SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.
The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with high levels of HER2 expression (IHC 3+ or 2+/FISH positive) are classified as HER2-positive. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes.
With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases which result in a significantly worse prognosis compared to those without brain metastases. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. However, CNS progression usually occurs within 6-12 months post-treatment. Furthermore, Whole-Brain Radiation Therapy, while commonly used for multiple brain metastases, is linked with cognitive decline, which is a particular concern for HER2+ breast cancer patients who can live several years after their diagnosis.
With regards to systemic treatment options for brain metastases, various other HER2-directed therapies have been explored including Tucatinib (TUKYSA®), which can cross the blood brain barrier. Tucatinib combined with Trastuzumab and Capecitabine is currently the preferred systemic treatment for HER2+ metastatic breast cancer patients with active brain metastases. The HER2CLIMB study investigated this combination in patients who had been previously treated. In patients with measurable brain metastasis at baseline, those receiving Tucatinib combined with Capecitabine, and Trastuzumab showed a confirmed intracranial Objective Response Rate (ORR) of 47.3%. CNS Progression-Free Survival (PFS) was 9.9 months for all patients and 9.6 months for those with active brain metastases.
Trastuzumab Deruxtecan-T-DXd (ENHERTU®) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). T-DXd has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike ado-Trastuzumab emtansine (KADCYLA®), another ADC targeting HER2, T-DXd has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.
T-DXd has also shown promising intracranial activity in several studies, such as DESTINY-Breast01, 02, and 03, as well as the ongoing DESTINY-Breast07 and the DEBBRAH study, among others. These studies reported encouraging responses in patients with active brain metastases, suggesting potential efficacy in this difficult-to-treat population.
DESTINY-Breast12 is an open-label, multicentre, Phase IIIb/IV 2-cohort, non-comparative clinical trial designed to evaluate the efficacy and safety of T-DXd 5.4 mg/kg in patients with previously treated advanced/metastatic HER2-positive breast cancer. This study included two cohorts – patients without brain metastases (Cohort 1) and patients with brain metastases (Cohort 2), who have experienced disease progression following prior anti-HER2-based regimens and have received no more than two lines of therapy in the metastatic setting. Patients were enrolled into one of two cohorts according to the presence or absence of brain metastases at baseline. A total of 504 eligible patients (N=504) were enrolled across multiple sites of whom 263 patients had baseline brain metastases, and 241 patients had no baseline brain metastases. All patients received T-DXd 5.4 mg per kg every three weeks until disease progression or unacceptable toxicity occurred. Notably, patients with leptomeningeal metastases were excluded, as well as those who had received Tucatinib in prior treatments, to avoid confounding effects from a drug known to affect CNS lesions. The study allowed the inclusion of patients with stable or active brain metastases (previously treated and progressing), though it excluded those with no clinical indication for immediate retreatment of their brain metastases. Tumor assessments were performed regularly using MRI or CT scans. The Primary endpoint of Cohort 1 (non-brain metastases cohort) was Objective Response Rate (ORR) as assessed by Independent Review and the Primary endpoint of Cohort 2 (brain metastases cohort) was Progression-Free Survival (PFS). Additional endpoints included CNS PFS, CNS ORR, ORR in the brain metastases cohort and Safety.
Results showed a 12-month PFS rate of 61.6% for patients with brain metastases, with CNS-specific PFS of 58.9%. Those with stable brain metastases had a 12-month PFS of 62.9%, while patients with active brain metastases had a 12-month CNS PFS of 60.1%. For patients without brain metastases at baseline, the ORR was 62.7%, with a significant proportion achieving Partial or Complete Responses. A post-hoc analysis revealed a CNS ORR of 82.6% in patients with active brain metastases who had not undergone prior local CNS therapy and 50% in those who had progressed after prior local CNS treatments. Importantly, the safety profile of T-DXd was consistent with prior studies, though Interstitial Lung Disease (ILD) or pneumonitis occurred in approximately 13-16% of patients, with a small percentage experiencing Grade 5 (fatal) events.
In summary, the DESTINY-Breast12 study highlights the efficacy of Trastuzumab deruxtecan in treating HER2+ metastatic breast cancer, particularly in patients with brain metastases. These findings provide valuable insights into managing a challenging subset of breast cancer patients who often experience poor outcomes due to CNS progression. Further research is warranted to refine treatment strategies, especially for patients with ILD risk factors, and to explore potential combinatory regimens for long-term CNS control.
Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Harbeck, N., Ciruelos, E., Jerusalem, G. et al .for the the DESTINY-Breast12 study group. Nat Med (2024). https://doi.org/10.1038/s41591-024-03261-7
