T-DXd Sustained Substantial, Durable Clinical Activity in Patients With HER2+ Metastatic Breast Cancer

According to research presented at the European Society for Medical Oncology Congress 2024 in Barcelona, Spain, by Nancy Lin, MD, trastuzumab deruxtecan (T-DXd) was found to be safe in treating patients with HER2–positive (HER2+) metastatic breast cancer (mBC). This included numerous patients who had stable or active brain metastases (BM).

“Approximately half of patients with HER2+ [mBC] will develop brain metastases,” explained Lin, who is the associate chief of the Division of Breast Oncology at Dana-Farber Cancer Institute in Boston, as she presented the preliminary abstract. “The median PFS [progression-free survival] with patients with brain metastases in the HER2 CLIMB clinical trial was less than 8 months.”

T-DXd has been used to treat patients with metastatic or unresectable HER2+ breast cancer if they had already received anti-HER2–based therapies. The DESTINY-Breast12 phase 3b/4 study is the largest prospective study of this population known to the researchers. This study aimed to assess the PFS and overall response rate (ORR) of patients with either stable or active BM who received T-DXd after being treated with 1 or more prior anti-HER2–based regimens.

T-DXd proved effective in patients with HER2+ metastatic breast cancer with or without brain metastases | Image credit: Pixel-Shot - stock.adobe.com

The BM cohort and non-BM cohort were made up of adults with HER2+ mBC and progression in 2 or less prior lines of therapy (LOT). Patients in the BM cohort were further split into stable or active groups based on whether their BM was untreated or treated progressing. All patients received T-DXd every 3 weeks through an intravenous delivery, with a dose totaling 5.4 mg/kg. PFS and ORR were the primary end points of the study but end points also included central nervous system (CNS) PFS, CNS ORR, and ORR in the BM cohort with safety.

Patients were included if they were 18 years and older, did not receive more than 2 prior therapy regimens in a metastatic setting, had disease progression on at least 1 anti-HER2–based regimen, and had a score of 1 or 2 on the Eastern Cooperative Oncology Group performance status.

There were 504 patients treated, of whom 263 were in the BM cohort and 241 were in the non-BM cohort. A total of 157 patients had stable BM and 106 had active BM, of whom 39 had previously untreated disease. The median (range) prior LOT was 1 (0-4) in both cohorts and the median follow-up time was 15.4 (0.1-30.0) months in the BM cohort and 16.1 (0.8-28.4) months in the non-BM cohort.

The PFS over a 12-month period was 61.6% (95% CI, 54.9%-67.6%) in the BM cohort; the CNS PFS over 12 months was 58.9% (95% CI, 51.9%-65.3%) in the same cohort. Stable (57.8%; 95% CI, 48.2%-66.1%) and active (60.1%; 95% CI, 49.2%-69.4%) BM groups had similar rates of CNS PFS. The CNS ORR was found to be 79.2% (95% CI, 70.2%-88.3%) in stable BM and the active BM cohort had a CNS ORR of 62.3% (95% CI, 50.1%-74.5%).

A total of 16.0% of the BM cohort and 12.9% of the non-BM cohort reported interstitial lung disease/pneumonitis, of which 5 events co-occurred with opportunistic infection, affecting 1.9% of the BM cohort.

The overall survival, said Lin, was high, with patients with BM having a 12-month overall survival of 90.3% and patients without brain metastases having a survival of 90.6%. The median overall survival was not reached.

“In terms of safety, grades 3 or higher adverse events occurred in approximately half of patients in both cohorts,” said Lin. “However, treatment discontinuation due to toxicity was uncommon, occurring in 15% of patients without brain metastasis and 9.5% of patients without brain metastases.”

The most common adverse event that led to discontinuation was interstitial lung disease, which was recorded in 16.0% of patients with baseline BM. Lin noted that there were a total of 11 treatment-related deaths during the study and that only 1 case of radiation necrosis was recorded, though she speculated on whether there was incomplete recording on that adverse event.

There were limitations to the study. The study was a single-arm, open-label study and excluded patients with leptomeningeal metastases. Conclusions on the efficacy of the treatment were based on single-arm time-to-event efficacy analyses. Cross-trial comparisons are difficult as the final data set is immature and there are no long-term follow-up data. Patients with no measurable disease at baseline were included in the ORR analysis in the non-BM cohort. Intracranial radiotherapy had been used previously in some of the patients with stable or active BM, which could have affected the results. Brain imaging was not performed in patients without baseline BM, and thus only symptomatic CNS metastases could be evaluated. Patients of Black and Asian ethnicities were underrepresented.

The researchers concluded that T-DXd was found to provoke substantial and durable overall and intracranial clinical activity in patients with HER2+ mBC. There were also no new safety signals presented during the course of the study. The new data indicate that T-DXd can be used in patients with HER2+ mBC who were previously treated, including in patients with active and stable BM.

“Overall, we believe that results from DESTINY-Breast12 support the use of T-DXd for patients with HER2+ [mBC], irrespective of the presence or absence of stable or active brain metastases,” Lin concluded.

References

1. Harbeck N, Ciruelos E, Jerusalem G, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) with or without brain metastases (BM)- DESTINYBreast-12 primary results. Presented at: European Society for Medical Oncology Congress 2024; September 13-17, 2024; Barcelona, Spain. Abstract LBA18
2. Harbeck N, Ciruelos E, Jersualem G, et al. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med. Published online September 13, 2024. doi:10.1038/s41591-024-03261-7