Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic Advances in the Management of Patients with Advanced RET Fusion-Positive Non-Small Cell Lung Cancer

  • Lung Cancer (TA Leal, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Screening for activating driver gene alterations at the time of diagnosis is the standard of care for advanced non-small cell lung cancer (NSCLC). Activating RET fusions are identified in approximately 1–2% of NSCLCs and have emerged as a targetable driver alteration. Selpercatinib and pralsetinib are RET-selective tyrosine kinase inhibitors (TKIs) with encouraging efficacy, intracranial activity, and tolerability that we recommend as first-line therapy. As with use of TKIs in other oncogene-addicted NSCLCs, development of acquired resistance is pervasive and should be specifically delineated through use of repeat tissue biopsy with genetic profiling at the time of disease progression. If an actionable resistance mechanism emerges for which there is a candidate targeted therapy, combination inhibition should be considered. Alternatively, or in the absence of such findings, platinum doublet chemotherapy or particularly platinum-pemetrexed therapy with or without bevacizumab demonstrates a moderate effect.

We would not recommend the routine use of nonselective multi-targeted TKIs such as cabozantinib and vandetanib, which have modest activity but limited tolerability due to predictable off-target effects. Single-agent immunotherapy has minimal activity in RET fusion-positive NSCLC. The role of combination chemotherapy and immunotherapy requires further study but may be considered, particularly in the presence of an activating KRAS alteration. While further development of novel RET-selective TKIs may address common RET-specific resistance mutations, they will not have activity against off-target, RET-independent resistance mechanisms. This again highlights the importance of serial biopsy and next-generation sequencing for the rational choice of sequential therapy in RET fusion-positive NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Notes

  1. For cost analyses, average wholesale prices as reported in the IBM Micromedex Red Book as of January 2021 are cited [30].

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Shaw AT, Riely GJ, Bang Y-J, Kim D-W, Camidge DR, Solomon BJ, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019;30:1121–6. https://doi.org/10.1093/annonc/mdz131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Solomon BJ, Mok T, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, et al. First-Line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77. https://doi.org/10.1056/NEJMoa1408440.

    Article  CAS  PubMed  Google Scholar 

  3. Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim D-W, et al. Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med. 2017;377:829–38. https://doi.org/10.1056/NEJMoa1704795.

    Article  CAS  PubMed  Google Scholar 

  4. Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376:629–40. https://doi.org/10.1056/NEJMoa1612674.

    Article  CAS  PubMed  Google Scholar 

  5. Zhou C, Wu Y-L, Chen G, Feng J, Liu X-Q, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–42. https://doi.org/10.1016/S1470-2045(11)70184-X.

    Article  CAS  PubMed  Google Scholar 

  6. Planchard D, Besse B, Groen HJM, Souquet P-J, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17:984–93. https://doi.org/10.1016/S1470-2045(16)30146-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Farago AF, Le LP, Zheng Z, Muzikansky A, Drilon A, Patel M, et al. Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer. J Thorac Oncol. 2015;10:1670–4. https://doi.org/10.1097/01.JTO.0000473485.38553.f0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UK, Demetri GD, et al. Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N Engl J Med. 2018;378:731–9. https://doi.org/10.1056/NEJMoa1714448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Weinstein IB. Addiction to oncogenes—the Achilles heal of cancer. Science. 2002;297:63–4. https://doi.org/10.1126/science.1073096.

    Article  CAS  PubMed  Google Scholar 

  10. Torti D, Trusolino L. Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med. 2011;3:623–36. https://doi.org/10.1002/emmm.201100176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985;42:581–8. https://doi.org/10.1016/0092-8674(85)90115-1.

    Article  CAS  PubMed  Google Scholar 

  12. Ceccherini I, Bocciardi R, Luo Y, Pasini B, Hofstra R, Takahashi M, et al. Exon structure and flanking intronic sequences of the human RET proto-oncogene. Biochem Biophys Res Commun. 1993;196:1288–95. https://doi.org/10.1006/bbrc.1993.2392.

    Article  CAS  PubMed  Google Scholar 

  13. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 2014;14:173–86. https://doi.org/10.1038/nrc3680.

    Article  CAS  PubMed  Google Scholar 

  14. Kawamoto Y, Takeda K, Okuno Y, Yamakawa Y, Ito Y, Taguchi R, et al. Identification of RET autophosphorylation sites by mass spectrometry. J Biol Chem. 2004;279:14213–24. https://doi.org/10.1074/jbc.M312600200.

