Defining resistance mechanisms to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer
Authors: L. Tan, B.J. Solomon
Journal: Annals of Oncology (2020)

Activation of the rearranged during transfection (RET) proto-oncogene by chromosomal rearrangements and point mutations results in ligand-independent kinase activation and consequent oncogene dependence in various malignancies.1Kato S. Subbiah V. Marchlik E. Elkin S.K. Carter J.L. Kurzrock R. RET patients aberrations in diverse cancers: next-generation sequencing of 4,871.Clin Cancer Res. 2017; 23: 1988-1997Crossref PubMed Scopus (99) Google Scholar, 2Romei C. Ciampi R. Elisei R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma.Nat Rev Endocrinol. 2016; 12: 192-202Crossref PubMed Scopus (150) Google Scholar, 3Stransky N. Cerami E. Schalm S. Kim J.L. Lengauer C. The landscape of kinase fusions in cancer.Nat Commun. 2014; 5: 4846Crossref PubMed Scopus (513) Google Scholar RET fusions are found in 1%–2% of non-small-cell lung cancer (NSCLC) and 10%–20% of papillary thyroid cancers, whereas RET mutations occur in 60% of sporadic and more than 90% of hereditary medullary thyroid cancers (MTCs).1Kato S. Subbiah V. Marchlik E. Elkin S.K. Carter J.L. Kurzrock R. RET patients aberrations in diverse cancers: next-generation sequencing of 4,871.Clin Cancer Res. 2017; 23: 1988-1997Crossref PubMed Scopus (99) Google Scholar,4Gautschi O. Milia J. Filleron T. et al.Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry.J Clin Oncol. 2017; 35: 1403-1410Crossref PubMed Scopus (186) Google Scholar While cabozantinib and vandetanib, both multikinase inhibitors with nonselective RET inhibitory activity, have been approved by the US Food and Drug Administration (FDA) for MTCs, these drugs demonstrate only modest efficacy and substantial toxicities in RET fusion-positive NSCLC.5Drilon A. Rekhtman N. Arcila 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: 1653-1660Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 6Yoh K. Seto T. Satouchi M. Vandetanib in patients with previously treatment RET-rearranded advanced non-small cell lung cancer (LURET): an open-label, multicentre, phase 2 trial.Lancet Respir Med. 2017; 5: 42-50Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 7Lee S.H. Lee J.K. Ahn M.J. 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: 292-297Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 8Elisei R. Schlumberger M.J. Muller S.P. et al.Cabozantinib in progressive medullary thyroid cancer.J Clin Oncol. 2013; 31: 3639-3646Crossref PubMed Scopus (668) Google Scholar, 9Wells Jr., S.A. Robinson B.G. Gagel R.F. et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.J Clin Oncol. 2012; 30: 134-141Crossref PubMed Scopus (908) Google Scholar More recently, two potent and highly selective RET tyrosine kinase inhibitors (TKIs), selpercatinib (LOXO292) and pralsetinib (BLU667), were tested in advanced RET-altered solid tumours.10Subbiah V. Velcheti V. Tuch B.B. et al.Selective RET kinase inhibition for patients with RET-altered cancers.Ann Oncol. 2018; 29: 1869-1876Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar,11Subbiah V. Gainor J.F. Rahal R. et al.Precision targeted therapy with BLU-667 for RET-driven cancers.Cancer Discov. 2018; 8: 836-849Crossref PubMed Scopus (173) Google Scholar Phase I/II trial of selpercatinib and pralsetinib in RET fusion-positive NSCLC demonstrated substantial efficacy, including intracranial activity, with objective response rates of 56%–64% in patients who had previously received platinum-based chemotherapy and 60%–85% in those who were previously untreated.12Drilon A. Oxnard G.R. Tan D.S.W. et al.Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer.N Engl J Med. 2020; 383: 813-824Crossref PubMed Scopus (127) Google Scholar,13Gainor J.F. Curigliano G. Kim D.-W. et al.Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC).J Clin Oncol. 2020; 38: 9515Crossref Google Scholar Responses appeared durable; for example, a median duration of response of 17.5 months was reported with selpercatinib.12Drilon A. Oxnard G.R. Tan D.S.W. et al.Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer.N Engl J Med. 2020; 383: 813-824Crossref PubMed Scopus (127) Google Scholar The results of these trials have led to the accelerated FDA approval of both selpercatinib and pralsetinib for the treatment of patients with metastatic RET fusion-positive NSCLC. A major predictable limitation to long-term clinical benefit of TKIs, however, is the development of acquired resistance to these targeted therapies. In this issue of Annals of Oncology, Lin et al.14Lin J.J. Liu S.V. McCoach C.E. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small cell lung cancer.Ann Oncol. 2020; 31: 1725-1733Abstract Full Text Full Text PDF Scopus (39) Google Scholar analysed post-treatment tissue or liquid biopsies from 18 RET fusion-positive NSCLC patients whose disease progressed on selpercatinib or pralsetinib. Using various broad-based next-generation sequencing platforms for both tissue and plasma genotyping, the authors identified MET amplification in three patients (15%), RET solvent front mutations in two patients (10%), and KRAS amplification in one patient, but no clear mechanism of resistance in the majority of patients. Of note, both RET solvent front mutations and MET amplification have previously been reported as mechanisms of resistance to selpercatinib.15Solomon B.J. Tan L. Lin J.J. et al.RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies.J Thorac Oncol. 2020; 15: 541-549Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar,16Zhu V.W. Madison R. Schrock A.B. Ignatius Ou S.H. Emergence of high level of MET amplification as off-target resistance to selpercatinib treatment in KIF5B-RET NSCLC.J Thorac Oncol. 