Targeting MET Exon 14 Skipping Alterations: Has Lung Cancer MET Its Match?

Abstract

The treatment landscape of NSCLC has been transformed by the approval of molecularly targeted agents against critical drivers in this disease, including EGFR, anaplastic lymphoma kinase, and ROS1.1Tsao A.S. Scagliotti G.V. Bunn Jr., P.A. et al.Scientific advances in lung cancer 2015.J Thorac Oncol. 2016; 11: 613-638Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Several other targets are showing great promise in clinical trials, including the receptor tyrosine kinase MET proto-oncogene receptor tyrosine kinase (MET). Although initial studies undertaken with MET inhibitors were disappointing, the recent emergence of splicing alterations of MET proto-oncogene receptor tyrosine kinase gene MET exon 14 (METex14) in NSCLC as a primary driver has reinvigorated interest in the development of MET inhibitors in this disease.2Frampton G.M. Ali S.M. Rosenzweig M. et al.Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.Cancer Discov. 2015; 5: 850-859Crossref PubMed Scopus (511) Google Scholar METex14 alterations are complex and diverse, and they are comprehensively reviewed in the article by Drilon et al. in this edition of the Journal of Thoracic Oncology. METex14 alterations occur at a prevalence of approximately 3% to 4% in lung adenocarcinoma compared with 2% in squamous cell lung cancer.3Drilon A. Cappuzzo F. Ou S-H.I. Camidge D.R. Targeting MET in lung cancer: will expectations finally be MET?.J Thorac Oncol. 2017; 12: 15-26Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 4Tong J.H. Yeung S.F. Chan A.W. et al.MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis.Clin Cancer Res. 2016; 22: 3048-3056Crossref PubMed Scopus (278) Google Scholar These aberrations tend not to be observed in younger patients with NSCLC and seem to be enriched in pulmonary pleomorphic/sarcomatoid carcinomas.5Liu X. Jia Y. Stoopler M.B. et al.Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations.J Clin Oncol. 2016; 34: 794-802Crossref PubMed Scopus (246) Google Scholar, 6Awad M.M. Oxnard G.R. Jackman D.M. et al.MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression.J Clin Oncol. 2016; 34: 721-730Crossref PubMed Scopus (436) Google Scholar Interestingly, concurrent MET amplification is observed in approximately 20% of METex14-aberrant NSCLC, and such tumors have also been shown to harbor a significantly total higher mutational burden.7Schrock A.B. Frampton G.M. Suh J. et al.Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations.J Thorac Oncol. 2016; 11: 1493-1502Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar Several bona fide MET inhibitors with varying potencies, specificities, and underlying mechanisms of action are currently in clinical trials.8Cui J.J. Targeting receptor tyrosine kinase MET in cancer: small molecule inhibitors and clinical progress.J Med Chem. 2014; 57: 4427-4453Crossref PubMed Scopus (162) Google Scholar The MET inhibitors currently being assessed in phase II studies involving patients with METex14-aberrant NSCLC include the type I inhibitors crizotinib (Xalkori [Pfizer, New York, NY]) and capmatinib (INC280 [Novartis, Basel, Switzerland]), as well as the type II inhibitors cabozantinib (Cabometyx [Exelixis, Inc., South San Francisco, CA]), tepotinib (MSC2156119J, [Merck Serono, Darmstadt, Germany]), and glesatinib (MGCD265 [Mirati Therapeutics, San Diego, CA]). These small molecule MET inhibitors are all adenosine triphosphate–competitive, but whereas type I MET inhibitors bind to the MET unique autoinhibitory conformation through the interaction of the aromatic ring of the inhibitor (π-stacking) with Y1230 in the MET activation loop, type II inhibitors bind to the adenosine triphosphate adenine binding site. Of these agents, it is likely that crizotinib will be the first to obtain U.S. Food and Drug Administration approval for this molecularly selected patient population, adding to its registration for use in anaplastic lymphoma receptor tyrosine kinase gene (ALK)- and ROS1-rearranged NSCLC. Early data from the PROFILE-1001 study reported a 44% overall response rate in 18 patients with evaluable treatment-naive or chemotherapy-refractory METex14-aberrant NSCLC.9Drilon A.E. Camidge D.R. Ou S.I. et al.Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC).J Clin Oncol. 2016; 34 ([abstract]): 108Google Scholar Other phase II crizotinib studies involving this indication are ongoing, including the NCI-MATCH trial (NCT02465060) in the United States and the National Lung Matrix Trial (NCT02664935) in the United Kingdom. One of the key challenges with molecularly targeted agents is understanding and addressing the inevitable development of drug resistance. In vitro studies have already identified several predominant resistance mutations in MET-dependent tumors after treatment with type I MET inhibitors such as crizotinib, including MET Y1230 and D1228 mutations.10Qi J. McTigue M.A. Rogers A. et al.Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors.Cancer Res. 2011; 71: 1081-1091Crossref PubMed Scopus (175) Google Scholar Any mutations (Y1230 or D1228) that directly or indirectly weaken the interactions between these type I inhibitors and the MET activation loop may potentially lead to drug resistance. In this edition of the Journal of Thoracic Oncology, Ou et al. report the detection of a MET Y1230C mutation that appears to confer resistance to crizotinib in a patient with METex14 (D1010H)-aberrant NSCLC who had a durable response for 13 months.11Ou S-H.I. Young L. Schrock A.B. et al.Emergence of preexisting MET Y1230C mutation as a resistance mechanism to crizotinib in NSCLC with MET exon 14 skipping.J Thorac Oncol. 