Interim safety analysis of phase IB trial of HER2 inhibitor tucatinib combined with PI3Kα inhibitor alpelisib in HER2+ PIK3CA -mutated metastatic breast cancer.

e13021 Background: Activating mutations in the gene of phosphotydylinisotol-3 kinase catalytic subunit ( PIK3CA ) are present in up to 40% of breast cancers overexpressing human epidermal growth factor receptor 2 (HER2). These mutations are associated with resistance to HER2-targeted agents and adverse patient (pt) outcomes. Based on preclinical efficacy, we are conducting phase IB trial of HER2 inhibitor tucatinib combined with PI3Kα inhibitor alpelisib in pts with HER2-positive (HER2+) PIK3CA -mutated metastatic breast cancer (MBC). Methods: This phase IB study is aimed at finding maximal tolerated doses of tucatinib and alpelisib using Time-to-Event Bayesian Optimal Interval Design, with dose limiting toxicity (DLT) window of 28 days. Safety is assessed by CTCAE v.5.0 with standard definition for DLTs. Post-menopausal women, or pre-menopausal women on ovarian suppression, diagnosed with HER2+ PIK3CA -mutated MBC, and treated with at least 2 HER2-targeted agents are eligible. Pts are allowed 1 prior line of HER2 tyrosine kinase inhibitor for MBC, including tucatinib. Treatment consists of twice-daily tucatinib and daily alpelisib at prespecified dose level (DL) with concurrent fulvestrant for hormone receptor-positive cases. Results: As of January 11, 2024, 6 pts have been treated. The median age was 54 years (range: 47-66), with a median of 2.5 prior lines of therapy for MBC (range: 1-4). Previous HER2-targeted therapies included trastuzumab and pertuzumab (6 pts), T-DM1 (5 pts), tucatinib (4 pts), T-DXd (3 pts) and margetuximab (1 pts). Five pts had visceral metastases and 3 had CNS metastases. No DLTs were observed in 3 pts treated at DL1 (tucatinib 300mg BID, alpelisib 250mg daily). However, at DL2 (tucatinib 300mg BID, alpelisib 300mg daily), all 3 pts experienced DLT. Two pts had grade 3 (G3) diarrhea that resolved with treatment hold; they resumed therapy with dose reduction. One pt developed G3 rash with mucositis, eosinophilia and G4 elevated creatinine and came off study; these symptoms resolved without sequelae following hydration and steroid treatment. Other notable adverse events, primarily G1-2, included hyperglycemia (4 pts), elevated liver enzymes (4 pts), weight loss (3 pts), and infections (3 pts), all manageable with supportive medications. There was no new safety signal from the study drugs, and no death on study. Two pts had a partial response after 2 treatment cycles, showing reduction of liver and lung metastases and resolution of cancer lymphangitic spread in the lungs. The longest treatment duration is currently 9 months and ongoing. Conclusions: Tucatinib and alpelisib combination is tolerable at DL1 and demonstrates promising antitumor activity, including responses in pts treated with prior tucatinib and T-DXd. Enrollment continues at DL1. Updated safety and efficacy findings will be presented at ASCO 2024 conference. Clinical trial information: NCT05230810 .