Trial to Assess Alpelisib in Combination with Tucatinib in PIK3CA-Mutated HER2-Positive Metastatic Breast Cancer

Phosphatidylinositol 2-kinase (PI3K) plays a key role in resistance to drugs targeting human epidermal growth factor receptor 2 (HER2), with activating mutations in the gene encoding alpha catalytic subunit of PI3K (PI3KCA) present in approximately 30% of HER2-positive tumors. Such mutations are linked to drug resistance and decreased survival in patients with HER2-positive breast cancer. This phase 1B/2 multicenter clinical trial conducted through the Academic Breast Cancer Consortium, with the University of Colorado Cancer Center as its lead site, aims to evaluate the combination of HER2 small molecular inhibitor tucatinib with PI3K inhibitor alpelisib in patients with HER2-positive metastatic breast cancer.

This phase 1B/rollover phase 2 study will follow time-to-event Bayesian optimal interval design and enroll 9 to 19 patients to identify maximally tolerated doses of tucatinib in combination with alpelisib. Twenty-one to 31 patients will be enrolled in phase 2, for a total of 40 patients in the final analysis. Primary objectives are to assess safety and tolerability of tucatinib plus alpelisib, as well as efficacy by progression-free survival. An exploratory assessment of biomarkers will be performed with liquid biopsy samples. Eligibility criteria are as follows:


This study is still enrolling patients and aims to enlist 2 additional sites. For additional information, please see NCT05392608.


Shagisultanova E, Wisinski K, Gawryletz C, et al. Clinical trial of alpelisib and tucatinib in patients with PIK3CA-mutant HER2-positive metastatic breast cancer (NCT05230810). San Antonio Breast Cancer Symposium 2022. Abstract OT3-09-01.

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