    Article  CAS  PubMed  Google Scholar 

  15. Takahashi M. The GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev. 2001;12:361–73. https://doi.org/10.1016/s1359-6101(01)00012-0.

    Article  CAS  PubMed  Google Scholar 

  16. Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23:1988–97. https://doi.org/10.1158/1078-0432.CCR-16-1679.

    Article  CAS  PubMed  Google Scholar 

  17. Moura MM, Cavaco BM, Pinto AE, Domingues R, Santos JR, Cid MO, et al. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas. Br J Cancer. 2009;100:1777–83. https://doi.org/10.1038/sj.bjc.6605056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Marsh DJ, Mulligan LM, Eng C. RET proto-oncogene mutations in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. Horm Res. 1997;47:168–78. https://doi.org/10.1159/000185461.

    Article  CAS  PubMed  Google Scholar 

  19. Pietrantonio F, Di Nicolantonio F, Schrock AB, Lee J, Morano F, Fuca G, et al. RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. Ann Oncol. 2018;29:1394–401. https://doi.org/10.1093/annonc/mdy090.

    Article  CAS  PubMed  Google Scholar 

  20. Santos C, Sanz-Pamplona R, Salazar R. RET-fusions: a novel paradigm in colorectal cancer. Ann Oncol. 2018;29:1340–3. https://doi.org/10.1093/annonc/mdy132.

    Article  CAS  PubMed  Google Scholar 

  21. Santoro M, Carlomagno F, Hay ID, Herrmann MA, Grieco M, Melillo R, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest. 1992;89:1517–22. https://doi.org/10.1172/JCI115743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Paratala BS, Chung JH, Williams CB, Yilmazel B, Petrosky W, Williams K, et al. RET rearrangements are actionable alterations in breast cancer. Nat Commun. 2018;9:4821. https://doi.org/10.1038/s41467-018-07341-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lipson D, Capelletti M, Yelensky R, Ottto G, Parker A, Jarosz M, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18:382–4. https://doi.org/10.1038/nm.2673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang R, Hu H, Pan Y, Li Y, Ye T, Li C, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30:4352–9. https://doi.org/10.1200/JCO.2012.44.1477.

    Article  CAS  PubMed  Google Scholar 

  25. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18:378–81. https://doi.org/10.1038/nm.2658.

    Article  CAS  PubMed  Google Scholar 

  26. Platt A, Morten J, Ji Q, Elvin P, Womack C, Su X, et al. A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized phase III studies. BMC Cancer. 2015;15:171. https://doi.org/10.1186/s12885-015-1146-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non–small cell lung cancer. J Thorac Oncol. 2018;13:27–45. https://doi.org/10.1016/j.jtho.2017.10.021.

    Article  CAS  PubMed  Google Scholar 

  28. Gautschi O, Milia J, Filleron T, Wolf J, Carbone DP, Owen D, et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol. 2017;35:1403–10. https://doi.org/10.1200/JCO.2016.70.9352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ju YS, Lee W-C, Shin J-Y, Lee S, Bleazard T, Won J-K, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 2012;22:436–45. https://doi.org/10.1101/gr.133645.111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. IBM Micromedex RED Book. IBM Watson Health, an IBM Company. https://www.ibm.com/us-en/marketplace/micromedex-red-book 2017. Accessed 30 Jan 2021.

  31. Brandhuber B, Haas J, Tuch B, Ebata K, Bouhana K, McFaddin E, et al. The development of a potent, KDR/VEGFR2-sparing RET kinase inhibitor for treating patients with RET-dependent cancers. Eur J Cancer. 2016;69:S144. https://doi.org/10.1016/S0959-8049(16)33028-3.

    Article  Google Scholar 

  32. Subbiah V, Velcheti V, Tuch BB, Ebata K, Busaidy NL, Cabanillas ME, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol. 2018;29:1869–76. https://doi.org/10.1093/annonc/mdy137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. •• Drilon A, Oxnard GR, Tan DS, Loong HHF, Johnson M, Gainor J, et al. Efficacy of selpercatinib in RET fusion-positive non–small-cell lung cancer. N Engl J Med. 2020;383:813–24. https://doi.org/10.1056/NEJMoa2005653In a phase 1/2 trial, patients with advanced RET fusion-positive NSCLC treated with the RET-selective TKI selpercatinib had marked, durable responses and encouraging tolerability.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Subbiah V, Gainor JF, Oxnard GR, Tan DS, Owen DH, Cho BC, et al. Intracranial activity of selpercatinib (LOXO-292) in RET fusion-positive non-small cell lung cancer (NSCLC) patients on the LIBRETTO-001 trial. J Clin Oncol. 2020;38(Suppl 15):9516. https://doi.org/10.1200/JCO.2020.38.15_suppl.9516.

