Tucatinib + Trastuzumab Emtansine for Brain Metastases

Overseen By Ecaterina E Dumbrava

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, CYP3A4 inducers

Disqualifiers: Seizures, Cardiopulmonary disease, 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

Compensation: Varies

Number of Visits: 1

Duration: 21 days per cycle

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if the drugs tucatinib and trastuzumab emtansine (T-DM1) can control tumors that have spread to the brain. Participants will take tucatinib tablets twice daily and receive T-DM1 intravenously every three weeks. The trial seeks individuals with HER2-positive tumors that have spread to the brain, whether untreated or previously treated brain metastases that have grown. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use strong CYP3A4 or CYP2C8 inducers or inhibitors during the study and for 2 weeks after stopping the study treatment.

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

Research has shown that the combination of tucatinib and trastuzumab emtansine (T-DM1) is generally well-tolerated by patients. Studies have found that this combination causes side effects considered acceptable. Most participants experienced mild to moderate issues, such as fatigue, nausea, and diarrhea. Importantly, this treatment has been tested in individuals who have already undergone multiple cancer therapies, making these results quite encouraging. Although some negative effects occurred, the treatment's safety appears manageable for most patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of tucatinib and trastuzumab emtansine (T-DM1) for treating brain metastases because it offers a novel approach by combining two powerful mechanisms. Tucatinib is a targeted therapy that specifically inhibits the HER2 protein, which plays a key role in the growth of some cancer cells, especially in HER2-positive cancers. T-DM1 combines trastuzumab, an antibody that targets HER2, with a chemotherapy drug, delivering a potent punch directly to cancer cells while sparing more healthy tissue. This dual-action strategy could potentially enhance treatment effectiveness and reduce side effects compared to traditional therapies, which often rely on broader, less targeted approaches.

What evidence suggests that tucatinib and trastuzumab emtansine could be effective for brain metastases?

Research shows that using tucatinib with trastuzumab emtansine (T-DM1), the combination studied in this trial, looks promising for treating advanced or spreading HER2-positive breast cancer. Studies found that this combination reduced the risk of cancer progression or death by 24%. For patients with cancer that has spread to the brain, early results are encouraging. Previous patients tolerated the combination well and showed early signs of tumor shrinkage. These findings suggest that tucatinib and T-DM1 together might effectively control tumors that have spread to the brain. ^{1 2 3 4 6}

Who Is on the Research Team?

Ecaterina E Dumbrava

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults (18+) with HER2-positive metastatic solid tumors that have spread to the brain. Participants must be willing to use birth control and undergo biopsies, have a life expectancy of at least 3 months, and their body should be functioning well enough to handle the trial. People can't join if they're pregnant, breastfeeding, or planning pregnancy; are on high-dose steroids; have uncontrolled seizures due to brain metastases; or have had recent cancer treatments.

Inclusion Criteria

Patients with specific characteristics on screening brain MRI including untreated or previously treated brain metastases not requiring immediate local CNS therapy, measurable untreated brain lesion, and evaluable extracranial disease

I am 18 or older with a certain level of physical health and expected lifespan.

My blood and organ tests are within normal ranges.

Exclusion Criteria

I have a chronic liver disease or a known viral infection.

Eligibility for a specific concurrent study

Other factors impacting patient safety or compliance

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tucatinib tablets twice daily and T-DM1 intravenously on Day 1 of each 21-day cycle

21 days per cycle

1 visit (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Trastuzumab emtansine
• Tucatinib

Trial Overview The study is testing tucatinib combined with ado-trastuzumab emtansine (T-DM1) in patients whose solid tumors have spread to the brain. The goal is to see if these drugs can help manage the disease.

How Is the Trial Designed?

Group I: Tucatinib and Adotrastuzumab Emtansine (T-DM1) Experimental Treatment 2 Interventions

Each study cycle is 21 days (3 weeks) Participants will take tablets of tucatinib two (2) times a day, about 8-12 hours apart. Participants will receive T-DM1 by vein over about 30 minutes on Day 1 of each cycle

Trastuzumab emtansine is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as Kadcyla for:

• HER2-positive metastatic breast cancer
• HER2-positive early breast cancer with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment

Approved in European Union as Kadcyla for:

• HER2-positive metastatic breast cancer
• HER2-positive early breast cancer with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment

Approved in United Kingdom as Kadcyla for:

• HER2-positive metastatic breast cancer
• HER2-positive early breast cancer with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Seagen Inc.

Industry Sponsor

Trials

212

Recruited

73,800+

Founded

1997

Headquarters

Bothell, USA

Known For

Antibody-Drug Conjugates

Top Products

Adcetris (brentuximab vedotin), Tukysa (tucatinib), Padcev (enfortumab vedotin-ejfv), Tivdak (tisotumab vedotin-tftv)

Dr. Roger Dansey

Seagen Inc.

Chief Medical Officer since 2018

MD from University of Witwatersrand

David R. Epstein

Seagen Inc.

Chief Executive Officer since 2022

BSc in Pharmacy from Rutgers University, MBA from Columbia University

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

Trastuzumab emtansine (Kadcyla®) is effective in reducing the risk of invasive disease recurrence or death by 50% compared to trastuzumab in patients with HER2-positive early breast cancer after neoadjuvant treatment, as shown in the KATHERINE trial.

