Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+, HER2 Mutated and/or HER2-amplified Metastatic Breast Cancer and Leptomeningeal Disease: A Multi-centre Phase II, Single Arm Feasibility Study

Breast cancer is the most common cancer among women worldwide, and the second leading cause of brain metastases (BrM). Despite recent treatment advances, the prognosis of patients with breast cancer BrM remains poor, and the prognosis among those with leptomeningeal disease (LMD) is particularly dire with a median survival of only 2-4 months.

Patients with HER2+ metastatic breast cancer have a high life-time risk of central nervous system (CNS) metastases, with an approximately 50% lifetime risk. Although the cause of death among patients with breast cancer BrM is challenging to ascertain, approximately 50% of patients with HER2+ BrM are thought to die from central nervous system (CNS) disease involvement. Among patients with LMD specifically, the cause of death is most commonly related to CNS disease.

In an analysis of 430 patients (96 of whom had breast cancer) treated for LMD in the National Cancer Database between 2005 and 2014, those patients treated with chemotherapy plus radiotherapy had a longer median overall survival of 5 months (3.5 - 6.5 months) compared to patients treated with XRT or chemotherapy alone. In addition, a majority (n=18/26, 69%) of observational studies irrespective of primary tumor site have shown an "improvement or likely improvement" in survival with the use of XRT for LMD, either alone or in combination with systemic therapy. Hence, this proposed study will evaluate the safety and efficacy of XRT followed by systemic therapy (which is considered standard of care) among patients with HER2+ metastatic breast cancer and LMD.

In addition to enrolling patients with established HER2+ metastatic breast cancer, those with HER2 mutations and/or HER2-amplifications in their blood and/or CSF are also eligible to enroll. This is on the basis that the HER2 status is known to "flip" in a relatively high proportion of patients from HER2-negative to HER2-positive at the time that CNS metastases develop51, 52, 53. Given that HER2 status of CNS metastases is not easy to obtain (most patients with CNS metastases do not have surgical resection or biopsy to obtain tissue due to the invasive nature of this surgical approach), patients with fluid samples suggestive of a HER2-driven malignancy (HER2 mutations and/or amplifications) in the blood and/or CSF will be permitted to enrol. Most patients with HER2 amplified tumors would be considered to have HER2-positive disease on tissue samples, but ASCO/CAP guidelines for HER2-positive status only apply to tissue; hence, a separate inclusion criterion for these patients has been established.

Inclusion criteria

Phase 1

• Men or women with HER2+, HER2 mutated and/or HER2-amplified metastatic breast cancer. HER2+ status will be defined in accordance with ASCO-CAP 2018 guidelines, and can be diagnosed at any time prior to enrolment. HER2 mutations and/or HER2-amplifications can be identified in the blood and/or cerebrospinal fluid (CSF) at any time prior to enrolment; testing blood and/or CSF is not part of the study protocol and must be evaluated using a clinically validated test.
• Evidence of LMD* in the brain and/or spine (either positive cerebral spinal fluid cytology and/or magnetic resonance imaging evidence of LMD). Measurable disease in the central nervous system is not required. * The diagnosis of LMD can occur at any time prior to enrolment;
• Age 18+ at time of consent;
• ECOG ≤ 2;
• More than 14 days or 5 half-lives from the last dose of any experimental agent is required, whichever is greater;
• All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1 prior to enrollment, except for alopecia; neuropathy, must have resolved to ≤ Grade 2.

Phase 2: Inclusion Criteria

• Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by ECHO or MUGA documented within 2 weeks prior to starting systemic therapy on the study;
• Adequate hematologic, liver, and renal function within 2 weeks prior to phase 2 enrollment, as follows:

• Hemoglobin ≥ 9 g/dL
• ANC ≥ 1 x109/L
• Platelets ≥ 100 x109/L
• Total bilirubin ≤ 1.5 X upper limit of normal (ULN)
• AST and ALT ≤ 2.5X ULN
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN
• Creatinine clearance (CrCL) ≥ 50 mL/min
• The last dose of prior therapy must have been completed 14 days prior to study enrollment. Prior chemotherapy, immunotherapy, endocrine therapy, targeted therapy and experimental agents are allowed (including prior use of trastuzumab or other antibody-based therapy). Prior use of capecitabine either alone or in combination with other HER2-targeted therapies (including other tyrosine kinase inhibitors) is permitted;

Exclusion criteria

Phase 1

• Prior WBRT for brain metastases (prior stereotactic radiosurgery for parenchymal CNS metastases received <7 days prior to consent );
• Prior therapy specifically directed at LMD, including prior radiotherapy or systemic therapy;
• Inability to comply with MRI-based surveillance of CNS disease;
• Inability to swallow pills or any significant gastrointestinal diseases such as inflammatory bowel disease who suffer from uncontrolled diarrhea (based on the investigator's assessment),, which would preclude adequate absorption of oral medications;
• Diagnosed with Hereditary fructose intolerance;
• Diagnosed with Gilbert's disease;
• Prior history of other cancer (except non melanoma skin, cervical intraepithelial neoplasia) with evidence of disease within the last 5 years;
• Prior use of tucatinib at any time prior to enrollment.
• Hypersensitivity to any of the active substances in tucatinib, trastuzumab, or capecitabine.

Phase 2:

• Currently pregnant or breastfeeding;
• Use of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of systemic therapy (see Appendix C and D);
• Myocardial infarction or unstable angina within 6 months prior to the first dose of systemic therapy.
• Blood product transfusions in order to meet eligibility criteria