Introduction: Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic activity in early clinical trials; however, their efficacy in the real-world setting is unknown., Methods: A retrospective efficacy and safety analysis was performed on data from RET fusion-positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021., Results: Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38-89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1-8). The objective response rate (ORR) was 68% [95% confidence interval (CI), 53-81] in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8-22.4) after a median follow-up of 9 months. In patients with measurable brain metastases ( n = 8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade ⩾ 3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death., Conclusions: In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated., Competing Interests: Conflict of interest statement: Oliver Illini, Received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Menarini, Merck Sharp & Dohme, Pfizer, and Roche. Maximilian Johannes Hochmair, Honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Hannah Fabikan, Speaker fee from Roche. Christoph Weinlinger, No conflict of interest. Amanda Tufman, Advisory Boards: Lilly, Pfizer, MSD, BMS, GSK, Celgene, Roche, Takeda, Boehringer Ingelheim, Amgen, AstraZeneca. Projects financed by AstraZeneca und Takeda. Aurélie Swalduz, Roche, Bristol-Myers Squibb, Takeda, Lilly, Pfizer, AstraZeneca, Boehringer-Ingelheim. Kristina Lamberg, Advisory boards: MSD and AstraZeneca. Sayed M.S. Hashemi, Advisory board/research grants: Abbvie, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, GSK, MSD, Novartis, Roche, Takeda, Xcovery. Florian Huemer, Advisory Boards and Honoraria: MSD, BMS, Roche, Sanofi, Lilly, Takeda, Astra Zeneca, Boehringer Ingelheim. Anders Vikström, Ad-boards: AstraZeneca, Abbvie, BMS, Boehringer-Ingelheim, Pfizer, Roche, Takeda. Lectures: AstraZeneca, BMS, Boehringer-Ingelheim, MSD, Roche, Takeda. Grants: Boehringer-Ingelheim Consultancies: Astra Zeneca, Boehringer-Ingelheim, Roche. Martin Wermke, Received speaker fees and/or honoraria for advisory boards from BMS, Merck, Roche, Novartis, Kite, Boehringer Ingelheim, Astra Zeneca, Heidelberg Pharma. Gudrun Absenger, Honoraria from: AMGEN, AstraZeneca, BMS, Böhringer Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Alfredo Addeo, Personal fees from Bristol-Myers Squibb, AstraZeneca, Roche, Pfizer, Merck Sharp and Dohme, and Boehringer-Ingelheim for work performed outside of the current study. Shantanu Banerji, Honoraria for advisory board: AstraZeneca, Bayer, BMS, EMD-Serono, Merck, Novartis, Pfizer, Roche, Takeda Speaker Fees: None Research Funds: AstraZeneca. Antonio Calles, Honoraria/consulting fees from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Takeda, Novartis, Merck Sharp & Dohme, and Bristol-Myers Squibb; Research grants from MSD and PharmaMar. Stephen Clarke, Advisory board and speaking remuneration from AstraZeneca. Massimo Di Maio, Honoraria and had roles as consultant or advisor for AstraZeneca, Pfizer, Novartis, Roche, Takeda, Eisai, Janssen, Astellas; received institutional research grant by Tesaro – GlaxoSmithKline. Alice Durand, No conflict of interest. Michaël Duruisseaux, Membership of an advisory council or committee for Roche, BMS, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, Merus, Amgen and Pfizer; consulting fees from Roche, BMS, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, and Pfizer; research grants from Takeda, NanoString, and Blueprint. Malinda Itchins, AdBoard: Pfizer, Takeda. Consultancy: Roche, Merck. Honoraria: AZ, Pfizer, takeda, Roche, Novartis. Academic travel support: Roche, MSD. Okko-Sakari Kääränien, No conflict of interest associated with this study. Florian Krenn, Advisory Boards: Roche, MSD. Eckart Laack, Honoraria for advisory boards: AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, Roche, Takeda, MSD, Novartis, Lilly. Speaker fees. AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, Roche, Takeda, MSD, Novartis, Lilly. Research grants and clinical study: AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, Roche, Takeda, MSD, Novartis, Lilly. Adrianus Johannes de Langen, Research grants: BMS, MSD, AstraZeneca, Boehringer, Merus Non-financial support: Merck, Roche Advisory boards: Lilly, Bayer, MSD, AstraZeneca. Katja Mohorcic, Honoraria for ad-boards and speaker from MSD, Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, BMS, Abbvie. Georg Pall, Speakers honoraria and advisory board-member: Eli Lilly, Roche. Antonio Passaro, Honoraria for consulting, advisory role or lectures from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck Sharp & Dohme, Pfizer and Roche Genentech. Gerald Prager, Advisory Board Meetings/Symposiums: Merck, Roche, Amgen, Sanofi, Lilly, Servier, Taiho, Bayer, BMS, MSD, Celgene, Pierre Fabre, Terumo. Achim Rittmeyer, Grants as an advisor or speaker: AbbVie, Astra Zeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Pfizer and Roche. Jeffrey Rothenstein, Advisory Boards: Amgen, AZ, BMS, Merck, Pfizer, Roche. Michael Schumacher, Consulting, speakers fee, advisory panel membership, travel grants: AstraZeneca, Pfizer, Boehringer Ingelheim, Takeda, Roche, Amgen, Eli Lilly, MSD, BMS, Novartis. Ewald Wöll, Advisory boards or speaker fees: Amgen, Astra Zeneca, BMS, Celgen, Ebewe, Eli Lilly, Eisai, Janssen Cilag, Merck, MSD, Pierre Fabre, Pfizer, Ratiopharm, Roche, Sanofi Aventis. Arschang Valipour, Personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, Merck, Novartis, and Roche for lectures and/or advisory boards outside of the submitted study., (© The Author(s), 2021.)