Kadcyla + Neratinib for Breast Cancer

Overseen By David Cescon, MD PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must be taking: T-DM1

Must not be taking: HER2 inhibitors

Disqualifiers: Metastatic disease, Cardiovascular diseases, others

Stay on Your Current Meds You can continue your current medications while participating

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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 12 months

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding neratinib (Nerlynx) to the standard breast cancer treatment, T-DM1, can improve outcomes for patients with certain types of breast cancer. It targets patients with HER2-positive breast cancer who have undergone initial treatments but still show signs of molecular residual disease (small amounts of cancer remaining). Suitable candidates for this trial are those who have received treatment for HER2-positive breast cancer and have evidence of remaining cancer after initial therapies. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must not have taken neratinib or other HER2 tyrosine kinase inhibitors before, and there is a 14-day period without radiation therapy required before starting the trial.

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

Research shows that the combination of Kadcyla (T-DM1) and neratinib is generally well-tolerated by patients with HER2-positive breast cancer. In previous studies, patients received this combination after other treatments, and most side effects were manageable. Common side effects include diarrhea, nausea, and tiredness, which are usually mild to moderate.

Some studies have found that a few patients might experience more serious side effects, but these are less common. Earlier trials suggested that this drug combination is safe enough for further testing, which is why researchers are using it in the current study. Prospective participants should discuss with their doctor to determine if this treatment is suitable for them. ^{1 2 3 4 5}

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

Researchers are excited about the combination of Kadcyla (T-DM1) and Neratinib for breast cancer because it offers a novel approach to treatment. Unlike standard therapies that focus solely on stopping cancer cell growth, Neratinib targets specific pathways responsible for cancer cell signaling, potentially blocking the cancer's ability to grow and spread. This combination could enhance the effectiveness of existing treatments and provide a more comprehensive strategy against breast cancer, offering hope for improved outcomes for patients.

What evidence suggests that this trial's treatments could be effective for breast cancer?

Research has shown that neratinib can help treat HER2-positive breast cancer. In the ExteNET study, patients who took neratinib for a year after other treatments were less likely to experience cancer recurrence. Specifically, these patients had a 2.5% higher chance of remaining cancer-free and a 1.7% higher chance of preventing cancer spread over five years compared to those who didn’t take it. Furthermore, about 91% of patients who received neratinib were still alive after more than eight years, indicating long-term benefits. In this trial, participants will receive a combination of standard T-DM1 and neratinib, which may improve outcomes for patients with HER2-positive breast cancer. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with HER2+ stage I-III breast cancer, who've had surgery and are on T-DM1 therapy but still show signs of cancer at a molecular level. They should be in good health otherwise, able to follow the study plan, and willing to use effective birth control.

Inclusion Criteria

I am willing and able to follow the study's treatment plan and attend all visits.

I have no known allergies or adverse reactions to T-DM1 or neratinib.

I had radiation therapy but it ended at least 14 days ago.

Exclusion Criteria

My cancer has spread to other parts of my body.

I have HIV that is not being treated with medication.

I have or had hepatitis B or C, but it's not active now.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard T-DM1 adjuvant therapy with Neratinib for up to 12 months

12 months

Every 3 weeks for T-DM1 infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Neratinib

Trial Overview The trial tests if adding neratinib (a pill taken daily) to standard T-DM1 therapy can clear remaining cancer traces after initial treatment. It's given for up to a year unless there's recurrence or side effects leading to stopping the drug.

How Is the Trial Designed?

Group I: Neratinib Arm Experimental Treatment 1 Intervention

Standard T-DM1 (3.6mg/kg) IV infusion every 3 weeks administered with Neratinib (160 mg) orally once daily up to 1 year.

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

Neratinib, a pan-HER tyrosine kinase inhibitor, shows promising efficacy when combined with other targeted therapies like mTOR inhibitors and CDK4/6 inhibitors in HER2+ cancers, leading to significant increases in event-free survival in patient-derived xenograft models.

The study found that combining neratinib with palbociclib increased event-free survival in all tested models, suggesting a strong potential for this combination in treating HER2+ breast cancer and possibly other HER2+ tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer. Zhao, M., Scott, S., Evans, KW., et al.[2022]

In a study of 72 patients with advanced HER2-positive breast cancer, neratinib, either alone or combined with capecitabine, demonstrated a median progression-free survival (PFS) of 5.9 months and an overall survival (OS) of 15.0 months, indicating its efficacy in a real-world setting.

Diarrhea was the most common side effect, affecting 64% of patients, but with proper anti-diarrheal prophylaxis, the treatment was generally well-tolerated, allowing for safe administration without severe toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib in advanced HER2-positive breast cancer: experience from the royal Marsden hospital. Cunningham, N., Shepherd, S., Mohammed, K., et al.[2022]

In a phase III trial involving 621 patients with HER2-positive metastatic breast cancer, the combination of neratinib and capecitabine (N+C) showed significant improvement in progression-free survival (PFS) compared to lapatinib and capecitabine (L+C).

