부산대학교 도서관

This phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of pilaralisib was determined using a 3 + 3 dose-escalation design (starting dose 200 mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of pilaralisib was determined at 400 mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8% in Arm 1 vs. 66.7% in Arm 2), fatigue (14.3 vs. 42.9%), and rash (33.3 vs. 38.1%). The most frequently reported treatment-related grade ≥ 3 AEs were erythematous rash (9.5%) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3% each) in Arm 2. Steady-state pilaralisib exposure was similar to previous studies with pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20%) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm. Keywords HER2-positive * PI3K * Pilaralisib * Trastuzumab * Metastatic breast cancer
Introduction Human epidermal growth factor receptor 2 (HER2) overexpression is associated with a poor prognosis in breast cancer [1]. Adding the anti-HER2 monoclonal antibody trastuzumab to standard chemotherapy improves disease-free [...]