2020; 15: e124-e127Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Lin et al. identified RET G810S and RET G810C mutations in two selpercatinib-resistant cases, respectively, confirming RET solvent front mutations as a recurring mechanism of resistance to RET-selective inhibitors. One of these cases was previously included in a series of five patients with RET-altered cancers (NSCLC or MTC) where RET solvent front mutations were first described as an acquired mechanism of resistance to selpercatinib.15Solomon B.J. Tan L. Lin J.J. et al.RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies.J Thorac Oncol. 2020; 15: 541-549Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar,16Zhu V.W. Madison R. Schrock A.B. Ignatius Ou S.H. Emergence of high level of MET amplification as off-target resistance to selpercatinib treatment in KIF5B-RET NSCLC.J Thorac Oncol. 2020; 15: e124-e127Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Structural modelling and functional studies confirmed that RET G810 mutations, which are located in the solvent front of the kinase domain, sterically interfere with selpercatinib binding, resulting in biochemical and clinical resistance.15Solomon B.J. Tan L. Lin J.J. et al.RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies.J Thorac Oncol. 2020; 15: 541-549Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar While this report sheds light on the frequency of RET solvent front mutations, which appears low in this relatively small, retrospective cohort of RET fusion-positive NSCLC patients, the frequency of these acquired mutations in RET fusion-positive NSCLC and other tumours will become clearer with additional studies. Resistance to RET inhibition through utilisation of bypass signalling mechanisms has been demonstrated preclinically17Nelson-Taylor S.K. Le A.T. Yoo M. Resistance to RET-inhibition in RET-rearranged NSCLC is mediated by reactivation of RAS/MAPK signalling.Mol Cancer Ther. 2017; 16: 1623-1633Crossref PubMed Scopus (39) Google Scholar,18Plenker D. Riedel M. Bragelmann J. Drugging the catalytically inactive state of RET kinase in RET-rearranged tumours.Sci Transl Med. 2017; 9: eaah6144Crossref PubMed Scopus (37) Google Scholar and Zhu et al.16Zhu V.W. Madison R. Schrock A.B. Ignatius Ou S.H. Emergence of high level of MET amplification as off-target resistance to selpercatinib treatment in KIF5B-RET NSCLC.J Thorac Oncol. 2020; 15: e124-e127Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar recently reported a clinical case with MET amplification as a likely off-target resistance mechanism to selpercatinib. In this series of patients, Lin et al. were able to identify MET amplification through various next-generation sequencing platforms including cell-free DNA assays in three patients. While the absence of functional studies and issues related to standardised definition of gene amplification are limitations, this report confirms that off-target resistance mechanisms, such as bypass signalling through MET amplification, is an additional recurrent—albeit low-frequency—resistance mechanism. Furthermore, this raises the possibility of combination targeted therapy or the use of multikinase inhibitors with activity against both MET and RET as a therapeutic strategy, at least in some patients. These studies provide early insight into the genomic landscape of resistance to RET-selective inhibitors. However, the relatively low prevalence of acquired mutations, compared with EGFR-mutant or ALK-rearranged NSCLC, raises the question of other mechanisms of therapeutic evasion. Increasingly, nongenetic mechanisms of drug resistance are being recognised as a contributing factor to tumour heterogeneity and therapy resistance.19Bell C.C. Gilan O. Principles and mechanisms of non-genetic resistance in cancer.Br J Cancer. 2020; 122: 465-472Crossref PubMed Scopus (30) Google Scholar Hence, the identification of recurrent, nongenetic resistance pathways may better characterise the contributions of both genetic and nongenetic mechanisms of acquired RET-selective inhibitor resistance and will be important in developing therapies to prevent or overcome this resistance. Importantly, the identification of resistance alterations in this study highlights the critical role of repeat tumour or liquid biopsies in patients progressing on RET inhibitors. As with other oncogene-driven lung cancers, resistance is likely driven by clonal heterogeneity which may not be apparent from tissue taken from a single lesion at the time of progression. The use of circulating tumour DNA in plasma as a liquid biopsy overcomes many limitations of tissue sampling as it allows longitudinal monitoring of genetic alterations and captures the genomic heterogeneity of the disease. While circulating tumour DNA alone cannot detect histologic transformation, it is interesting to note that this was not observed this study. The study by Lin et al. is the largest study to analyse a series of RET-TKI-resistant patients reported to date and provides valuable information about the frequency of recurrent mechanisms of resistance to selective RET inhibitors. The relatively small size and retrospective nature of this series emphasise the need for larger, prospective studies incorporating molecular monitoring using tissue or liquid biopsy at the time of progression to characterise the nature and frequency of resistance mechanisms to guide further treatment. Additionally, the use of standardised testing platforms for assessing these genetic alterations and incorporation of methodology to identify nongenetic resistance are key for future studies and paramount for development of new therapeutic strategies to overcome resistance. BJS is supported by a National Health and Medical Research Council (NHMRC) Investigator grant (no grant number).