitis (ILD/pneumonitis) was the most common grade 3 or higher AE leading to treatment discontinuation (16% in BMs cohort and 13% in non-BMs cohort).

DESTINY-Breast12 is the largest prospective study demonstrating T-DXd's intracranial activity in HER2+ mBC patients with baseline BMs. The 12-month PFS rate in the BMs cohort is comparable to that observed in an exploratory analysis of patients with stable and active BMs from the DESTINY-Breast03 study. While the overall ORR was lower in patients with stable BMs compared to those with active BMs, the post-hoc analysis considering only patients with measurable disease showed a higher ORR in the stable BMs subgroup, likely reflecting an imbalance in measurable disease between subgroups. The study's results extend previous observations from smaller prospective studies, showing promising CNS activity in patients with active BMs, including those with untreated and previously treated/progressing BMs. The CNS ORR observed in this study is numerically higher than that reported in pooled analyses of previous studies, which may be due to the differences in patient populations. The safety profile of T-DXd was consistent with previous reports, with ILD/pneumonitis remaining a significant safety concern. Although no direct comparison was made with tucatinib-based regimens, treatment selection should consider individual patient efficacy and toxicity profiles.

T-DXd demonstrated substantial and durable overall and intracranial activity in patients with HER2+ mBC, including those with stable and active BMs. ILD/pneumonitis remains a critical safety consideration. These findings support T-DXd's use in previously treated HER2+ mBC patients, irrespective of BMs status. Future research could explore T-DXd's efficacy in other HER2-positive cancers and further investigate its activity in patients with leptomeningeal metastases.

DESTINY-Breast12 was an open-label, single-arm study, limiting direct comparisons with other treatments. The exclusion of patients with leptomeningeal metastases and the lack of a formal hypothesis test are limitations. The study also had an underrepresentation of patients from Black and Asian ethnicities. The relatively short follow-up duration may limit the assessment of long-term outcomes. The absence of an adjudication committee for ILD/pneumonitis may influence the interpretation of those results. The lack of planned long-term follow-up restricts the ability to make longer-term efficacy conclusions. For the non-BMs cohort, the focus on ORR as the primary endpoint, while including patients without measurable disease at baseline, omits PFS data.