The safety profile of trastuzumab emtansine is consistent with previous findings, with more adverse events reported compared to trastuzumab, leading to its recommendation as a preferred treatment option in updated guidelines for high-risk breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Emtansine: A Review of Its Adjuvant Use in Residual Invasive HER2-Positive Early Breast Cancer. Lyseng-Williamson, KA.[2022]

Ado-trastuzumab emtansine (T-DM1) was approved in the U.S. for treating HER2 positive metastatic breast cancer based on the EMILIA phase III trial, which showed it was more effective than the standard treatment of lapatinib plus capecitabine.

Ongoing and planned trials are exploring T-DM1's use in various stages of breast cancer, and the review discusses its toxicity management and potential resistance mechanisms, highlighting its importance in current cancer treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ado-trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: latest evidence and clinical potential. Peddi, PF., Hurvitz, SA.[2022]

In the phase III EMILIA study involving 991 patients with HER2-positive advanced breast cancer, trastuzumab emtansine (T-DM1) significantly improved overall survival in patients with pre-existing CNS metastases compared to capecitabine-lapatinib (XL), with a median survival of 26.8 months versus 12.9 months.

The incidence of CNS progression was higher in patients with baseline CNS metastases, but the rate of CNS progression was similar between T-DM1 and XL in patients without CNS metastases, indicating that T-DM1 is effective for those with existing CNS involvement without introducing new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Krop, IE., Lin, NU., Blackwell, K., et al.[2023]

Tucatinib, when combined with T-DM1, was found to have a maximum tolerated dosage of 300 mg twice daily, showing acceptable toxicity levels in a phase 1b trial involving 57 patients with ERBB2/HER2-positive metastatic breast cancer.

The treatment demonstrated preliminary antitumor activity, with most adverse events being mild (grade 1 or 2), although some patients experienced more serious reactions like thrombocytopenia and hepatic transaminitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial. Borges, VF., Ferrario, C., Aucoin, N., et al.[2019]

In a study of 398 patients with HER2-positive breast cancer and brain metastases, trastuzumab emtansine (T-DM1) demonstrated a best overall response rate of 21.4% and a clinical benefit rate of 42.9%, indicating its potential effectiveness in this challenging population.

The median progression-free survival was 5.5 months and overall survival was 18.9 months, with T-DM1 showing a tolerable safety profile, although nervous system adverse events were more common in patients with brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial☆. Montemurro, F., Delaloge, S., Barrios, CH., et al.[2021]

Trastuzumab emtansine (T-DM1) has shown a favorable safety profile in 884 patients with HER2-positive metastatic breast cancer, with most adverse events being manageable and asymptomatic, such as fatigue and nausea.

The treatment demonstrated superior efficacy compared to standard therapies in previous studies, making T-DM1 a promising option for further exploration in other breast cancer settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis. Diéras, V., Harbeck, N., Budd, GT., et al.[2019]

In murine models of HER2-positive breast cancer brain metastases, the antibody-drug conjugate T-DM1 significantly delayed tumor growth and improved survival compared to trastuzumab, with median survival increasing from 28 days to 112 days.

T-DM1 was found to induce greater cancer cell apoptosis, suggesting that its cytotoxic component effectively overcomes resistance to trastuzumab in brain lesions, making it a promising candidate for clinical trials in patients with CNS metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment. Askoxylakis, V., Ferraro, GB., Kodack, DP., et al.[2022]

In a study of 214 patients with HER2-positive breast cancer brain metastases, trastuzumab emtansine (T-DM1) significantly improved overall survival compared to lapatinib plus capecitabine, with median survival times of 17.7 months versus 9.6 months, respectively.

T-DM1 also demonstrated better outcomes in terms of time to next treatment and real-world progression-free survival, indicating its superior effectiveness in managing this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine vs lapatinib and capecitabine in HER2-positive metastatic breast cancer brain metastases: A real-world study. Sanglier, T., Shim, J., Lamarre, N., et al.[2023]

Citations

1. aacr.org aacr.org/about-the-aacr/newsroom/news-releases/tucatinib-plus-trastuzumab-emtansine-may-benefit-patients-with-advanced-or-metastatic-her2-positive-breast-cancer/

Tucatinib Plus Trastuzumab Emtansine May Benefit ... Tucatinib Plus Trastuzumab Emtansine May Benefit Patients With Advanced or Metastatic HER2-positive Breast Cancer.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05673928?term=AREA%5BBasicSearch%5D(ONT-380)&rank=7

A Phase II Study of Tucatinib and Ado-trastuzumab Emtansine (T ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

3. lbbc.org lbbc.org/news/tucatinib-plus-t-dm1-effective-against-her2-positive-breast-cancer

Tucatinib plus T-DM1 effective against HER2-positive ... People taking tucatinib had a 24% lower risk of cancer progression or death. The data for people with brain metastases show a positive trend in favor of ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29955792/

Tucatinib Combined With Ado-Trastuzumab Emtansine in ... In this study, tucatinib in combination with T-DM1 appeared to have acceptable toxicity and to show preliminary antitumor activity among heavily pretreated ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1914609

Tucatinib, Trastuzumab, and Capecitabine for HER2 ... Adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo.

6. aacrjournals.org aacrjournals.org/cancerres/article/84/9_Supplement/GS01-10/743442/Abstract-GS01-10-HER2CLIMB-02-Randomized-Double

Abstract GS01-10: HER2CLIMB-02: Randomized, Double ... HER2CLIMB-02 demonstrated that the addition of tucatinib to T-DM1 significantly improved median PFS in patients with previously treated HER2+ LA/MBC.