Two biotechs with drug candidates targeting the RET oncogene, a 'driver' gene in human cancers, presented encouraging early data at the International Association for the Study of Lung Cancer meeting in Chicago in September. The preliminary lung cancer results from San Diego–based Mirati Therapeutics and Stamford, Connecticut-based Loxo Oncology are fuelling hopes that targeting fusions and mutations in the RET (rearranged during transfection) gene could benefit patients who have acquired resistance mechanisms to therapeutic agents and potentially enhance responses to anti-PD-1 agents. Mirati presented early data from two ongoing studies of sitravatinib, its multi-kinase inhibitor, whose targets include RET, MET, Trk and other key cell growth regulators. One of them, a single-agent study, showed tumor reduction in four non-small-cell lung cancer (NSCLC) patients with RET fusion mutations. The other study is evaluating the drug in combination with the anti-PD-1 checkpoint inhibitor Opdivo (nivolumab), a Bristol-Myers Squibb drug. Findings so far suggest that RET inhibition enhances antitumor immune responses by altering the tumor microenvironment, and making the body more receptive to treatment with Opdivo. Loxo demonstrated proof of concept for its Loxo-292 selective RET inhibitor, obtaining partial responses in two patients who had progressed after treatment with multi-tyrosine-kinase inhibitors. The companies are focusing their development efforts on NSCLC patients with rare genetic alterations in the RET proto-oncogene. The oncogene encodes a receptor tyrosine kinase involved in extracellular signaling but, when mutated, can give rise to cancers. RET gene fusions and mutations have been identified in approximately 2% of NSCLC, 10–20% of papillary thyroid cancer, and a subset of colon and other cancers. RET point mutations account for approximately 60% of medullary thyroid cancer. Both cancers associated with RET fusions and select cancers associated with RET mutations depend primarily on this single activated kinase for their proliferation and survival, according to Loxo. Several approved multi-tyrosine-kinase inhibitors targeting RET are in trials in lung cancer, including South San Francisco–based Exelixis's Cabometyx (cabozantinib) and Cambridge, UK–based AstraZeneca's Caprelsa (vandetanib). In addition to Loxo-292, more selective RET inhibitors include RXDX-105 from Ignyta, in San Diego, and Cambridge, Massachusetts–based Blueprint Medicines' BLU-667. Inhibitors of ALK (anaplastic lymphoma kinase), such as Basel, Switzerland–based Roche's Alecensa (alectinib), also have documented clinical activity against RET fusions in NSCLC.