2017; 12: 137-140Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar In this study, although it was not possible to make a direct comparison between the mutational allele frequencies of the different aberrations detected because baseline and disease progression sampling involved different tissue (tumor versus circulating plasma DNA [cpDNA]), the presence of the MET Y1230C mutation at reportable levels in cpDNA at disease progression is compelling. Whether this was a preexisting versus acquired mutation will require larger studies to characterize and validate such mutations and other resistance mechanisms in the clinic through the increased analysis of biopsy samples and cpDNA collected before treatment and after treatment at disease progression. Therefore, the significance of this potential de novo MET Y1230C mutation in two of 762 sequencing reads (well below reportable levels of the assay) before therapy is currently unknown but seems to bear striking similarity to the gatekeeper EGFR T790M mutation in providing tumors with a growth advantage. For example, de novo EGFR T790M mutation “degrades” the response of first- and second-generation EGFR inhibitors, suggesting that the MET Y1230C mutation may have similar effects on MET inhibitors. An acquired critozitnib resistance mutation in the MET kinase domain D1228N has also recently been described in a patient with advanced METex14-aberrant NSCLC treated with crizotinib.12Heist R.S. Sequist L.V. Borger D. et al.Acquired resistance to crizotinib in NSCLC with MET exon 14 skipping.J Thorac Oncol. 2016; 11: 1242-1245Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Although it may be possible that switching from type I to type II MET inhibitors may overcome such MET Y1230 and D1228 resistance mutations, it is likely that second-generation inhibitors specifically targeting such MET aberrations will ultimately be required. Another important approach to consider pursuant to delaying single-agent resistance will be the combination of small molecule MET inhibitors with hepatocyte growth factor antibodies or antibodies that inhibit ligand binding to the MET receptor or block its dimerization, so as to achieve “total blockade” of the MET axis. To address such challenges in the clinic, we need to redesign clinical trials to consider type I to II MET inhibitor switching, novel combination therapies, and the incorporation of both tumor and serial cpDNA tissue sampling to monitor mutation allele frequencies of MET aberrations and identify putative resistance mechanisms in an efficient manner. From a practical point of view, such trial designs should include patients with lung adenocarcinomas and squamous cell lung carcinomas, as well as patients with lung pleomorphic/sarcomatoid carcinomas, without limitations on lines of prior therapies, to optimize accrual. In view of its great diversity, a major challenge for the development of MET inhibitors is the development of a robust, sensitive, and rapid analytically validated companion diagnostic for routine detection of METex14 alterations. It is unlikely that MET expression through immunohistochemistry assays will suffice. Current molecular testing mainly involves nonstandardized DNA-based hybrid capture next-generation sequencing, which is not sufficiently comprehensive to capture the wide range of METex14 alterations.7Schrock A.B. Frampton G.M. Suh J. et al.Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations.J Thorac Oncol. 2016; 11: 1493-1502Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar Also, The Cancer Genome Atlas has also reported that certain METex14 alterations detected have resulted in incomplete METex14 skipping.13Cancer Genome Atlas Research NetworkComprehensive molecular profiling of lung adenocarcinoma.Nature. 2014; 511: 543-550Crossref PubMed Scopus (3529) Google Scholar It is therefore imperative that confirmatory assays, such as quantitative reverse-transcriptase polymerase chain reaction or direct RNA sequencing, be utilized to confirm METex14 skipping alterations. However, given the typical small sizes of diagnostic NSCLC biopsy specimens, the amount of tissue available after initial DNA-based next-generation sequencing may ultimately be insufficient for further RNA-based assays. The use of serial cpDNA sampling will provide a practical and relatively less invasive method for the detection of resistance mutations, such as MET Y1230 or D1228 alterations, but it will likely be affected by false-negatives. Ultimately, as both METex14 alterations and MET amplification are relatively rare events, the development of a cpDNA assay to rapidly screen patients with NSCLC for such aberrations will be important. At the present time, the incidence of brain metastases at diagnosis and frequency of intracranial failure with MET inhibitors in patients with METex14-altered NSCLC is unknown. In this issue, Klempner et al. present a compelling case of a patient with known METex14-aberrant NSCLC with intracranial progression while receiving crizotinib despite ongoing extracranial response.14Klempner S.J. Borghei A. Hakimian B. Ali S.M. Ou S-H.I. Intracranial activity of cabozantinib in MET exon 14 positive NSCLC with brain metastases.J Thorac Oncol. 