Introduction: Oncogenic alterations in RET occur in 1–2% of non-small-cell lung cancers (NSCLCs). The efficacy and safety of the first-in-class, highly selective, and potent RET inhibitor selpercatinib in Chinese patients with RET fusion-positive NSCLC remains unknown. Methods: In this open-label, multicenter, phase II study (NCT04280081), patients with advanced RET-altered solid tumors received selpercatinib (160 mg orally twice daily) in a 28-day cycle. The primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included duration of response, central nervous system (CNS) response, and safety. Efficacy against NSCLC was assessed in the primary analysis set (PAS; centrally confirmed RET status) and in all enrolled patients with NSCLC. Results: Of 77 enrolled patients, 47 had RET fusion-positive NSCLC. After 9.7 months of median follow-up, IRC-assessed ORR in the PAS ( n = 26) was 69.2% [95% confidence interval (CI), 48.2–85.7] and 94.4% of responses were ongoing; the ORR was 87.5% and 61.1% in treatment-naïve and pre-treated patients, respectively. IRC-assessed ORR in all patients with NSCLC ( n = 47) was 66.0% (95% CI, 50.7–79.1). Among five patients with measurable CNS metastases at baseline, four (80%) achieved an IRC-assessed intracranial response. In the safety population ( n = 77), most treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common grade ⩾3 TEAE was hypertension (19.5%). Three (3.9%) patients discontinued therapy due to treatment-related AEs; no deaths occurred due to treatment-related AEs. Conclusion: Selpercatinib, with potent and durable antitumor activity including intracranial activity, was well tolerated in Chinese patients with RET fusion-positive NSCLC, consistent with LIBRETTO-001 (ClinicalTrials.gov: NCT04280081).