Abstract OT1-10-02: Trial of Neratinib Plus Capecitabine in Subjects With HER2-Negative Metastatic Breast Cancer With Brain Metastases and Abnormally Active HER2 Signaling
Authors: Dhakal Ajay , O’Regan Ruth , Falkson Carla , Hicks David , Hawkins Douglas , Turner Bradley , Mohile Nimish 
Published: March 2023

Background: Development of brain metastasis (BM) portends poor prognosis in patients (pts) with metastatic breast cancer (MBC) mainly due to lack of systemic therapy with strong activity in CNS. While survival in HER2+ BC BMs has improved due to development of various HER2 therapies with activity against BM, outcome for HER2- BC BMs remains dismal. A novel assay (CELsignia) which measures underlying HER2 signal (HS) of live cancer cells in response to HER2 agonists & antagonists showed that about 25% of BC deemed HER2- by standard methods have underlying abnormal HS. Preclinical data showed various HER2 therapies inhibit tumor growth of such HER2- BC with abnormal HS. Among tested HER2 inhibitors with known CNS activity, neratinib had the lowest IC50. We propose a trial which identifies HER2- BC BM pts with abnormal HS & assesses activity of neratinib based therapy. Design: This is a phase II single arm study with 2 steps- step 0 (biopsy) & step 1 (treatment). Pts eligible for Step 0 will be registered as “Immediate Treatment (IT)” (intent to register to Step 1 immediately) or “Future Treatment” [registration can be delayed up to 28 weeks (wks)] & undergo biopsy of most accessible extra CNS (eCNS) tumor. Tumor will be sent for CELsignia testing (2 wks turn around). Additional biopsies may be obtained for standard of care (SOC). IT pts can be treated with a brief course of capecitabine 1gm/m2 BID for 1 wk followed by 1 wk off while waiting for CELsigia result. Pts with BC having abnormal HS will be screened & registered to step 1. Enrolled pts will receive neratinib 240mg daily (with SOC antidiarrheal prophylaxis) + capecitabine 750mg/m2 BID for 2 wks in every 3 wks cycle (C). Tumor assessments will be done prior to C3, 5 & 7 then every 12 wks with MRI brain, CT chest abdomen pelvis & bone scan using RECIST1.1 (eCNS disease) and a modified BM RANO criteria (&gt;5mm, measurable disease, CNS). In isolated CNS progression, investigators have option of treatment beyond progression after SOC local treatment of progressing BMs. Key Eligibility Criteria: Step 0: Inclusion Criteria (IC): histologically confirmed HER2- BC (primary or metastatic); has radiological evidence of BM; prior treatment with CDK4/6 inhibitor + endocrine therapy required for hormone receptor+ BC, no prior specific treatment required for triple negative BC; radiological evidence of eCNS measurable disease (RECIST1.1) accessible for biopsy. Exclusion Criteria (EC): prior use of capecitabine in metastatic setting; known/suspected leptomeningeal disease. Step 1: IC: Abnormal HS; New or progressing BM that is measurable (&gt;5mm); minimum washout periods in wks: last chemotherapy 2, hormonal therapy 1 except fulvestrant 4, targeted therapies 3, eCNS radiation 1, any investigational treatment 4. ECOG performance status 0-2; adequate end organ functions. EC: whole brain radiation in last 3 months (m). Endpoints: Co-primary: Overall survival (OS) and CNS progression free survival (CNS PFS). Key Secondary: Objective response rate, clinical benefit rate and duration of response (CNS using BM RANO, eCNS using RECIST1.1), eCNS PFS, various feasibility endpoints. Safety. Statistical methods: To detect 70% improvement in this trial in CNS PFS and OS compared to historical control (BEACON trial BM subset) 2.7m vs. 4.6m and 4.8m vs. 8.2 m with 80% power and 1-sided 5% significance level, a sample size of 22 is required. About 88 patients will undergo biopsy to enroll 22 pts in step 1. One futility assessment is planned when the first 12 pts have been treated for at least 6 wks or have failed (died or progressed) prior to 6 wks. If 9 or more in the first 12 have died or progressed by 6 wks of treatment, the study will close for futility. PFS and OS will be analyzed using Kaplan-Meier survival functions. Contact: Ajay Dhakal MBBS, ajay_dhakal@urmc.rochester.edu NCT#: NCT04965064 Funding: Celcuity, Puma Biotechnology Status: IRB approved. Anticipated activation Aug 2022, Accrual duration: 2 years. Seeking participating sites.

Citation Format: Ajay Dhakal, Ruth O’Regan, Carla Falkson, David Hicks, Douglas Hawkins, Bradley Turner, Nimish Mohile. Trial of Neratinib Plus Capecitabine in Subjects With HER2-Negative Metastatic Breast Cancer With Brain Metastases and Abnormally Active HER2 Signaling [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-10-02.