The Aurora kinase A inhibitor alisertib shows activity in breast cancer and small cell lung cancer.
Major finding: The Aurora kinase A inhibitor alisertib shows activity in breast cancer and small cell lung cancer.
Approach: The safety and activity of alisertib was evaluated in patients with relapsed or refractory solid tumors.
Impact: Studies of alisertib in combination with other anticancer drugs in these tumor types are warranted.
Aurora kinase A is required for proper mitotic spindle formation and progression through mitosis, and its overexpression in various tumor types is associated with poor prognosis. Preclinical studies have shown that alisertib, an oral, selective inhibitor of Aurora kinase A, results in mitotic defects and induces cell death, and preliminary antitumor activity has been observed in phase I clinical trials of both hematologic and solid tumors. Melichar and colleagues report the results of a phase II study evaluating the safety and activity of alisertib in patients with one of five predefined types of advanced refractory or relapsed solid tumors characterized by high Aurora kinase A expression. Two hundred forty-nine patients with breast cancer, small cell lung cancer (SCLC), non–small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), or gastroesophageal adenocarcinoma, each of whom had received previous cytotoxic treatments, were enrolled, and the proportion of patients with an objective response was determined as the primary endpoint. Treatment with alisertib resulted in objective partial responses in nine (18%) of 49 patients with breast cancer, in particular those with hormone receptor–positive or HER2-positive disease, and ten (21%) of 48 patients with SCLC. In contrast, only one (4%) of 23 patients with NSCLC, four (9%) of 45 patients with HNSCC, and four (9%) of 47 patients with gastroesophageal adenocarcinoma achieved partial responses. Alisertib exhibited a manageable safety profile with similar adverse events across all five tumor types, including neutropenia, fatigue, alopecia, anemia, and diarrhea. Although additional work is needed to understand the differential activity of alisertib among solid tumors and to identify predictive markers of response, these findings demonstrate the antitumor activity of this inhibitor in patients with advanced breast cancer and SCLC and support future clinical trials of alisertib in combination with other therapeutic agents.
Melichar B, Adenis A, Lockhart AC, Bennouna J, Dees EC, Kayaleh O, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol 2015 Feb 26 [Epub ahead of print].