Neratinib + Endocrine Therapy + Trastuzumab for Breast Cancer

Recruiting at3 trial locations

Overseen by Ruth O'Regan, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Ruth O'Regan

Must be taking: Aromatase inhibitors

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Metastatic disease, Active infection, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial involves treating breast cancer patients with three drugs: neratinib, an aromatase inhibitor, and trastuzumab. These drugs work together to block cancer growth signals, lower estrogen levels, and help the immune system attack cancer cells. The treatment is aimed at patients with HER2-positive breast cancer who may not respond well to standard treatments. Trastuzumab is a well-established treatment for HER2-positive breast cancer, often used in combination with other therapies.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot use moderate or strong CYP3A4 inhibitors or inducers during the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination Neratinib, Endocrine Therapy, and Trastuzumab for breast cancer?

Research shows that combining anti-HER2 therapy like trastuzumab with aromatase inhibitors such as letrozole or anastrozole improves outcomes in hormone receptor-positive and HER2-positive breast cancer. Trastuzumab is effective against aggressive HER2-positive breast cancers, and combining it with other treatments can enhance its antitumor activity. ^{1 2 3 4 5}

Is the combination of Neratinib, Endocrine Therapy, and Trastuzumab safe for breast cancer treatment?

The combination of letrozole (an endocrine therapy) and trastuzumab has been shown to be safe in patients with HER2-positive and hormone receptor-positive metastatic breast cancer, with most side effects being mild or moderate. Trastuzumab, when used in breast cancer treatment, can cause serious infusion-related reactions and heart-related issues, but these are considered against the benefits of the treatment. ^{5 6 7 8 9}

What makes the drug combination of Neratinib, Endocrine Therapy, and Trastuzumab unique for breast cancer treatment?

This drug combination is unique because it combines neratinib, an oral irreversible inhibitor targeting multiple HER receptors, with trastuzumab and endocrine therapy, offering a novel approach for patients with hormone receptor-positive and HER2-positive breast cancer, especially those who may not respond to standard trastuzumab-based treatments. ^{4 10 11 12 13}

Research Team

Ruth O'Regan, MD

Principal Investigator

University of Rochester

Eligibility Criteria

This trial is for postmenopausal women over 18 with stage I-III invasive breast cancer that's larger than 10mm, HER2-positive, and ER-positive. Candidates must have a good performance status, resectable cancer suitable for pre-op therapy, agree to biopsies, and have proper heart function. Excluded are those needing strong CYP3A4 inhibitors/inducers or with active infections, recent major surgery side effects, GI issues affecting drug absorption, metastatic disease or certain cardiovascular conditions.

Inclusion Criteria

You have invasive breast cancer that is stage I, II, or III and is larger than 10 millimeters.

You have been tested positive for HER2 according to the latest ASCO-CAP criteria.

Written informed consent and HIPAA authorization for release of personal health information

Exclusion Criteria

You cannot take certain medications that affect the way your body processes other drugs during the study.

You have a serious infection that needs treatment throughout your body.

Treatment with any investigational drug within 14 days prior to registration or within 5 half-lives of the investigational product, whichever is longer

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Participants receive either Neratinib, Letrozole or Anastrozole, or a combination of Neratinib and an aromatase inhibitor for the first 3 weeks

3 weeks

1 visit (in-person) for breast biopsy prior to Day 1 of week 4

Main Treatment

Participants receive Neratinib, Letrozole or Anastrozole, and Trastuzumab for 24 weeks prior to surgery

24 weeks

Post-Surgery Treatment

Participants receive standard of care HER2-directed and endocrine therapy at the treating physician's discretion

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Anastrozole (Aromatase Inhibitor)
• Letrozole (Aromatase Inhibitor)
• Neratinib (Tyrosine Kinase Inhibitor)
• Trastuzumab (Monoclonal Antibodies)

Trial Overview The study tests the combination of Neratinib (a targeted therapy), an aromatase inhibitor (Letrozole or Anastrozole), and Trastuzumab (an immune therapy) given for 24 weeks before surgery in treating HER2-positive breast cancer. The initial three weeks involve varying combinations of these drugs followed by standard care after surgery.

