Entrectinib Shows Strong Activity Against a Range of Rare Solid Tumors with Molecular Abnormalities

Wayne Kuznar

June 2016, Vol 7, No 5 - Emerging Therapies


Entrectinib, an investigational potent oral inhibitor of tyrosine kinases, ROS1, and ALK proteins, achieves rapid and durable responses in patients with a range of advanced or metastatic solid tumors harboring NTRK, ROS1, or ALK gene fusions. Data from 2 phase 1 clinical trials presented at the 2016 American Association for Cancer Research meeting demonstrated that treatment with entrectinib achieved objective responses in 79% of patients with solid tumors associated with NTRK, ROS1, or ALK gene rearrangements, said lead investigator Alexander Drilon, MD, Medical Oncologist, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Fusions involving the NTRK, ROS1, and ALK genes “cause heightened activity of the TrkA/B/C, ROS1, and ALK proteins coded for by these genes, thus promoting cancer-cell proliferation and survival,” said Dr Drilon. These recurrent gene rearrangements have a high prevalence in rare adult and pediatric cancers, including mammary analog secretory carcinoma, breast secretory carcinoma, congenital meso­blastic nephroma, and congenital fibrosarcoma, but they are less prevalent in more common cancers, such as non–small-cell lung cancer (NSCLC). The clinical experience with entrectinib encompasses 119 patients with cancers harboringNTRK, ROS1, or ALK gene mutations who were enrolled in 2 phase 1 studies, ALKA-372-001 and STARTRK-1. In the ALKA-372-001 study, entrectinib was dosed intermittently and continuously; in the STARTRK-1 study, dosing was continuous. A total of 45 patients received entrectinib 600 mg daily; this dose had been previously established in a phase 2 study. The data presented involved 24 patients with no previous exposure to a tyrosine kinase inhibitor. The objective response rate to entrectinib in patients with extracranial solid tumors in these 2 clinical trials was 79% (19 of 24 patients). The 19 responses represented diverse cancers, including NSCLC, colo­rectal cancer, melanoma, and mammary analog secretory carcinoma. The responses were rapid, occurring within 4 weeks of treatment with entrectinib. In addition, there was evidence of tumor shrinkage in a patient with NTRK mutation–positive astrocytoma, said Dr Drilon. This latter complete response in the brain was encouraging, given the frequency with which NSCLC metastasizes to the brain. Responses were achieved in 12 of 14 (86%) patients with ROS1-rearranged tumors, with 2 complete responses. These responses included 11 of 13 (85%) patients with ROS1-rearranged NSCLC and 1 patient with melanoma. “The long ongoing response is approaching 2 years and 3 months,” Dr Drilon said. In a subgroup analysis of 5 patients with NTRK-rearranged cancers, all the patients with 5 different tumor histologies and fusion types responded to entrectinib. Treatment with entrectinib resulted in dramatic intracranial activity in the 3 patients with central nervous system (CNS) disease. Entrectinib is highly penetrant in the CNS, Dr Drilon explained. “We observed durable responses in both primary brain tumors and metastatic disease, including complete response in the CNS.” “What we’re seeing here are results from trials that are not targeting particular cancers, but rather people who have cancers characterized by particular molecular abnormalities,” commented Louis M. Weiner, MD, Director, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. A phase 2 basket clinical trial, STARTRK-2, is ongoing to determine whether these early results can be confirmed in a larger cohort of patients.