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

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.

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