Higher levels of HER2 protein expression were linked to longer PFS and greater benefits from N+C treatment, while PIK3CA mutations were associated with shorter PFS, indicating that biomarker status can influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer. Saura, C., Matito, J., Oliveira, M., et al.[2023]

In a Phase I/II study involving 91 patients, the combination of neratinib (240 mg/day) and vinorelbine (25 mg/m2) demonstrated promising antitumor activity in HER2-positive metastatic breast cancer, with an objective response rate of 41% in patients who had not previously received lapatinib.

The treatment was generally well-tolerated, with diarrhea (96%) and neutropenia (54%) being the most common side effects, but no unexpected toxic effects were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. Awada, A., Dirix, L., Manso Sanchez, L., et al.[2020]

Neratinib significantly reduces the risk of invasive disease recurrence or death in women with early-stage HER2-positive breast cancer who have completed trastuzumab therapy, as shown in the ExteNET trial over 12 months, with benefits observed at both 2 and 5 years post-treatment.

Patients with hormone receptor-positive disease and those who start neratinib within 1 year of completing trastuzumab experience greater benefits, leading to its approval in the EU as an extended adjuvant therapy for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib in Early-Stage Breast Cancer: A Profile of Its Use in the EU. Dhillon, S.[2021]

Neratinib is an oral, irreversible inhibitor targeting HER1, HER2, and HER4, specifically developed for treating HER2-positive breast cancer, and is approved in the USA for patients who have previously received trastuzumab-based therapy.

The drug is currently in various stages of clinical development for other cancers, including metastatic breast cancer and solid tumors like non-small cell lung cancer and glioblastoma, indicating its potential broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib: First Global Approval. Deeks, ED.[2019]

Neratinib, a tyrosine kinase inhibitor, shows promising efficacy in treating HER2-positive breast cancer, with a higher response rate when used in combination with other therapies compared to monotherapy.

While neratinib is associated with a high incidence of adverse events, particularly diarrhea (83.9% of patients), these side effects are generally manageable, and the drug has been linked to improved survival outcomes in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy Profile of Neratinib: A Systematic Review and Meta-Analysis of 23 Prospective Clinical Trials. Tao, Z., Li, SX., Shen, K., et al.[2021]

In a phase I study involving 21 women with HER2-positive metastatic breast cancer, the combination of neratinib, trastuzumab, and paclitaxel showed significant clinical benefits, with 38% of patients achieving objective responses and 52% experiencing clinical benefit lasting at least 24 weeks.

The recommended dose of neratinib was found to be 200 mg/day, and while common side effects included diarrhea and fatigue, the implementation of prophylactic measures effectively managed severe diarrhea, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2‑positive breast cancer: an NSABP Foundation Research Program phase I study. Jankowitz, RC., Abraham, J., Tan, AR., et al.[2019]

Neratinib combined with paclitaxel showed a high overall response rate of 73% in patients with HER2-positive breast cancer, indicating its efficacy as a treatment option.

The combination therapy had manageable side effects, with common adverse events including diarrhea and peripheral sensory neuropathy, but no dose-limiting toxicities were observed during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Chow, LW., Xu, B., Gupta, S., et al.[2023]

In a Phase 1 study involving 21 Japanese patients with advanced solid tumors, neratinib was found to have a maximum-tolerated dose of 240 mg daily, with common side effects including diarrhea and fatigue.

The study showed that neratinib led to partial responses in 2 breast cancer patients and stable disease in several others, indicating its potential efficacy in treating solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study. Ito, Y., Suenaga, M., Hatake, K., et al.[2022]

Neratinib was approved by the FDA for the extended treatment of early-stage HER2-positive breast cancer, showing a significant improvement in invasive disease-free survival (iDFS) with a 2-year rate of 94.2% compared to 91.9% for placebo in a study of 2,840 women.

While neratinib is effective, it is associated with a high incidence of diarrhea (40% grade 3 or 4), which is the most common reason for treatment discontinuation, though most adverse effects are manageable and reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer. Singh, H., Walker, AJ., Amiri-Kordestani, L., et al.[2019]

Citations

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Neratinib in HER-2-positive breast cancer: results to date and ... Efficacy in 15 evaluable patients demonstrated an ORR 38% (CR 2 and PR 6) and overall clinical benefit 52% (including CR, PR and stable disease ⩾24 weeks). It ...

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Overall survival with neratinib after trastuzumab-based ... With 91% of patients in the neratinib group alive after a median follow-up of 8.1 years in ExteNET and no detrimental effect versus placebo on ...

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Cost-Effectiveness Analysis of Adjuvant Neratinib ... Based on 5-year data from ExteNET, neratinib following adjuvant trastuzumab is not projected to be cost-effective, even among those patients shown to derive the ...

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45P Long-term efficacy of neratinib in HER2-positive early ... The phase III ExteNET trial (NCT00878709) showed an absolute iDFS benefit of 2.5% and distant disease-free survival benefit of 1.7% with neratinib after 5 years ...

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Neratinib and ado-trastuzumab emtansine for pretreated ... Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

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NSABP FB-10: a phase Ib/II trial evaluating ado-trastuzumab ... We previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer ...

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Safety and Efficacy of T-DM1 Plus Neratinib in Patients With ... We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus ...

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Neratinib and ado-trastuzumab emtansine for pretreated ... Up to half of patients with HER2-positive metastatic breast cancer will experience a brain recurrence, including brain-only relapses after ...