Detection of RET fusion in late-line treatment of NSCLC followed by long-term disease control with selpercatinib

Czech version

Authors: Miriam Šuranová ¹; MUDr. Ondřej Bílek, Ph.D. ²; MUDr. Aleš Neumann, Ph.D. ³; Mgr. Jitka Berkovcová, Ph.D. ⁴; doc. MUDr. Tomáš Kazda, Ph.D. ⁵; prof. MUDr. Igor Kiss, Ph.D. ²
Authors‘ workplace: LF MU, Brno ¹; Klinika komplexní onkologické péče LF MU a MOÚ, Brno ²; Úsek radiologie, MOÚ, Brno ³; Úsek diagnostické patologie, MOÚ, Brno ⁴; Klinika radiační onkologie LF MU a MOÚ, Brno ⁵
Published in: Klin Onkol 2026; 39(5): 368-371
Category: Case Report
doi: https://doi.org/10.48095/ccko2026368

Overview

Background: RET gene fusions represent a rare but clinically relevant genetic alteration in non-small cell lung cancer (NSCLC), particularly in adenocarcinoma, with a prevalence of approximately 1–2%. Identification of this driver mutation has enabled the development of selective RET tyrosine kinase inhibitors, which significantly improve treatment outcomes in these patients. Molecular testing, including detection of RET fusions, is currently a standard component of the diagnostic algorithm for advanced NSCLC. Case report: We present the case of a 55-year-old female non-smoker diagnosed with metastatic lung adenocarcinoma with central nervous system (CNS) involvement. Initial molecular testing revealed no alterations in EGFR, ALK, or ROS1, and PD-L1 expression was negative. The patient underwent hippocampus-avoiding whole-brain radiotherapy followed by three lines of systemic treatment including chemotherapy and immunotherapy. Upon disease progression, next--generation sequencing analysis of a rebiopsy specimen obtained from a supraclavicular metastasis identified a RET gene fusion. Based on this finding, treatment with selpercatinib was initiated in January 2022 as the fourth-line therapy. Treatment resulted in a rapid and profound response, including complete regression of CNS metastases. Therapy was well tolerated; initial hepatotoxicity was successfully managed by dose reduction. The patient has remained on RET inhibitor therapy for nearly 4 years with sustained disease control. Conclusion: This case highlights the importance of comprehensive molecular testing in patients with advanced NSCLC. Identification of RET fusion may enable the use of highly effective targeted therapy even after failure of multiple lines of systemic treatment.

Keywords:

Non-small cell lung cancer – targeted therapy – RET fusion – selpercatinib

Sources

1. Dušek L, Mužík J, Kubásek M et al. Epidemiologie zhoubných nádorů v České republice. [online]. Brno: Masarykova univerzita 2005. Dostupné z: http: //www.svod.cz.

2. Chevallier M, Borgeaud M, Addeo A et al. Oncogenic driver mutations in non-small cell lung cancer: Past, present and future. World J Clin Oncol 2021; 12 (4): 217–237. doi: 10.5306/wjco.v12.i4.217.

3. Lin C, Wang S, Xie W et al. The RET fusion gene and its correlation with demographic and clinicopathological features of non-small cell lung cancer: a meta-analysis. Cancer Biol Ther 2015; 16 (7): 1019–1028. doi: 10.1080/15384047.2015.1046649.

4. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer 2014; 14 (3): 173–186. doi: 10.1038/nrc3680.

5. Ackermann CJ, Stock G, Tay R et al. Targeted therapy for RET-rearranged non-small cell lung cancer: clinical development and future directions. Onco Targets Ther 2019; 12 : 7857–7864. doi: 10.2147/OTT.S171665.

6. Negrao MV, Skoulidis F, Montesion M et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J Immunother Cancer 2021; 9 (8): e002891. doi: 10.1136/jitc-2021-002891.

7. Drilon A, Oxnard GR, Tan DS et al. Efficacy of selpercatinib in RET fusion-positive non–small-cell lung cancer. N Engl J Med 2020; 383 (9): 813–824. doi: 10.1056/NEJMoa2005653.

8. Gainor JF, Curigliano G, Kim DW et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol 2021; 22 (7): 959–969. doi: 10.1016/S1470-2045 (21) 00247-3.

9. Lindeman NI, Cagle PT, Aisner DL et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med 2018; 142 (3): 321–346. doi: 10.5858/arpa.2017-0388-CP.

10. Drilon A, Oxnard G, Wirth L et al. PL02.08 registrational results of LIBRETTO-001: a phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers. J Thoracic Oncol 2019; 14 (10): S6–S7. doi: 10.1016/j.jtho.2019.08.059.

11. Gautschi O, Park K, Solomon BJ et al. Selpercatinib in RET fusion-positive non-small cell lung cancer: final safety and efficacy, including overall survival, from the LIBRETTO-001 phase I/II trial. J Clin Oncol 2025; 43 (15): 1758–1764. doi: 10.1200/JCO-24-02076.

12. European Medicines Agency. Retsevmo –⁠ selpercatinib. [online]. [cit. 2021-8-29]. Available from: https: //www.ema.europa.eu/en/documents/smop-initial/chmp-summary-positive-opinion-retsevmo_en.pdf.

13. Linkos. Modrá kniha České onkologické společnosti (31. aktualizace). [online]. Brno: Masarykův onkologický ústav 2025. Dostupné z: https: //www.linkos.cz/lekar-a-multidisciplinarni-tym/personalizovana-onkologie/modra-kniha-cos/aktualni-vydani-modre-knihy/.

14. Suay G, Aparisi F, Juan-Vidal O. European Society of Medical Oncology (ESMO) guidelines for oncogene-addicted metastatic non-small cell lung cancer (NSCLC): a personalized treatment for each patient. Chin Clin Oncol 2024; 13 (3): 46. doi: 10.21037/cco-23-100.

15. Subbiah V, Cote GJ. Advances in targeting RET-dependent cancers. Cancer Discov 2020; 10 (4): 498–505. doi: 10.1158/2159-8290.CD-19-1116.