BACKGROUND: RET fusions are oncogenic drivers in 1 to 2small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 6495CI], 54 to 73). The median duration of response was 17.5 months (95 12.0 to could not be evaluated), and 63up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 8595 70 to 94), and 90 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 9195 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14, an increased alanine aminotransferase level (in 12, an increased aspartate aminotransferase level (in 10, hyponatremia (in 6, and lymphopenia (in 6. A total of 12 of 531 patients (2 discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).