    Article  Google Scholar 

  35. Oxnard GR, Drilon AE, Shah MH, Wirth LJ, Bauer TM, Velcheti V, et al. Detection and clearance of RET variants in plasma cell free DNA (cfDNA) from patients (pts) treated with LOXO-292. J Clin Oncol. 2018;36(Suppl 15):9048. https://doi.org/10.1200/JCO.2018.36.15_suppl.9048.

    Article  Google Scholar 

  36. Drilon A, Rekhtman N, Arcila M, Wang L, Ni A, Albano M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single centre, phase 2, single-arm trial. Lancet Oncol. 2016;17:1653–60. https://doi.org/10.1016/S1470-2045(16)30562-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lee S-H, Lee J-K, Ahn M-J, Kim D-W, Sun J-M, Keam B, et al. Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial. Ann Oncol. 2017;28:292–7. https://doi.org/10.1093/annonc/mdw559.

    Article  PubMed  Google Scholar 

  38. Yoh K, Seto T, Satouchi M, Nishio M, Yamamoto N, Murakami H, et al. Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Respir Med 2017;5:42–50. doi:https://doi.org/10.1016/S2213-2600(16)30322-8.

  39. Hida T, Velcheti V, Reckamp KL, Nokihara H, Sachdev P, Kubota T, et al. A phase 2 study of lenvatinib in patients with RET fusion-positive lung adenocarcinoma. Lung Cancer. 2019;138:124–30. https://doi.org/10.1016/j.lungcan.2019.09.011.

    Article  PubMed  Google Scholar 

  40. FDA approves selpercatinib; pralsetinib may soon follow. Cancer Discov. 2020;10:OF1. https://doi.org/10.1158/2159-8290.CD-NB2020-052.

  41. McCoach CE, Tan DSW, Besse B, Goto K, Zhu VW, Rolfo CD, et al. Hypersensitivity reactions to selpercatinib in RET fusion+ non-small cell lung cancer (NSCLC) patients (pts) following immune checkpoint inhibition (CPI). Ann Oncol. 2020;31(Suppl 4):S835–6. https://doi.org/10.1016/j.annonc.2020.08.1605.

    Article  Google Scholar 

  42. Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, et al. Precision targeted therapy with BLU-667 for RET-driven cancers. Cancer Discov. 2018;8:836–49. https://doi.org/10.1158/2159-8290.CD-18-0338.

    Article  CAS  PubMed  Google Scholar 

  43. Evans EK, Hu W, Cao F, Hoeflich K, Dorsch M. Pralsetinib (BLU-667) demonstrates robust activity in RET-fusion-driven intracranial tumor models. In: The 2019 World Conference on Lung Cancer. 2019;Abstract P2.03-44.

  44. •• Gainor JF, Curigliano G, Kim D-W, Lee DH, Besse B, Baik CS, et al. ET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(Suppl 15):9515. https://doi.org/10.1200/JCO.2020.38.15_suppl.9515Phase I/II trial demonstrating potent, durable clinical activity in patients with RET fusion-positive NSCLC treated with the RET-selective TKI pralsetinib.

    Article  Google Scholar 

  45. Gainor JF, Lee DH, Curigliano G, Doebele RC, Kim D-W, Baik CS, et al. Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(Suppl 15):9008. https://doi.org/10.1200/JCO.2019.37.15_suppl.9008.

    Article  Google Scholar 

  46. Lee DH, Subbiah V, Gainor JF, Taylor MH, Zhu VW, Doebele RC, et al. Treatment with pralsetinib (formerly BLU-667), a potent and selective RET inhibitor, provides rapid clearance of ctDNA in patients with RET-altered non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). Ann Oncol. 2019;30(Suppl 9:ix122). https://doi.org/10.1093/annonc/mdz431.

  47. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–308. https://doi.org/10.1158/1535-7163.MCT-11-0264.

    Article  CAS  PubMed  Google Scholar 

  48. Drilon A, Somwar R, Wagner JP, Vellore NA, Eide CA, Zabriskie MS, et al. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clin Cancer Res. 2016;22:2351–8. https://doi.org/10.1158/1078-0432.CCR-15-2013.

