Gene fusions of NTRK1/2/3, ROS1 and ALK (encoding TrkA/B/C, ROS1 and ALK proteins, respectively) lead to constitutive activation of oncogenic pathways and are clinically validated targets for anti-cancer therapies. These fusions have been detected in a wide range of solid and hematological tumors, including cancers of the head and neck, such as salivary gland cancer, thyroid cancer and head and neck squamous cancer. The lists of distinct fusion partners and tumor histologies in which these gene fusions occur continue to grow with the continued development of detection technologies and broader application of molecular diagnostics.
Entrectinib (RXDX-101) is an orally available, brain-penetrant, highly potent and selective inhibitor with low nanomolar potency against kinase activities of TrkA/B/C, ROS1 and ALK. Against a panel of Ba/F3 cells engineered to express clinically identified NTRK1/2/3, ROS1 and ALK rearrangements, entrectinib exhibited potent, low nM anti-proliferative activity. In vitro and in vivo studies using cancer cell lines, patient-derived tumor cells (PDCs) and patient-derived xenografts (PDXs) endogenously expressing these gene fusions also demonstrated potent anti-tumor efficacy with entrectinib at clinically achievable concentrations in various cancer histologies, including cancers of the head and neck. Importantly, clinical proofs of concept have been achieved in a number of molecularly selected patients, including an ETV6-NTRK3 fusion-positive mammary analog secretory carcinoma (MASC) patient, who achieved a rapid and deep response (PR: 89% reduction at nadir) with entrectinib.
In conclusion, compelling preclinical and clinical data for entrectinib fully support molecular testing of head and neck cancers and enrollment of patients with oncogenic NTRK1/2/3, ROS1 and ALK fusions.