Trastuzumab Deruxtecan for Brain Cancer

Overseen By Shanu Modi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Heart failure, Lung disease, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 24 months

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, trastuzumab deruxtecan (also known as Enhertu or DS-8201a), to determine its effectiveness in treating brain cancers with high levels of the HER2 protein. The study aims to assess the drug's ability to reach and impact brain tumors. Participants may qualify if they have brain tumors requiring surgery and cancers involving the HER2 protein or specific gene mutations. The trial explores different scenarios: some patients will receive the drug for the first time, while others will continue treatment after previous exposure. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, there is a mention of an adequate treatment washout period, which suggests you might need to stop certain treatments before joining the study. It's best to discuss this with the trial team or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that trastuzumab deruxtecan (T-DXd) holds promise for treating patients whose HER2-positive cancer has spread to the brain. Studies indicate that most patients tolerate T-DXd well.

In one study, patients with active brain cancer spread managed T-DXd with controllable side effects. Another study found that most patients responded well, with 61.6% experiencing no cancer growth for a year. While side effects like nausea or tiredness can occur, they are usually mild and manageable, and serious side effects are less common.

Overall, evidence suggests that T-DXd is a promising treatment with a reasonable safety profile for patients with brain cancer spread. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for brain cancer?

Trastuzumab Deruxtecan is unique because it targets Her2-expressing tumors and ERBB2 mutations, which are often found in various types of cancer, including those with brain metastases. Most treatments for brain cancer focus on chemotherapy or radiation, but Trastuzumab Deruxtecan combines an antibody with a chemotherapy agent to deliver targeted therapy directly to cancer cells, sparing more healthy cells in the process. This targeted approach not only aims to be more effective but also potentially reduces side effects, which is why researchers are excited about its potential to improve outcomes for patients with challenging conditions like brain metastases and recurrent glioblastoma.

What evidence suggests that trastuzumab deruxtecan might be an effective treatment for brain cancer?

Research has shown that trastuzumab deruxtecan (T-DXd) holds promise for treating brain cancers with the HER2 protein. Studies have found that it works effectively and has lasting effects in patients with brain metastases from HER2-positive cancers. Specifically, one study revealed that 61.6% of patients with active or stable brain metastases did not experience cancer progression for at least a year. This trial will evaluate T-DXd in different cohorts: Cohort A includes participants with no prior T-DXd exposure, Cohort B includes those with prior T-DXd exposure and documented CNS progression, and Cohort C includes participants with recurrent glioblastoma. Overall, the drug offers hope for people with these specific types of brain cancer. ^{1 2 4 6 7}

Who Is on the Research Team?

Nelson Moss, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with brain cancer that expresses the HER2 protein, who have a life expectancy of more than 12 weeks and are scheduled for neurosurgical resection/biopsy. Participants must be over 18, not pregnant or breastfeeding, and have recovered from previous treatments. They should not have had a heart attack recently or suffer from significant illnesses that could interfere with the study.

Inclusion Criteria

Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential

My diagnosis is glioblastoma confirmed by a biopsy.

I can care for myself but may need occasional help.

Exclusion Criteria

I have had symptoms of heart failure.

You have had an allergic reaction to T-DXd in the past, or it is not safe for you to take T-DXd.

I have had a lung removed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trastuzumab deruxtecan (T-DXd) to assess tumor penetration and efficacy

Up to 24 months

Surgery

Participants undergo neurosurgical resection/biopsy to evaluate T-DXd penetration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Trastuzumab Deruxtecan

Trial Overview

The trial is testing Trastuzumab deruxtecan (T-DXd) to see how well it penetrates brain tumors and if it's effective against certain types of brain cancers related to the HER2 protein. It will involve patients receiving T-DXd injections before their planned surgeries.

How Is the Trial Designed?

Group I: Cohort C Experimental Treatment 1 Intervention

Participants with recurrent glioblastoma requiring neurosurgical resection/biopsy

Group II: Cohort B Experimental Treatment 1 Intervention

Participants with Her2-expressing or solid tumors with activating ERBB2 mutations with 1 or more CNS metastases requiring neurosurgical resection/biopsy with no prior T-DXd and prior T-DXd exposure and with documented radiological CNS progression while on T-DXd, requiring neurosurgical resection/biopsy of 1 or more recurrent metastases, with continuation of T-DXd until prior to surgery

Group III: Cohort A Experimental Treatment 1 Intervention

Participants with Her2-expressing or solid tumors with activating ERBB2 mutations with 1 or more CNS metastases requiring neurosurgical resection/biopsy with no prior T-DXd

Trastuzumab Deruxtecan is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

Approved in United States as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma
• HER2-low breast cancer

Approved in Japan as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

Trastuzumab deruxtecan (ENHERTU®) is an innovative treatment that combines an antibody targeting HER2 with a DNA topoisomerase I inhibitor, specifically designed for HER2-expressing solid tumors, including various types of cancer.

It received accelerated approval in the USA based on the promising results from the phase 2 DESTINY-Breast01 trial, which focused on patients with advanced HER2-positive breast cancer who had already undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. Keam, SJ.[2020]

Trastuzumab deruxtecan is an innovative HER2-targeted therapy that can effectively penetrate the blood-tumor barrier, making it a promising option for treating brain metastases.

