The Combination of Tucatinib and Alpelisib Shows Efficacy in Patients with HER2-positive Metastatic Breast Cancer

The combination of tucatinib and alpelisib is both tolerable and effective at treating patients with HER2-positive (HER2+) PIK3CA-mutated metastatic breast cancer (MBC), according to a study presented at the 2024 San Antonio Breast Cancer Symposium.

In this phase IB study, which used a Time-to-Event Optimal Interval Design, researchers sought to determine the maximal tolerated doses of tucatinib and alpelisib with a dose limiting toxicity (DLT) window of 28 days. Safety was assessed using CTCAE v.5.0 with standard definition for DLTs. The population of interest were all post-menopausal women or premenopausal women undergoing ovarian suppression, diagnosed with HER2+ PIK3CAmutated MBC, and previously treated with at least two HER2-targeted agents. All patients are permitted one prior line of HER2 tyrosine kinase inhibitor for MBC, including prior tucatinib.

So far, eight patients (median age, 53) have been treated in this study. The patients have a median of two prior lines of therapy for MBC (range: 1-4). Prior HER2- targeted therapies included trastuzumab and pertuzumab (8 patients), T-DM1 (5 patients), tucatinib (4 patients), T-DXd (4 patients), and margetuximab (1 patient). Six patients had
visceral metastases and 4 had CNS metastases. Overall, all patients who experienced PR had PIK3CA H1047R mutation. The investigators noted that PRs occurred following two cycles of therapy and included significant reduction of breast tumors, liver and lung metastases and resolution of cancer lymphangitic spread in the lungs. Four out of 8 patients remained on
the regimen for more than 6 months. The longest treatment duration is 15 months and ongoing

“The combination of tucatinib and alpelisib is tolerable at DL1 and shows remarkable antitumor activity with partial responses in 3 out of 5 evaluable patients (60% overall response rate), including responses in patients treated with prior tucatinib and TDXd. Enrollment continues at DL1,” the researchers noted of the findings.