2017; 12: 152-156Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Upon switching to cabozantinib because of crizotinib-induced grade 4 transaminitis, the patient achieved a complete intracranial response and maintained a systemic response, providing the first evidence of central nervous system (CNS) penetration and activity of cabozantinib in a patient with prior exposure to crizotinib, potentially suggesting “reversal of resistance” after a switch from type I to a II MET inhibitors. Because crizotinib is likely to be the first MET inhibitor approved for METex14-altered NSCLC, in view of its poor CNS penetration, there will still be an unmet need for a potent CNS-penetrant type II MET inhibitor. Whether the current cadre of type II MET inhibitors, such as cabozantinib, will fulfill this niche role remains to be assessed. Apart from METex14-altered NSCLC, it is now clear that MET inhibitors will also play a critical role in the treatment of patients with MET-amplified NSCLC. In this issue, Caparica et al. report two patients with high-level MET amplification (MET/CEP7 ratio ≥5) without concomitant METex14 alterations who responded to crizotinib, supporting its importance as a true NSCLC driver.15Caparica R. Yen C.T. Coudry R. et al.Responses to crizotinib can occur in high-level MET-amplified non-small cell lung cancer independent of MET exon 14 alterations.J Thorac Oncol. 2017; 12: 141-144Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar These findings imply that any companion diagnostic for MET inhibitors in NSCLC should also include testing for high-level MET amplification. Moving forward, studies should also assess the significance of MET amplification clonality in predicting antitumor responses to MET inhibitors by evaluating the degree of heterogeneity using in situ heterogeneity mapping of fluorescence in situ hybridization.16Pearson A. Smyth E. Babina I.S. et al.High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial.Cancer Discov. 2016; 6: 838-851Crossref PubMed Scopus (192) Google Scholar We have come a long way from the previous dispiriting negative NSCLC phase III trials of tivantinib (ARQ197 [ArQule, Burlington, MA/Daiichi Sankyo, Tokyo, Japan]) and onartuzumab (MetMab [Roche, Basel, Switzerland]) in combination with erlotinib.1Tsao A.S. Scagliotti G.V. Bunn Jr., P.A. et al.Scientific advances in lung cancer 2015.J Thorac Oncol. 2016; 11: 613-638Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar The present data confirm that MET remains a key oncogenic driver in NSCLC with definite therapeutic viability. Priority must now be given to achieving rapid regulatory approval by designing registration trials to assess single-agent MET inhibitors using a robust molecular profiling assay in tumor and cpDNA for the selection and monitoring of MET-addicted patients with MET-amplified and/or METex14-altered NSCLC. Expectations must be met! Drs. Yap and Popat acknowledge the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden National Health Service Foundation Trust and The Institute of Cancer Research). Dr. Yap acknowledges funding from the Academy of Medical Sciences and the British Lung Foundation. Emergence of Preexisting MET Y1230C Mutation as a Resistance Mechanism to Crizotinib in NSCLC with MET Exon 14 SkippingJournal of Thoracic OncologyVol. 12Issue 1PreviewMET proto-oncogene, receptor tyrosine kinase gene exon 14 skipping (METex14) alterations represent a unique subset of oncogenic drivers in NSCLC. Preliminary clinical activity of crizotinib against METex14-positive NSCLC has been reported. The full spectrum of resistance mechanisms to crizotinib in METex14-positive NSCLC remains to be identified. Full-Text PDF Open AccessResponses to Crizotinib Can Occur in High-Level MET-Amplified Non–Small Cell Lung Cancer Independent of MET Exon 14 AlterationsJournal of Thoracic OncologyVol. 12Issue 1PreviewActivation of the MET proto-oncogene (MET) highly sensitive to MET inhibition has recently been described in NSCLC through two mechanisms: high-level amplification of the MNNG HOS Transforming gene (MET) (usually expressed relative to the chromosome 7 centromere [CEP7] when using fluorescence in situ hybridization) and exon 14 alterations. As partial overlap of these biomarkers occurs, whether one is purely a surrogate for the other or both can represent true oncogenic driver states continues to be explored. Full-Text PDF Open ArchiveTargeting MET in Lung Cancer: Will Expectations Finally Be MET?Journal of Thoracic OncologyVol. 12Issue 1PreviewThe hepatocyte growth factor receptor (MET) is a potential therapeutic target in a number of cancers, including NSCLC. In NSCLC, MET pathway activation is thought to occur through a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggests a role for MET activation as both a primary oncogenic driver in subsets of lung cancer and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. Full-Text PDF Open ArchiveIntracranial Activity of Cabozantinib in MET Exon 14–Positive NSCLC with Brain MetastasesJournal of Thoracic OncologyVol. 12Issue 1PreviewA significant portion of NSCLCs with MET proto-oncogene, receptor tyrosine kinase gene (MET) exon 14 skipping alterations are sensitive to small-molecule mesenchymal-epithelial transition tyrosine kinase inhibitors. However, the incidence and management of brain metastases in this molecular subset is unknown and represents an unmet clinical need. Full-Text PDF Open Archive