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Background Patients (pts) with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (MBC) who have brain metastases (BM) have limited treatment options and lower health-related quality of life (HRQoL) compared with pts without BM (Hurvitz 2019). HER2CLIMB is a randomized trial (2:1) of tucatinib vs. placebo in combination with trastuzumab and capecitabine in pts with HER2+ MBC that included pts with stable and active brain metastases (NCT02614794). In HER2CLIMB, the addition of tucatinib to trastuzumab + capecitabine demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) in pts with HER2+ MBC and in those with stable and active BM, with importantly, a tolerable and manageable safety profile (Murthy 2020). An evaluation of the impact of tucatinib on HRQoL in pts with stable and active BM is presented here. Methods HRQoL data were available from 330 of 612 pts, including 163 pts with BMs. HRQoL was assessed using the EQ-5D-5L tool which includes a visual analog scale (EQ-VAS) and a descriptive system (EQ-5D) comprising 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Data were collected at Cycle 1 Day 1, Cycles 3-9 (every 2 cycles; 21-day cycles), Cycle 12 and beyond (every 3 cycles), and at the 30-day follow-up. The EQ-5D-5L scores were summarized by cycle for each treatment arm. Time to deterioration, defined as a >7-point change from baseline on the EQ-VAS, was estimated by the Kaplan-Meier approach. The median time to deterioration (and 95% CIs) were computed for each arm. Results In total, 163 pts with stable and active BM were included in this HRQoL analysis, 107 pts on the tucatinib arm and 56 pts on the placebo arm. Compared to the placebo arm, pts on the tucatinib arm had an approximately 49% reduction in the risk of deterioration (hazard ratio: 0.51; 95% CI: 0.28, 0.93); the median time to deterioration has not been reached in the tucatinib arm with available follow-up and was 5.5 months (95% CI; 4.2, -) in the placebo arm. Decline in all domains of the EQ-5D-5L and the EQ-VAS scores were seen once pts discontinued therapy, particularly on the ‘usual activities’ domain. Additional available QoL data will be presented. Conclusions Pts with MBC and BM treated with tucatinib in combination with trastuzumab + capecitabine demonstrated significantly longer and clinically meaningful time to deterioration of HRQoL. HRQoL was maintained throughout the treatment course, allowing them to receive full benefit of the therapeutic approach and resulting in statistically significant and clinically meaningful improvement in OS. References Hurvitz SA, O’Shaugnessy J, Mason G, et al. Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs. Clin Cancer Res. 2019;25(8):2433-2441.Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020;382(7):597-609. Citation Format: Andrew Wardley, Volkmar Mueller, Elisavet Paplomata, Laurence Crouzet, Nayyer Iqbal, Sramila Aithal, Margaret Block, Søren Cold, Marie-Agnes By, Olwen Hahn, Teja Poosarla, Erica Stringer-Reasor, Marco Colleoni, David Cameron, Giuseppe Curigliano, Kendra DeBusk, Muriel Siadak, Jorge Ramos, Xuebei An, Karen Gelmon. Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with stable and active brain metastases [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 PD13-04.