    Article  CAS  PubMed  Google Scholar 

  49. Huang Q, Schneeberger VE, Luetteke N, Jin C, Afzal R, Budzevich MM, et al. Preclinical modeling of KIF5B-RET fusion lung adenocarcinoma. Mol Cancer Ther. 2016;15:2521–9. https://doi.org/10.1158/1535-7163.MCT-16-0258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Drilon A, Lin JJ, Filleron T, Ni A, Milia J, Bergagnini I, et al. Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-rearranged lung cancers. J Thorac Oncol. 2018;13:1595–601. https://doi.org/10.1016/j.jtho.2018.07.004.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Morabito A, Piccirillo MC, Falasconi F, De Feo G, Del Giudice A, Bryce J, et al. Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. Oncologist. 2009;14:378–90. https://doi.org/10.1634/theoncologist.2008-0261.

    Article  CAS  PubMed  Google Scholar 

  52. Herbst RS, Sun Y, Eberhardt WEE, Germopre P, Saijo N, Zhou C, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010;11:619–26. https://doi.org/10.1016/S1470-2045(10)70132-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai C-M, Sunpaweravong P, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2011;29:1059–66. https://doi.org/10.1200/JCO.2010.28.5981.

    Article  CAS  PubMed  Google Scholar 

  54. De Boer RH, Arrieta Ó, Yang C-H, Gottfried M, Chan V, Raats J, et al. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2011;29:1067–74. https://doi.org/10.1200/JCO.2010.29.5717.

    Article  CAS  PubMed  Google Scholar 

  55. Lee JS, Hirsh V, Park K, Qin S, Blajman CR, Perng R-P, et al. Vandetanib versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol. 2012;30:1114–21. https://doi.org/10.1200/JCO.2011.36.1709.

    Article  CAS  PubMed  Google Scholar 

  56. Zhou C, Lu Y, Kim S-W, Reungwetwatttana T, Zhou J, Zhang Y, et al. Primary results of ALESIA: phase III, randomised open-label study of alectinib (ALC) vs crizotinib (CRZ) in Asian patients (pts) with treatment-naïve ALK+ advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 2018;29(Suppl 9:ix174). https://doi.org/10.1093/annonc/mdy483.001.

  57. Lin JJ, Kennedy E, Sequist LV, Brastianos PK, Goodwin KE, Stevens S, et al. Clinical activity of alectinib in advanced RET-rearranged non-small cell lung cancer. J Thorac Oncol. 2016;11:2027–32. https://doi.org/10.1016/j.jtho.2016.08.126.

    Article  PubMed  Google Scholar 

  58. Ribeiro MFSA, Alessi JVM, Oliveira LJC, Gongora ABL, Sacardo KP, Zucchetti BM, et al. Alectinib activity in chemotherapy-refractory metastatic RET-rearranged non-small cell lung carcinomas: a case series. Lung Cancer. 2020;139:9–12. https://doi.org/10.1016/j.lungcan.2019.10.020.

    Article  PubMed  Google Scholar 

  59. Takeuchi S, Murayama T, Yoshimura K, Kawakami T, Takahara S, Imai Y, et al. Phase I/II study of alectinib in lung cancer with RET fusion gene: study protocol. J Med Investig. 2017;64:317–20. https://doi.org/10.2152/jmi.64.317.

    Article  Google Scholar 

  60. Gainor JF, Chi AS, Logan J, Hu R, Oh KS, Brastianos PK, et al. Alectinib dose escalation reinduces central nervous system responses in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer relapsing on standard dose alectinib. J Thorac Oncol. 2016;11:256–60. https://doi.org/10.1016/j.jtho.2015.10.010.

    Article  PubMed  Google Scholar 

  61. Peled N, Ponce S, Alatorre-Alexander JA, Kinkolykh A, Vicuna BD, Mathiesen M, et al. Higher dose alectinib for advanced RET+ NSCLC: results from the RET+ cohort of the blood first assay screening trial (BFAST). In: The 2020 World Conference on Lung Cancer. 2021;Abstract P87.01.

  62. Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390:29–39. https://doi.org/10.1016/S0140-6736(17)30565-2.

    Article  CAS  PubMed  Google Scholar 

  63. Drilon A, Fu S, Patel MR, Fakih M, Wang D, Olszanski AJ, et al. A phase I/Ib trial of the VEGFR-sparing multikinase RET inhibitor RXDX-105. Cancer Discov. 2019;9:384–95. https://doi.org/10.1158/2159-8290.CD-18-0839.

