Trastuzumab Deruxtecan Demonstrates Real-World Intracranial Efficacy in Metastatic HER2+ Breast Cancer


Data from a real-world study in Japan showed that fam-trastuzumab deruxtecan-nxki displayed intracranial efficacy in patients with HER2-positive breast cancer harboring brain metastases and/or leptomeningeal carcinomatosis.

Image Credit: ©SciPro -

Image Credit: ©SciPro -

Data from a real-world study (UMIN000044995) in Japan showed that fam-trastuzumab deruxtecan-nxki (Enhertu) displayed intracranial efficacy in patients with HER2-positive breast cancer harboring brain metastases and/or leptomeningeal carcinomatosis.1

Findings published in NPJ Breast Cancer showed that patients included in the intracranial evaluation by independent central review (n = 51) achieved an intracranial overall response rate (IC-ORR) of 62.7% (95% CI, 48.1%-75.9%). All responders experienced an intracranial partial response; the rates of intracranial stable disease and intracranial progressive disease were 31.4% and 5.9%, respectively. The intracranial clinical benefit rate (IC-CBR) at 6 months was 70.6% (95% CI, 56.2%-82.5%).

“Although the proportion of patients with brain metastases was small, the IC-ORR was 62.7% in patients with measurable brain metastases. The IC-CBR was 70.6% in the present study, suggesting that clinical benefit could be obtained in most patients,” lead study author Naoki Niikura, MD, PhD, and colleagues wrote. Niikura is a member of the Department of Breast Oncology at Tokai University School of Medicine in Kanagawa, Japan.

To conduct the retrospective study, investigators surveyed 344 sites in Japan and received responses from 220. The study included 113 patients from 62 sites, and 104 who met the inclusion criteria were included in the total analysis population.

Patients were required to be at least 20 years of age at the initiation of treatment with trastuzumab deruxtecan. They needed to have pathologically documented HER2-positive breast cancer with brain metastases, comprising stable brain metastases after local treatment, brain metastases before local treatment, and symptomatic brain metastases. Patients who elected to not participate in the study and those who received trastuzumab deruxtecan during a clinical trial were excluded.

In the total population, investigators evaluated time to treatment failure (TTF), progression-free survival (PFS), ORR, overall survival (OS), and time to deterioration of central nervous system (CNS) metastases–related symptoms. Patients with available brain imaging were also evaluated for IC-ORR, IC-PFS, IC-duration of response (IC-DOR), and IC-CBR.

Among the total population (n = 104), 99.0% of patients were female, and the majority of patients were less than 65 years of age (72.1%). Patients had a HER2 status of immunohistochemistry (IHC) 3+ (80.8%) or IHC 2+ (17.3%), and no patients were IHC 0 or 1+. HER2 status by in situ hybridization (ISH) was unknown for 71.2% of patients, and 27.9% were ISH positive.

The study also included patients with estrogen receptor–positive disease (56.7%) and progesterone receptor–positive disease (41.3%). Additionally, 68.3% of patients underwent surgery for primary breast cancer.

In the metastatic setting, 76.0% of patients received 3 or more prior lines of therapy, and the median prior lines of therapy was 4 (interquartile range, 3-7). Prior treatments for metastatic breast cancer included trastuzumab (Herceptin; 90.4%), pertuzumab (Perjeta; 84.6%), ado-trastuzumab emtansine (Kadcyla; 87.5%), and lapatinib (Tykerb; 35.6%). The time from initial CNS diagnosis to the start of trastuzumab deruxtecan was 22.6 months (standard deviation, ±22.4).

ECOG performance status ranged from 0 (26.0%) to 1 (51.9%), 2 (11.5%), 3 or 4 (3.8%), and unknown (6.7%). Seventy-six percent of patients had visceral metastasis except for the brain.

Furthermore, 69.2% of patients had asymptomatic brain metastases, and 30.8% had symptomatic brain metastases. Notably, 14.4% of patients received steroids for symptoms of brain metastases, and 10.6% of patients were given anti-epileptics. Local treatment for brain metastases was given to 95.2% of patients, including 53.8% who had whole-brain radiation, 61.5% who had stereotactic irradiation, and 26.0% who had surgery to remove a tumor.

At baseline, 86.5% of patients had active brain metastases with leptomeningeal carcinomatosis (16.3%) or without leptomeningeal carcinomatosis (70.2%), and 5.8% of patients had stable brain metastases. Notably, 1.9% of patients had leptomeningeal carcinomatosis only. The number of brain metastases ranged from 1 (17.3%), 2 to 4 (26.9%), 5 to 9 (16.3%), and 10 or more (26.0%).

Additional data showed that the total population achieved a median PFS of 16.1 months (95% CI, 12.0–not estimable [NE]), and the 6- and 12-month PFS rates were 77.0% (95% CI, 67.4%-84.1%) and 61.9% (95% CI, 50.8%-71.1%), respectively. The median OS was not reached (95% CI, 16.1-NE), and the median TTF was 9.7 months (95% CI, 6.3-13.0).

Patients from the total population evaluable for response (n = 97) experienced an ORR of 55.7%, including a complete response rate of 5.2%.

Further data for patients in the brain imaging population showed that trastuzumab deruxtecan elicited a median IC-DOR that was NR, a 12-month IC-DOR rate of 74.0%, and a median IC-PFS of 16.1 months.

The IC-ORRs for patients with active brain metastases (n = 37), stable brain metastases (n = 5), and leptomeningeal carcinomatosis (n = 9) were 54.1% (95% CI, 36.9%-70.5%), 100% (95% CI, 47.8%-100.00%), and 77.8% (95% CI, 40.0%-97.2%), respectively. Patients with asymptomatic brain metastases (n = 32) experienced a higher IC-ORR (65.6%; 95% CI, 46.8%-81.4%) compared with patients with symptomatic brain metastases (n = 19; 57.9%; 95% CI, 33.5%-79.7%).

Patients who received steroids at baseline (n = 11) had an IC-ORR of 45.5% (95% CI, 16.7%-76.6%) vs 67.5% (95% CI, 50.9%-81.4%) for those who did not get steroids at baseline (n = 40).

Investigators noted that this retrospective study had some limitations, including that reporting bias could not be ruled out regarding the presence or absence of brain metastases. The ongoing phase 3b/4 DESTINY-Breast12 trial (NCT04739761) will prospectively evaluate the efficacy and safety of trastuzumab deruxtecan in patients with previously treated advanced/metastatic HER2-positive breast cancer with or without brain metastases whose disease has progressed on prior anti–HER2-based regimens and received no more than 2 prior lines of therapy in the metastatic setting.2


  1. Niikura N, Yamanaka T, Nomura H, et al. Treatment with trastuzumab deruxtecan in patients with HER2-positive breast cancer and brain metastases and/or leptomeningeal disease (ROSET-BM). NPJ Breast Cancer. Published online October 11, 2023. doi:10.1038/s41523-023-00584-5
  2. A study of T-DXd in participants with or without brain metastasis who have previously treated advanced or metastatic HER2 positive breast cancer (DESTINY-B12). Updated August 21, 2023. Accessed November 13, 2023.
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