Abstract P4-01-10: Evaluating the safety of tucatinib in combination with trastuzumab and capecitabine for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer in a real-world setting
Authors: Moore Heather , Anders Carey , Sammons Sarah L. , Erkanli Alaattin , Parish Alice , DiCola Christina 
Published: March 2023

Background: Tucatinib, a highly selective tyrosine kinase inhibitor (TKI) for human epidermal growth factor 2 (HER2) receptor, received FDA approval in combination with trastuzumab and capecitabine for metastatic HER2-positive breast cancer based on the HER2CLIMB trial. While the efficacy data is promising, the tucatinib-containing triplet regimen is associated with significant toxicity and many drug-drug interactions (DDIs). The toxicity profile of tucatinib in regards to adverse events (AEs) and DDIs has not been reported outside of the HER2CLIMB trial. Additionally, with the development of many new HER2 targeted therapies including antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan, efficacy in regards to therapy sequence is still unknown. Here, we describe the safety and efficacy of tucatinib in a real-world setting. Methods: This single-center, retrospective, cohort study included patients (pts) with a diagnosis of HER2- positive locally advanced or metastatic breast cancer pts that were newly initiated on tucatinib therapy at the Duke Breast Oncology Clinic following FDA approval from April 17, 2020 to June 9, 2021. Pts were evaluated for the pre-specified outcomes for the duration of tucatinib therapy, until progression of disease, or for at least 6 months follow-up. AEs reviewed included palmar-plantar erythrodysesthesia syndrome (PPE), diarrhea, fatigue, rash, anemia, thrombocytopenia, neutropenia, nausea, vomiting, mucositis, hepatotoxicity, and nephrotoxicity, defined according to the Common Terminology Criteria for Adverse Events (CTCAE) grading criteria. Overall response was categorized as complete response, partial response, stable disease, or progressive disease, defined according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, at first staging after therapy initiation. The overall response rate was stratified by prior standard therapies, pts who did not receive capecitabine therapy with tucatinib, and the presence or absence of brain metastases. Results: A total of 23 pts (N=23) were included in the cohort, 52% of which had brain metastases and 9% with leptomeningeal disease. Pts had a median of 3 prior lines of therapy in the metastatic setting including: lapatinib (9%), neratinib (30%), trastuzumab deruxtecan (13%), trastuzumab emtansine (74%). All pts experienced AEs, most of which were mild or moderate severity. The most common AEs reported were fatigue (70%), PPE (61%), nausea (61%), and anemia (61%). Severe AEs occurred in 6 pts (26%) with grade 3 or 4 hepatotoxicity in 13%. Only 2 pts discontinued therapy due to AEs (grade 4 hepatoxicity, grade 2 fatigue). Due to capecitabine intolerance, 13% received tucatinib and trastuzumab doublet therapy. There were 9 pts (39%) that experienced a DDI with tucatinib requiring therapy modification or close monitoring. At first staging, partial response was seen in 26% while 35% demonstrated stable disease and 30% progressive disease. Pts with previous neratinib therapy demonstrated a partial response of 14% and a stable disease response of 29%. No pts with previous trastuzumab deruxtecan or omission of capecitabine therapy experienced a partial or stable disease response. Conclusions: The rate of AEs were similar in a real-world setting compared to the HER2CLIMB trial with a lower rate of severe adverse events, however, a higher rate of hepatotoxicity. Given the high rate of drug interactions identified with tucatinib, concurrent medications should be reviewed for appropriate therapy adjustments and monitoring. Additional data is needed in regards to sequencing and impact on therapy efficacy.

Citation Format: Heather Moore, Carey Anders, Sarah L. Sammons, Alaattin Erkanli, Alice Parish, Christina DiCola. Evaluating the safety of tucatinib in combination with trastuzumab and capecitabine for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer in a real-world setting [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 P4-01-10.