    Article  CAS  PubMed  Google Scholar 

  64. Horiike A, Takeuchi K, Uenami T, Kawano Y, Tanimoto A, Kaburaki K, et al. Sorafenib treatment for patients with RET fusion-positive non-small cell lung cancer. Lung Cancer. 2016;93:43–6. https://doi.org/10.1016/j.lungcan.2015.12.011.

    Article  PubMed  Google Scholar 

  65. Gainor JF, Gadgeel S, Ou SI, Yeap B, Otterson GA, Shaw AT. A phase II study of the multikinase inhibitor ponatinib in patients with advanced. RET-rearranged NSCLC JTO Clin Res Rep. 2020;1:100045. https://doi.org/10.1016/j.jtocrr.2020.100045.

    Article  Google Scholar 

  66. Lin C, Wang S, Xie W, Zheng R, Gan Y, Chang J. Apatinib inhibits cellular invasion and migration by fusion kinase KIF5B-RET via suppressing RET/Src signaling pathway. Oncotarget. 2016;7:59236–44. https://doi.org/10.18632/oncotarget.10985.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Kang CW, Jang KW, Sohn J, Kim S-M, Pyo K-H, Kim H, et al. Antitumor activity and acquired resistance mechanism of dovitinib (TKI258) in RET-rearranged lung adenocarcinoma. Mol Cancer Ther. 2015;14:2238–48. https://doi.org/10.1158/1535-7163.MCT-15-0350.

    Article  CAS  PubMed  Google Scholar 

  68. Plenker D, Diedel M, Brägelmann J, Dammert MA, Chauhan R, Knowles PP, et al. Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer. Sci Transl Med. 2017;9:eaah6144. https://doi.org/10.1126/scitranslmed.aah6144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543–51. https://doi.org/10.1200/JCO.2007.15.0375.

    Article  CAS  PubMed  Google Scholar 

  70. Drilon A, Bergagnini I, Delasos L, Sabari J, Woo KM, Plodkowski A, et al. Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers. Ann Oncol. 2016;27:1286–91. https://doi.org/10.1093/annonc/mdw163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee CK, Man J, Lord S, Links M, Gebski V, Mok T, et al. Checkpoint inhibitors in metastatic EGFR-mutated non–small cell lung cancer – a meta-analysis. J Thorac Oncol. 2017;12:403–7. https://doi.org/10.1016/j.jtho.2016.10.007.

    Article  PubMed  Google Scholar 

  72. Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res. 2016;22:4585–93. https://doi.org/10.1158/1078-0432.CCR-15-3101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hellmann MD, Ciuleanu T-E, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378:2093–104.

    Article  CAS  Google Scholar 

  74. Offin M, Guo R, Wu SL, Sabari J, Land JD, Ni A, et al. Immunophenotype and response to immunotherapy of RET-rearranged lung cancers. JCO Precis Oncol. 2019;3. https://doi.org/10.1200/PO.18.00386.

  75. • Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30:1321–8. https://doi.org/10.1093/annonc/mdz167Multinational registry study characterizing the effect of ICIs in NSCLC with targetable driver alterations, demonstrating minimal response to immunotherapy for patients with RET fusion-positive NSCLC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen N, Fang W, Lin Z, Peng P, Wang J, Zhan J, et al. KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma. Cancer Immunol Immunother. 2017;66:1175–87. https://doi.org/10.1007/s00262-017-2005-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hegde A, Andreev-Drakhlin AY, Roszik J, Huang L, Liu S, Hess K, et al. Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies. ESMO Open. 2020;5:e000799. https://doi.org/10.1136/esmoopen-2020-000799.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378:2078–92. https://doi.org/10.1056/NEJMoa1801005.

    Article  CAS  PubMed  Google Scholar 

  79. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378:2288–301. https://doi.org/10.1056/NEJMoa1716948.

    Article  CAS  PubMed  Google Scholar 

  80. Non-Small Cell Lung Cancer (Version 2.2021). National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 30 Jan 2021.

  81. • Lin JJ, Liu SV, McCoach CE, Zhu VW, Tan AC, Yoda S, et al. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer. Ann Oncol. 2020;31:1725–33. https://doi.org/10.1016/j.annonc.2020.09.015Multicenter molecular profiling study identifying both off-target, RET-independent mechanisms and acquired RET mutations as mechanisms of resistance to the RET-selective TKIs selpercatinib and pralsetinib.

