Abstract OT-28-04: Neratinib and tepotinib combination in advanced breast cancer and inflammatory breast cancer patients with abnormal HER2 and c-Met pathway activity as measured by the CELsignia signaling pathway activity test
Authors: Hobbs Evthokia , Lindquist Eric , Sullivan Brian , Yoon Esther , Yuan Ying , Marx Angela , Willey Jie , Sun Huiming , Layman Rachel , Stover Daniel , Yuan Yuan , Lim Bora 
Published: February 2021

Abstract
Background: While HER2 targeted therapeutics have significantly improved outcomes of patients with HER2 overexpressed advanced breast cancer (ABC), c-Met pathway activation serves as a resistance mechanism in about 60% of patients. Neratinib is an irreversible tyrosine kinase inhibitor of the ErbB family of receptors (EGFR, HER2, and HER4) and tepotinib is a tyrosine kinase inhibitor of c-Met. From live extracted cells from patient biopsies, the CELsignia Pathway Activity Test measures in real-time ErbB and c-Met signaling activity and the dynamic response to pathway inhibition by targeted therapy ex vivo. The CELsignia test may identify patients with ABC who would benefit from the combination of neratinib and tepotinib regardless of the molecular breast cancer subtype. Trial Design: We designed a phase Ib/II multi-center, non-randomized, open-label study of combination of neratinib with tepotinib in patients with advanced breast cancer including those with inflammatory breast cancer. The study sites include UT MD Anderson Cancer Center, City of Hope, and The Ohio State University Cancer Center. Four dose levels of neratinib, and two dose levels of tepotinib will be studied in phase Ib to determine the maximum tolerated dose (MTD). Phase II portion of the study will test the early efficacy of neratinib and tepotinib combination in patients with HER2-/HR+ ABC with abnormal HER2 and c-Met signaling activity determined by the CELsignia test. Eligibility: All patients with IBC/ABC will be eligible for the phase Ib. Eligible patients must have measurable metastatic disease per RECIST v1.1 or unresectable disease amenable for biopsy and have had at &gt;1 line of systemic therapy for advanced disease. Patients will have an Eastern Cooperative Oncology Group performance status of 0 to 2. For the phase II component, patients must have hyperactive HER2 and c-Met signaling determined by CELsignia test. Aims: The primary objective of the phase Ib component is to determine the MTD of the combination in previously treated IBC/ABC of any molecular subtype. The primary objective of the phase II component is to determine the overall response rate (ORR) in patients with HER2-/HR+ ABC who have a positive CELsignia test result (described in the Eligibility). Secondary objectives include progression free and overall survival, clinical benefit rate, duration of response, and safety and tolerability. Exploratory objectives will be to assess HER2 and c-Met driven signaling pathways as either hyperactive or abnormally active by CELsignia test. Statistical Methods: The phase I study will be conducted using a Bayesian optimal interval (BOIN) design to establish the MTD and the recommended phase II dose and assess early efficacy of the combination with a maximum of 21 patients. Two dose levels of tepotinib, and four dose levels of neratinib will be studied. The phase II study will assess the ORR using Bayesian optimal phase 2 (BOP2) design to rule out a 10% ORR in favor of a 30% target ORR, with a power of 80% and two-sided 5% significance level. Accrual: Once MTD is determined, up to 29 evaluable CELsignia test positive subjects will be enrolled to the phase II component of the study and an interim analysis will be performed when the total number of enrolled patients reaches 15. We hope to complete the accrual of patients by July 2022 and to schedule the last patient visit by July 2023. Contact information: For more information or to refer a patient, email blim@mdanderson.org, eahobbs@mdanderson.org
Citation Format: Evthokia Hobbs, Eric Lindquist, Brian Sullivan, Esther Yoon, Ying Yuan, Angela Marx, Jie Willey, Huiming Sun, Rachel Layman, Daniel Stover, Yuan Yuan, Bora Lim. Neratinib and tepotinib combination in advanced breast cancer and inflammatory breast cancer patients with abnormal HER2 and c-Met pathway activity as measured by the CELsignia signaling pathway activity test [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-28-04.