Participant Groups

Group I: A Experimental Treatment 3 Interventions

Weeks 1-3\* patients receive either (a) Neratinib, (b) Letrozole or Anastrozole or (c) Neratinib + Letrozole or Anastrozole Weeks 4-24 patients receive Neratinib + Letrozole or Anastrozole and Trastuzumab \*Starting drug intervention varies for the first 3 weeks depending on arms: a, b, and c by randomization.

Anastrozole is already approved in Canada, Japan for the following indications:

Approved in Canada as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• Treatment of postmenopausal women with hormone receptor-positive advanced breast cancer

Approved in Japan as Arimidex for:

• Breast cancer

Who Is Running the Clinical Trial?

Ruth O'Regan

Lead Sponsor

Trials

1

Recruited

30+

Puma Biotechnology, Inc.

Industry Sponsor

Trials

58

Recruited

10,100+

University of Rochester

Collaborator

Trials

883

Recruited

555,000+

Kevin Koch

University of Rochester

Chief Executive Officer since 2020

PhD in Organic Chemistry from the University of Rochester

Brian Druker

University of Rochester

Chief Medical Officer since 2015

MD from Harvard Medical School

Findings from Research

In trials, combining lapatinib with letrozole (LAP + LET) significantly improved time to progression in post-menopausal women with hormone receptor-positive and HER2-positive metastatic breast cancer compared to aromatase inhibitor monotherapy.

However, from a cost-effectiveness perspective, LAP + LET is unlikely to be cost-effective compared to standard aromatase inhibitors, with a probability of only 1.4% versus letrozole and 9.2% versus anastrozole, but it may be more cost-effective compared to trastuzumab plus anastrozole, with a 51% probability, despite some uncertainty.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of Lapatinib plus Letrozole in Post-Menopausal Women with Hormone Receptor-and HER2-Positive Metastatic Breast Cancer. Delea, TE., Hawkes, C., Amonkar, MM., et al.[2021]

Trastuzumab (Herceptin) is highly effective in treating metastatic breast cancers that overexpress the HER-2/neu receptor, showing response rates comparable to traditional chemotherapy with significantly lower toxicity.

The success of trastuzumab in advanced cases has prompted ongoing clinical trials to explore its potential benefits in early-stage HER-2/neu-overexpressing breast cancer, indicating a shift towards more targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab: targeted therapy for the management of HER-2/neu-overexpressing metastatic breast cancer. Emens, LA.[2015]

In a study of 150 breast cancer patients, those receiving sequential treatment with letrozole and tamoxifen showed a higher overall response rate and fewer adverse reactions compared to those on letrozole alone.

Both treatment methods resulted in similar survival rates, but the sequential therapy group had a significantly lower recurrence rate and better improvement in blood lipid levels, indicating a potentially better prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, Safety, and Prognosis of Sequential Therapy with Tamoxifen and Letrozole versus Letrozole Monotherapy for Breast Carcinoma. Lu, X., Qian, C.[2023]

In a phase II study involving 103 women with advanced HER2+ breast cancer, the combination of enzalutamide and trastuzumab showed a clinical benefit rate of 24% at 24 weeks, indicating some patients experienced durable disease control despite prior treatments.

The treatment was generally well tolerated, with 94% of patients experiencing side effects, primarily fatigue, but serious adverse events were relatively low, suggesting a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer. Wardley, A., Cortes, J., Provencher, L., et al.[2021]

Letrozole, a third-generation aromatase inhibitor, has been shown to be more effective than tamoxifen in delaying disease progression in hormone receptor-positive breast cancer, making it a preferred treatment option in various settings including adjuvant and neoadjuvant therapy.

Combining letrozole with other agents like lapatinib or everolimus enhances its efficacy, particularly in patients with both HR+ and HER2+ breast cancer, suggesting that dual-targeted therapies can effectively overcome treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overview of letrozole in postmenopausal women with hormone-responsive breast cancer. Barnadas, A., Estévez, LG., Lluch-Hernández, A., et al.[2018]

The eLEcTRA trial demonstrated that combining letrozole with trastuzumab significantly improves median time to progression in patients with HER2 and hormone receptor positive metastatic breast cancer (MBC), with 14.1 months for the combination therapy compared to 3.3 months for letrozole alone.

