Trastuzumab deruxtecan (T-DXd), sold as Enhertu, has shown promising results in patients with HER2-positive metastatic breast cancer, particularly those with brain metastases. Data from the phase 3b/4 DESTINY-Breast12 trial indicates substantial and durable overall and intracranial clinical activity in this patient population. The findings, presented at the European Society for Medical Oncology (ESMO) Congress and published in Nature Medicine, suggest that T-DXd could be a valuable treatment option for HER2-positive metastatic breast cancer, irrespective of the presence of stable or active brain metastases.
DESTINY-Breast12 Trial Details
The DESTINY-Breast12 trial (NCT04739761) enrolled patients with HER2-positive advanced or metastatic breast cancer, with or without brain metastases at baseline. The study included 263 patients with baseline brain metastases and 241 patients without. Patients had received up to two prior lines of therapy in the metastatic setting. The primary endpoint for patients with brain metastases was progression-free survival (PFS), while for those without brain metastases, it was overall response rate (ORR).
Significant Progression-Free Survival
The estimated overall median progression-free survival (PFS) was 17.3 months in patients who received T-DXd. The 12-month PFS rate was 61.6% overall, 62.9% in those with stable brain metastases, and 59.6% in those with active brain metastases. The 12-month central nervous system (CNS) PFS overall was 58.9%, with consistent rates in both stable and active brain metastases subgroups (57.8% and 60.1%, respectively).
Overall Response Rates
The overall response rate (ORR) among patients with baseline brain metastases was 51.7%. ORRs were 49.7% and 54.7% among those with stable and active brain metastases, respectively. When restricted to patients with measurable disease at baseline (n=198), the ORR was 64.1%. The CNS ORR was 71.7% among 138 patients with measurable CNS disease at baseline (79% among patients with stable brain metastases, and 62.3% in those with active brain metastases).
In patients with no baseline brain metastases, the ORR was 62.7% in the overall population of 241 patients, and 68.4% among 215 patients who had measurable disease at baseline.
Overall Survival
Overall survival (OS) was high, with 12-month OS rates of 90.3% in the group with baseline brain metastases and 90.6% in the group without.
Safety Profile
The safety profile of T-DXd was consistent with previous reports, with no new safety signals identified. However, interstitial lung disease (ILD)/pneumonitis remains an important identified safety risk, particularly in patients with brain metastases on concomitant steroids. Careful attention to pneumocystis pneumonia prophylaxis and work-up for opportunistic infection is warranted.
Nancy Lin, MD, of the Dana-Farber Cancer Institute, noted that there were six cases of grade 5 ILD among patients with brain metastases, five of whom were on concomitant steroids and not on PCP prophylaxis, and four cases of ILD co-occurring with opportunistic infection.
Clinical Implications
These results support the use of T-DXd for HER2-positive metastatic breast cancer, irrespective of the presence or absence of stable or active brain metastases. Cristina Saura Manich, MD, PhD, of the Vall d'Hebron University Hospital in Barcelona, noted that prior to this, the preferred treatment option for patients in second line with active brain metastases was the tucatinib, trastuzumab, and capecitabine combination. She stated that T-DXd should now be the preferred option for second-line treatment, regardless of brain metastases status.
About half of patients with HER2-positive metastatic breast cancer will develop brain metastases, highlighting the importance of effective treatments that can cross the blood-brain barrier. The DESTINY-Breast12 trial provides additional prospective data, particularly in patients with active brain metastases, supporting the use of T-DXd in this challenging population.
