A recent post-hoc analysis of the DESTINY-Breast12 trial reveals that Enhertu (trastuzumab deruxtecan) exhibits significant clinical activity in patients with HER2-positive metastatic breast cancer, particularly those with brain metastases. The study highlights the potential of Enhertu to address a critical unmet need in this patient population, where treatment options are limited and prognosis is poor.
Efficacy in Brain Metastases
The analysis focused on patients with active brain metastases, a challenging subgroup often excluded from clinical trials. Among patients who had not received prior local CNS therapy, Enhertu demonstrated a CNS Objective Response Rate (ORR) of 82.6% (n=19/23). In patients who had progressed following prior local CNS therapy, the CNS ORR was 50.0% (n=19/38).
These findings suggest that Enhertu can effectively penetrate the blood-brain barrier and exert its anti-tumor effects in the central nervous system. This is particularly important as brain metastases are associated with reduced overall survival and significant neurological morbidity.
Safety Profile
The safety profile of Enhertu in DESTINY-Breast12 was consistent with previous breast cancer clinical trials, with no new safety concerns identified. The safety profile of Enhertu in the trial was also generally consistent between patients with brain metastases and patients without brain metastases.
Interstitial lung disease (ILD) or pneumonitis occurred in 12.9% of patients in the cohort without brain metastases and 16.0% in the cohort of patients with brain metastases as determined by the investigator. The majority of ILD events were low grade (Grade 1 or 2). In patients without brain metastases, there were 22 Grade 1 ILD events, six Grade 2 events, zero Grade 3 and 4 events, and three (1.2%) Grade 5 events. In patients with brain metastases, there were 26 Grade 1 ILD events, eight Grade 2 events, one Grade 3 event, one Grade 4 event and six (2.3%) Grade 5 events. Five ILD or pneumonitis events in the brain metastases cohort were reported by the investigator as co-occurring with opportunistic infection (one Grade 4 and four Grade 5).
DESTINY-Breast12 Trial Design
DESTINY-Breast12 is an open-label, multicentre, Phase IIIb/IV clinical trial designed to evaluate the efficacy and safety of Enhertu (5.4 mg/kg) in patients with previously treated advanced/metastatic HER2-positive breast cancer. The study includes patients without brain metastases (cohort 1) or 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. The primary endpoint of cohort 2 (brain metastases cohort) was PFS. Additional endpoints included CNS PFS, CNS ORR, ORR in the brain metastases cohort and safety. The trial enrolled 504 patients across multiple sites in Asia, Europe, North America and Oceania.
HER2-Positive Breast Cancer and Brain Metastases
Breast cancer is a leading cause of cancer-related deaths worldwide. HER2 protein overexpression is associated with aggressive disease and poor prognosis. Brain metastases occur in an estimated 10% to 15% of patients diagnosed with metastatic breast cancer, with a higher risk for those with HER2-positive disease. The median overall survival for patients with breast cancer who have developed brain metastases is eight months, highlighting the urgent need for effective therapies.
Implications for Treatment
The results from the DESTINY-Breast12 trial suggest that Enhertu could represent a valuable treatment option for patients with HER2-positive metastatic breast cancer and brain metastases. The observed CNS ORR, particularly in patients without prior local CNS therapy, is clinically meaningful and warrants further investigation in larger, randomized controlled trials.