The clinical benefit rate was also higher for the combination therapy (65%) compared to letrozole alone (39%), indicating that letrozole plus trastuzumab is a safe and effective treatment option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer - results of the eLEcTRA trial. Huober, J., Fasching, PA., Barsoum, M., et al.[2018]

In a phase III trial involving postmenopausal women with HER2 and hormone receptor co-positive metastatic breast cancer, the combination of trastuzumab and anastrozole significantly improved median progression-free survival compared to anastrozole alone.

The combination therapy also showed higher overall response and clinical benefit rates without any new or unexpected adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab : in HER2 and hormone receptor co-positive metastatic breast cancer. Orman, JS., Perry, CM.[2021]

Trastuzumab significantly improves treatment outcomes for women with HER2 positive breast cancer, as shown in four large randomized trials.

The main safety concerns associated with trastuzumab are serious infusion-related reactions and cardiotoxicity, highlighting the need to weigh the benefits against these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab in the adjuvant treatment of breast cancer. Svetlovska, D., Mardiak, J., Kristova, V.[2016]

Anastrozole, a highly specific aromatase inhibitor, has emerged as a potentially better tolerated and more effective treatment for postmenopausal patients with hormone-sensitive breast cancer compared to tamoxifen, which has safety and tolerability issues.

The ongoing Arimidex, Tamoxifen, Alone or in Combination trial indicates that anastrozole is an effective and well-tolerated option for adjuvant endocrine treatment in early breast cancer, suggesting its potential role in chemoprevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of anastrozole in adjuvant therapy for postmenopausal patients. Buzdar, AU.[2019]

In a study involving 392 patients with hormone receptor-positive and HER2-positive metastatic breast cancer, trastuzumab combined with endocrine therapy showed a median progression-free survival of 19.2 months, which was noninferior to the 14.8 months observed with trastuzumab plus chemotherapy.

The combination of trastuzumab and endocrine therapy resulted in significantly lower toxicity compared to the chemotherapy group, suggesting it may be a safer first-line treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Hua, X., Bi, XW., Zhao, JL., et al.[2023]

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]

In a phase III trial, lapatinib combined with letrozole significantly improved progression-free survival (PFS) in postmenopausal women with HER2-negative, low estrogen receptor (ER) expression metastatic breast cancer, showing a median PFS of 13.6 months compared to 6.7 months with letrozole alone.

No benefit from lapatinib was observed in patients with higher ER expression, indicating that low ER levels may be a key factor in determining which patients benefit from this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative ER and PgR assessment as predictors of benefit from lapatinib in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Finn, RS., Press, MF., Dering, J., et al.[2018]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of Lapatinib plus Letrozole in Post-Menopausal Women with Hormone Receptor-and HER2-Positive Metastatic Breast Cancer. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Trastuzumab: targeted therapy for the management of HER-2/neu-overexpressing metastatic breast cancer. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Efficacy, Safety, and Prognosis of Sequential Therapy with Tamoxifen and Letrozole versus Letrozole Monotherapy for Breast Carcinoma. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

An overview of letrozole in postmenopausal women with hormone-responsive breast cancer. [2018]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer - results of the eLEcTRA trial. [2018]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Trastuzumab : in HER2 and hormone receptor co-positive metastatic breast cancer. [2021]

8. Slovakia pubmed.ncbi.nlm.nih.gov

Trastuzumab in the adjuvant treatment of breast cancer. [2016]

9. United States pubmed.ncbi.nlm.nih.gov

Role of anastrozole in adjuvant therapy for postmenopausal patients. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). [2023]

11. England pubmed.ncbi.nlm.nih.gov

The role of neratinib in HER2-driven breast cancer. [2020]

12. New Zealand pubmed.ncbi.nlm.nih.gov

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

13. United States pubmed.ncbi.nlm.nih.gov

Quantitative ER and PgR assessment as predictors of benefit from lapatinib in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. [2018]