The use of patient-derived xenograft models and early-phase trials is crucial for evaluating the effectiveness of new treatments like trastuzumab deruxtecan in targeting brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain Metastasis from HER2-Positive Breast Cancer: An Evolving Landscape. Soffietti, R., Pellerino, A.[2023]

In a phase 1 trial involving 115 patients with HER2-positive breast cancer previously treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a manageable safety profile, with 59.5% of patients achieving a confirmed objective response.

Despite some serious treatment-emergent adverse events, including cases of interstitial lung disease and pneumonitis, the preliminary efficacy results suggest that trastuzumab deruxtecan is a promising treatment option, warranting further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Tamura, K., Tsurutani, J., Takahashi, S., et al.[2020]

Trastuzumab deruxtecan (Enhertu®) has been shown to significantly improve progression-free survival in adults with unresectable or metastatic HER2-positive breast cancer compared to the previous standard treatment, trastuzumab emtansine, in a pivotal phase 3 trial.

The treatment has a generally manageable safety profile, although it is associated with common adverse events like hematological and gastrointestinal disorders, and requires careful monitoring for interstitial lung disease (ILD)/pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. Nie, T., Blair, HA.[2023]

Trastuzumab deruxtecan (T-DXd) has shown promising efficacy in treating HER2+ breast cancer brain metastases, achieving a complete response in a patient with brain-only metastatic disease despite prior heavy treatment.

This case highlights T-DXd's potential to penetrate the blood-brain tumor barrier effectively, warranting further investigation into its use for CNS involvement in HER2+ breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multifocal and pathologically-confirmed brain metastasis complete response to trastuzumab deruxtecan. Moss, NS., Tosi, U., Santomasso, BD., et al.[2022]

Trastuzumab deruxtecan (Enhertu®) has been shown to be significantly more effective than standard chemotherapy in improving overall survival and achieving objective responses in adults with advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma, based on results from the phase II DESTINY-Gastric01 trial.

The treatment is generally well-tolerated, with common side effects including nausea and fatigue, but it does carry important safety warnings for interstitial lung disease and embryo-foetal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Gastric or Gastro-Oesophageal Junction Adenocarcinoma. Kang, C.[2023]

In a phase 2 study involving 184 patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a significant response rate of 60.9%, with a median response duration of 14.8 months.

While trastuzumab deruxtecan showed promising efficacy, it was associated with notable adverse effects, including interstitial lung disease in 13.6% of patients, highlighting the need for careful monitoring of pulmonary symptoms during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi, S., Saura, C., Yamashita, T., et al.[2021]

In the TUXEDO-1 trial involving 15 patients with HER2-positive breast cancer and brain metastases, trastuzumab deruxtecan achieved a high overall intracranial response rate of 73.3%, indicating its efficacy in treating this challenging condition.

The treatment was well-tolerated, with no new safety concerns reported, and patients maintained their quality of life and cognitive functioning throughout the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. Bartsch, R., Berghoff, AS., Furtner, J., et al.[2022]

In a phase 1 trial involving 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer, trastuzumab deruxtecan demonstrated a manageable safety profile, with the most common serious side effects being anemia and decreases in blood cell counts, but no drug-related deaths were reported.

The treatment showed promising preliminary activity, with 43.2% of patients achieving a confirmed objective response, indicating its potential effectiveness in patients who had previously been treated with trastuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Shitara, K., Iwata, H., Takahashi, S., et al.[2020]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12281696/

Trastuzumab deruxtecan in patients with active brain ...

Real life outcome analysis of breast cancer brain metastases treated with trastuzumab Deruxtecan. NPJ Precis Oncol. 2025;9(1):22. [DOI] [PMC ...

2.

nature.com

nature.com/articles/s41591-024-03261-7

Trastuzumab deruxtecan in HER2-positive advanced ...

These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 + mBC.

3.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40691796/

Trastuzumab deruxtecan in patients with active brain ...

In this real-world population, T-DXd yielded encouraging intracranial activity in HER2-positive/low MBC patients with active BMs with ...

4.

astrazeneca.com

astrazeneca.com/media-centre/press-releases/2024/enhertu-showed-substantial-clinical-activity-in-patients-with-her2-positive-metastatic-breast-cancer-and-brain-metastases.html

Enhertu showed substantial clinical activity in patients with ...

Enhertu achieved a 61.6% progression-free survival rate at one year in patients with active or stable brain metastases in DESTINY-Breast12.

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06058988

NCT06058988 | Trastuzumab Deruxtecan (T-DXd) for ...

The purpose of this study is to find out how much tratuzumab deruxtecan (T-DXd) can penetrate the tumor when injected into the body, and whether T-DXd may ...

6.

sciencedirect.com

sciencedirect.com/science/article/pii/S2666776225002479

Real-world efficacy and safety of trastuzumab deruxtecan ...

Although the absolute outcomes achieved with T-DXd in real-world settings were less favorable than those reported in clinical trials, T-DXd demonstrated ...

7.

esmoopen.com

esmoopen.com/article/S2059-7029(24)00975-X/fulltext

185P Safety, tolerability, and antitumor activity of ...

Safety, tolerability, and antitumor activity of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ metastatic breast cancer (mBC) and active brain ...