    Article  CAS  PubMed  Google Scholar 

  82. Solomon BJ, Tan L, Lin JJ, Wong SQ, Hoolizeck S, Ebata K, et al. RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies. J Thorac Oncol. 2020;15:541–9. https://doi.org/10.1016/j.jtho.2020.01.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Subbiah V, Shen T, Terzyan SS, Liu X, Hu X, Patel KP, et al. Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations. Ann Oncol. 2021;32:261–8. https://doi.org/10.1016/j.annonc.2020.10.599.

    Article  CAS  PubMed  Google Scholar 

  84. Rosen EY, Johnson ML, Clifford SE, Somwar R, Kherani JF, Son J, et al. Overcoming MET-dependent resistance to selective RET inhibition in patients with RET fusion–positive lung cancer by combining selpercatinib with crizotinib. Clin Cancer Res. 2021;27:34–42. https://doi.org/10.1158/1078-0432.CCR-20-2278.

    Article  CAS  PubMed  Google Scholar 

  85. Lin JJ, Ritterhouse LL, Ali SM, Bailey M, Schrock AB, Gainor JF, et al. ROS1 fusions rarely overlap with other oncogenic drivers in non–small cell lung cancer. J Thorac Oncol. 2017;12:872–7. https://doi.org/10.1016/j.jtho.2017.01.004.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Gainor JF, Varghese AM, Ou SI, Kabraji S, Awad MM, Katayama R, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res. 2013;19:4273–81. https://doi.org/10.1158/1078-0432.CCR-13-0318.

    Article  CAS  PubMed  Google Scholar 

  87. Song Z, Yu X, Zhang Y. Clinicopathologic characteristics, genetic variability and therapeutic options of RET rearrangements patients in lung adenocarcinoma. Lung Cancer. 2016;101:16–21. https://doi.org/10.1016/j.lungcan.2016.09.002.

    Article  PubMed  Google Scholar 

  88. Kim J-O, Lee J, Shin J-Y, Kim MY, Son KH, Jung C-K, et al. The clinical characteristics of RET rearranged lung adenocarcinoma patients. J Clin Oncol. 2015;33(Suppl 15):e18528. https://doi.org/10.1200/jco.2015.33.15_suppl.e18528.

    Article  Google Scholar 

  89. Codony-Servat J, García-Roman S, Molina-Vila MÁ, Bertran-Alamillo J, Viteri S, d’Hondt E, et al. Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells. Transl Oncol. 2021;14:100887. https://doi.org/10.1016/j.tranon.2020.100887.

    Article  PubMed  Google Scholar 

  90. Fujimura T, Furugaki K, Harada N, Yoshimura Y. Enhanced antitumor effect of alectinib in combination with cyclin-dependent kinase 4/6 inhibitor against RET-fusion-positive non–small cell lung cancer cells. Cancer Biol Ther. 2020;21:863–70. https://doi.org/10.1080/15384047.2020.1806643.

    Article  CAS  PubMed  Google Scholar 

  91. Subbiah V, Berry J, Roxas M, Guha-Thakurta N, Subbiah IM, Ali SM, et al. Systemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged non-small cell lung cancer with brain metastases. Lung Cancer. 2015;89:76–9. https://doi.org/10.1016/j.lungcan.2015.04.004.

    Article  PubMed  Google Scholar 

Download references

Funding

C.E.M. has received honoraria from Takeda, Guardant Health, Genentech, Astra Zeneca, and Novartis, and research funding from Novartis and Revolution Medicines.

Availability of data and materials

Not applicable.

Code availability

Not applicable.

Author information

Authors and Affiliations

  1. Department of Medicine, University of California, San Francisco, CA, 94143, USA

    Fangdi Sun MD & Caroline E. McCoach MD, PhD

Authors
  1. Fangdi Sun MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caroline E. McCoach MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fangdi Sun MD.

Ethics declarations

Conflict of Interest

F.S. has no conflict of interest to disclose. C.E.M. is currently employed by Genentech Inc, USA.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Lung Cancer

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, F., McCoach, C.E. Therapeutic Advances in the Management of Patients with Advanced RET Fusion-Positive Non-Small Cell Lung Cancer. Curr. Treat. Options in Oncol. 22, 72 (2021). https://doi.org/10.1007/s11864-021-00867-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11864-021-00867-8

Keywords

Search

Navigation