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BACKGROUND: Most HER2-positive breast cancers co-express estrogen receptor (ER). Given crosstalk between HER2 and ER signaling pathways, dual blockade may be beneficial.METHODS: In this randomized, open-label, phase 2 clinical trial, patients with ER-positive (ER ≥ 10%), HER2-positive metastatic breast cancer were randomized (1:1) to neratinib (240 mg daily) or the same dose of neratinib with fulvestrant. Any number of prior therapies was allowed; prior trastuzumab, pertuzumab and trastuzumab emtansine were required. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate, and duration of response. Exploratory objectives included the identification of predictive biomarkers via circulating tumor DNA (ctDNA).RESULTS: Of 21 patients enrolled, 18 were evaluable for outcomes and safety (neratinib-fulvestrant arm, n = 8; neratinib-only arm, n = 10). The study was closed before completing enrollment due to slow accrual. Median PFS did not differ between treatment arms (2.79 months with neratinib-fulvestrant versus 5.55 months with neratinib only [HR 0.94; 95% CI, 0.24-3.64; P = .98]). Grade 3 adverse events occurred in 1 (12.5%) patient in the neratinib-fulvestrant arm and 6 (60%) patients in the neratinib-only arm, with diarrhea being the most frequent. Median OS did not differ between the 2 arms (P = .91). Clearance of ctDNA was associated with PFS and OS.CONCLUSIONS: The combination of neratinib and fulvestrant is safe and tolerable. Due to early study closure, this study was underpowered to detect the benefit of adding fulvestrant to neratinib. Chemotherapy-free regimens targeting ER and HER2 warrant further investigation, along with prospective studies investigating ctDNA dynamics may guide treatment switch.