Rangaraju, Sunitha1; Wei, Ge1; Ho, Alan2; Saba, Nabil3; McIver, Bryan4, Li, Gary1; Patel, Rupal1; Christiansen, Jason1; Multani, Pratik1; Hornby, Zachary1; Potts, Steve1; Chung, Christine4
1 Ignyta, Inc., San Diego, CA, USA
2 Memorial Sloan Kettering Cancer Center, New York, NY, USA
3 Winship Cancer Institute of Emory University, Atlanta, GA, USA
4 Moffitt Cancer Center, Tampa, FL, USA
Background: Thyroid cancer is the most common type of endocrine malignancy. Although surgery and radiotherapy are often curative for many, patients whose tumors harbor specific molecular alterations may derive significant benefit from targeted therapy. NTRK, ROS1, ALK and RET fusions have been identified as oncogenic drivers in certain papillary thyroid carcinomas, and NTRK fusions have been detected in anaplastic thyroid carcinoma, whereas RET activating mutations are frequently found in medullary thyroid carcinoma.
Objectives: Two clinical stage investigational small molecule tyrosine kinase inhibitors entrectinib (RXDX-101) and RXDX-105 target TRK/ROS1/ALK and RET, respectively. Preclinical studies have been conducted, and clinical trials are underway to test if these two targeted agents are safe and efficacious in molecularly selected patients.
Methods: The anti-tumor effect of entrectinib and RXDX-105 were tested in preclinical models, including cell lines and patient-derived models driven by NTRK, ROS1, ALK or RET fusions. Patients prospectively selected for their molecular alterations receive entrectinib in the ongoing STARTRK-2 (NCT02568267) and RXDX-105 in the ongoing Phase1/1b RXDX-105-01 (NCT01877811) clinical trials.
Results: Entrectinib and RXDX-105 exerted potent inhibitory effect, in vitro and in vivo, on cancer models driven by NTRK, ROS1, ALK or RET alterations, irrespective of their histologies. Clinical studies to date of entrectinib and RXDX-105 have demonstrated durable RECIST responses in a high proportion of molecularly selected patients.
Conclusions: Entrectinib and RXDX-105 offer promising new treatment opportunities for thyroid cancer patients whose tumors harbor transforming alterations affecting TRK, ROS1, ALK or RET.