Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Taselisib, GDC-0032, PI3K, PI3K inhibitor, Metastatic breast cancer, PIK3CA, COMPREHENSIVE MOLECULAR PORTRAITS, PI3K INHIBITOR, PLUS PACLITAXEL, PATHWAY, PHARMACOKINETICS, CHEMOTHERAPY, MULTICENTER, CHALLENGES, MUTATIONS, THERAPY, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Carcinoma, Non-Small-Cell Lung, Class I Phosphatidylinositol 3-Kinases, Docetaxel, Female, Humans, Imidazoles, Lung Neoplasms, Maximum Tolerated Dose, Middle Aged, Mutation, Neoplasm Metastasis, Oxazepines, Paclitaxel, Receptor, ErbB-2, Survival Analysis, Treatment Outcome, Receptor, erbB-2, 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3202 Clinical sciences, 3211 Oncology and carcinogenesis

Abstract:

PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m2 docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m2 paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.