September 17, 2024
By Dibash Kumar Das, PhD
At the ESMO 2024 conference, new data from the largest prospective study to date on trastuzumab deruxtecan (T-DXd) in HER2-positive metastatic breast cancer (mBC) patients, including those with brain metastases, was presented, offering renewed hope for patients who have limited treatment options (Abstract LBA18). Led by Nancy U. Lin, MD, a medical oncologist at the Dana-Farber Cancer Institute, the DESTINY-Breast12 study provided compelling evidence of T-DXd’s efficacy, both systemically and intracranially, in this challenging patient population.
DESTINY-Breast12 is a Phase IIIb/IV multicenter, open-label clinical trial evaluating the efficacy of T-DXd in patients with HER2+ mBC who had progressed on up to two prior lines of therapy. This is the largest study of its kind to focus on patients with brain metastases—a group often excluded from clinical trials despite facing significant treatment challenges.
Unlike previous smaller or retrospective studies, the DESTINY-Breast12 study enrolled 504 patients—263 had brain metastases (brain metastases cohort) and 241 did not (non-brain metastases cohort). The trial evaluated two distinct endpoints: progression-free survival (PFS) in the brain metastases cohort and objective response rate (ORR) in the non-brain metastases cohort. Patients with either stable or active brain metastases (untreated or progressing despite therapy) were included in the brain metastases cohort, provided they did not require immediate local therapy.
At the data cutoff in February 2024, the study revealed impressive outcomes. Patients in the brain metastases cohort, treated with T-DXd at a dose of 5.4 mg/kg every 3 weeks, demonstrated a 12-month PFS rate of 61.6 percent, with a median PFS of 17.3 months. This included a central nervous system (CNS) PFS rate of 58.9 percent, indicating the drug’s ability to control intracranial disease. Notably, the efficacy was consistent across both stable and active brain metastases with PFS rates of 57.8 percent and 60.1 percent, respectively.
Further underscoring T-DXd activity in the brain, patients with stable brain metastases achieved a CNS ORR of 79.2 percent, while those with active brain metastases had a CNS ORR of 62.3 percent. The data show that, even in patients with more advanced disease, T-DXd maintained significant intracranial activity, addressing a critical unmet need for this patient population.
In patients without baseline brain metastases, T-DXd’s systemic efficacy was equally encouraging with an ORR of 62.7 percent. These results are consistent with earlier studies of T-DXd, reinforcing its broad utility in treating HER2+ mBC across different patient subsets. In addition to its impact on disease progression and response rates, T-DXd showed promising overall survival (OS) outcomes. After 12 months, OS was maintained in 90.3 percent of patients in the BM cohort and 90.6 percent of patients in the non-BM cohort. These results suggest that T-DXd offers durable survival benefits, even for patients with brain metastases.
Regarding safety, the study confirmed the known adverse event profile of T-DXd with no new safety signals emerging. Interstitial lung disease (ILD) and pneumonitis remained concerns, occurring in 16.0 percent of patients in the brain metastases cohort and 12.9 percent in the non-brain metastases cohort. Five cases were complicated by opportunistic infections.
“The safety profile of T-DXd was consistent with previous reports,” Lin noted. “No new safety signals were identified. ILD/pneumonitis remains an important identified safety risk of T-DXd.”
Summarizing the trial's findings, Lin emphasized the significant and durable clinical activity of T-DXd in this diverse patient population.
“In this prospective Phase IIIb/IV study, T-DXd exhibited substantial and durable overall and intracranial clinical activity in a large patient cohort with HER2+ mBC with stable and active BMs.
She further highlighted key efficacy metrics. “Twelve-month PFS was 61.6 percent overall (stable brain metastases: 62.9%; active brain metastases: 59.6%); estimated median PFS was 17.3 months. T-DXd activity in patients without baseline brain metastases was consistent with previous reports. 12-month OS was maintained in patients with brain metastases (90.3%) and without brain metastases (90.6%).”
Reflecting on the broader applicability of these findings, Lin concluded, “Results from DESTINY-Breast12 support the use of T-DXd for patients with HER2+ mBC, irrespective of the presence of stable or active brain metastases.”
Dibash Kumar Das is a contributing writer.