Neu Direction: Testing the Efficacy of Adding HER Inhibition to Standard of Care in Metastatic MLH1-low Endocrine-resistant ER+/HER2- Breast Cancer

Official title

Neu Direction: A Single Center Phase II Randomized Clinical Trial to Assess the Efficacy of Adding HER Inhibition to Standard of Care in Patients With Metastatic MLH1-low Endocrine-resistant ER+/HER2- Breast Cancer

Overview

The goal of this clinical trial is to learn if neratinib, an FDA-approved oral pan-HER2/3/4 inhibitor, improves disease control for participants with metastatic endocrine-resistant ER+/HER2-negative breast cancer. Neratinib is already approved for the treatment of HER2-postive breast cancers. The study will also learn about the safety of adding this drug to standard of care treatments. The main questions it aims to answer are: 1. Does adding neratinib to standard of care systemic therapy improve disease control for patients with metastatic hormone-driven breast cancer that is resistant to endocrine therapy? 2. What side effects do participants have when adding neratinib to standard of care therapy? Researchers will compare standard of care endocrine therapy regimens with and without neratinib to see if neratinib improves control of treatment-resistant metastatic breast cancer that has continued to progress while eon first line endocrine therapy. Participants will: 1. Take standard of care endocrine therapy for metastatic endocrine-resistant breast cancer as determined by their medical oncologist or standard of care therapy with neratinib daily 2. Visit the clinic every 3 months for checkups, tests and imaging studies

Detailed description

This is a prospective 2-arm Phase II study testing the efficacy of adding neratinib to standard of care therapy in patients with MLH1-low ER+/HER2- endocrine-resistant breast cancer . Patients with endocrine-resistant ER+/HER2- breast cancer who have lesions visible on CT scan will be recruited as they are seen in breast medical oncology and radiation oncology clinics at UC San Diego Health. Patients will be eligible if they have measurable persistent, recurrent, progressive or metastatic disease on imaging (including FDG PET scan) while on endocrine therapy. At least one lesion must be biopsied and confirmed ER+ by immunohistochemistry and HER2- within 6 months of study screening. Genomic mutation profile will be analyzed along with trial results to identify other potential mutations associated with MLH1 expression and/or neratinib response. Participants will be stratified by nuclear MLH1 expression on their biopsy tissue using immunohistochemistry. MLH1negative (nuclear MLH1 detectable in \<5% of tumor cells) and MLH1-low patients (\<50% tumor cells positive) hereafter grouped as "MLH1-low" will be randomized to standard of care without (75 participants) or with (75 participants) the addition of neratinib in Arm 1 and Arm 2 respectively . Standard of care therapy can include any endocrine therapy with or without CDK4/6 inhibitors. Prior exposure to CDK4/6 inhibitors is acceptable but not prior HER2-targeted therapy. Neratinib will be administered with a standard ramp up to therapeutic dose to minimize side effects with 120mg daily for 1 week, 160mg daily for 1 week and then 240mg daily thereafter. Treatment response will be monitored via imaging every 3 months while on study and measured using RECIST v. 1.1 criteria and/or mPERCIST criteria as appropriate using FDG-PET. Participants will remain on study until cessation due to side effects or disease progression. Biopsy at disease progression will be encouraged but not required.

Interventions

• Drug Neratinib + endocrine therapy
  Neratinib 120mg daily for 1 week, 160mg daily for 1 week and then 240mg daily thereafter
• Drug Endocrine therapy may include one of the following therapies: letrozole, anastrozole, exemestane, tamoxifen or fulvestrant
  Endocrine therapy with out without CDK4/6 inhibitor
• Drug CDK4/6 + Endocrine therapy
  Endocrine therapy with or without CDK 4/6 inhibitor

Primary outcome measures

• Median Progression-Free Survival [Time frame: From enrollment through study completion, an average of 1 year.]
• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [Time frame: From enrollment through study completion, an average of 1 year.]

Eligibility criteria

Inclusion criteria

• Female over the age of 18 at the time of study enrollment
• Not pregnant, planning to become pregnant or breast feeding
• Metastatic ER+/HER2- breast cancer that has progressed on 1st line therapy including endocrine therapy +/- CDK4/6 inhibitors
• At least one metastatic lesion visible on imaging (including FDG-PET)
• At least one metastatic lesion must be biopsied and confirmed ER+ and HER2- by immunohistochemistry within 6 months of study screening (HER2 equivocal disease will be confirmed HER2- by FISH)
• Tumors must be MLH1-low defined by <50% tumor cells positive for nuclear MLH1 expression on immunohistochemistry
• Standard of care next line endocrine therapy can include any endocrine therapy
• Performance status ECOG > 3
• Life expectancy > 1 year
• Ability to get serial imaging studies

Exclusion criteria

• History of concurrent use of other HER2-targeted therapy
• Concurrent use of other targeted systemic therapy
• History of other cancers other than non-melanoma skin cancer
• Actionable mutations on tumor genomic sequencing will be ineligible, and those participants encouraged to proceed with the relevant targeted therapy
• Participants where there is not at least one imaging apparent lesion that has not been treated with prior targeted therapy (for example palliative radiation or cryoablation)
• Contraindications to Neratinib use including allergy or hypersensitivity
• Baseline grade 3+ diarrhea

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

United States · 1 center

• UC San Diego Health Moores Cancer Center — La Jolla

Publications

• Mazumder A, Dewitt J, Oropeza E, Punturi N, Lozano D, Raghunathan M, Piscitelli J, Sajjadi E, GueriniRocco E, Venetis K, Ivanova M, Mane E, Dercole M, Concardi A, Fusco N, Manhart C, Bainbridge M, Haricharan S. Aberrant cytoplasmic localization of MLH1 characterizes a cell population that seeds breast cancer recurrence. Nat Commun. 2025 Dec 10;17(1):564. doi: 10.1038/s41467-025-67257-8. PMID 41372237
• Sajjadi E, Venetis K, Piciotti R, Invernizzi M, Guerini-Rocco E, Haricharan S, Fusco N. Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization. Cancer Cell Int. 2021 May 17;21(1):266. doi: 10.1186/s12935-021-01976-y. PMID 34001143
• Anurag M, Punturi N, Hoog J, Bainbridge MN, Ellis MJ, Haricharan S. Comprehensive Profiling of DNA Repair Defects in Breast Cancer Identifies a Novel Class of Endocrine Therapy Resistance Drivers. Clin Cancer Res. 2018 Oct 1;24(19):4887-4899. doi: 10.1158/1078-0432.CCR-17-3702. Epub 2018 May 23. PMID 29793947
• Haricharan S, Punturi N, Singh P, Holloway KR, Anurag M, Schmelz J, Schmidt C, Lei JT, Suman V, Hunt K, Olson JA Jr, Hoog J, Li S, Huang S, Edwards DP, Kavuri SM, Bainbridge MN, Ma CX, Ellis MJ. Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer. Cancer Discov. 2017 Oct;7(10):1168-1183. doi: 10.1158/2159 PMID 28801307
• Punturi NB, Seker S, Devarakonda V, Mazumder A, Kalra R, Chen CH, Li S, Primeau T, Ellis MJ, Kavuri SM, Haricharan S. Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer. Nat Commun. 2021 May 19;12(1):2940. doi: 10.1038/s41467-021-23271-0. PMID 34011995

Identifiers

NCT: NCT07729046 · BC250474 · BC250474 · 813310

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