Targeting MET Exon 14 Skipping Mutations in Non-Small Cell Lung Cancer

Paul K. Paik, MD, is a medical oncologist specializing in the care of patients with lung cancer and clinical director of thoracic oncology at Memorial Sloan Kettering Cancer Center (MSKCC), in New York. His research interest lies in developing targeted therapies for patients with NSCLC, with a particular focus on squamous cell lung cancers.  Dr Paik is the lead investigator on all clinical trials at MSKCC for squamous cell lung cancer.

Somatic mutations of MET are emerging as important driver mutations in lung cancer. MET is a widely expressed receptor tyrosine kinase involved in cell growth, proliferation, survival, migration, and differentiation. What is the prevalence of MET mutations in NSCLC, and is testing for such mutations now routine?

MET gene mutations that, for now, are considered actionable largely affect the expression of exon 14, a key regulatory domain that ultimately targets MET for degradation. Mutations that lead to exon 14 skipping, or deletion, occur in about 3% of all patients with NSCLC. Testing for MET exon 14 skipping is, indeed, now considered part of standard-of-care genetic testing for patients with NSCLC, as best reflected in an update to the NCCN guidelines last year.¹ Testing is recommended for patients with adenocarcinoma, large cell NSCLC, and NSCLC not otherwise specified. The NCCN also recommends that testing for MET exon 14 skipping be considered as part of broad molecular profiling in patients with squamous cell NSCLC who have small biopsy specimens or mixed-histology tumors.

Other guidelines are still more tentative about including evaluation of MET status as a routine part of genetic testing. As of September 2020, the European Society of Medical Oncology (ESMO) acknowledges MET exon 14 mutations, along with fusion genes involving RET, as evolving targets and biomarkers.² They point out that a multiplex genetic testing approach is increasingly likely to be necessary in order to provide a comprehensive means of assessment for mutations and, in some cases, fusion genes.

Joint guidelines from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology state that MET molecular testing is not indicated as a routine stand-alone assay outside the context of a clinical trial.³ It is appropriate, however, to include MET as part of larger testing panels performed either initially or when results of routine testing for EGFR, ALK, and ROS1 alterations are negative. But these recommendations were published in 2018, and recommendations continue to evolve.

Despite the wide spectrum of MET alterations in NSCLC, randomized trials have not shown MET inhibitors to have clinical benefit. Nevertheless, MET exon 14 splicing alterations have emerged as targetable mutations. Can you describe how these differ from other MET mutations?

The clinical significance of MET in NSCLC was initially thought to be its role in conferring resistance to certain therapies, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Approximately 60% of cases of acquired resistance to the first generation of EGFR-TKIs result from EGFR exon 20 T790M mutations, and MET amplification is also an acquired resistance mechanism that leads to treatment failure with these agents.⁴

MET and its ligand, hepatocyte growth factor (HGF), have been implicated in various oncogenic processes, including cell proliferation, survival, invasion, motility, and metastasis. Gain-of-function alterations in MET are varied and include gene amplification, protein overexpression, and mutations in the juxtamembrane and semaphorin domains.⁵ Clinical trials of MET-directed therapies have investigated tyrosine kinase inhibition and monoclonal antibody therapy directed against the receptor or HGF ligand.

The interest in MET as a therapeutic target in NSCLC increased with the recognition of MET exon 14 mutations as a clinically unique molecular subtype. MET exon 14 skipping alterations are distinct from other MET aberrations. They are strong oncogenic drivers that have been shown to drive tumor cell growth in preclinical models. MET exon 14 splice site alterations affect the flanking intronic sequences surrounding exon 14, a disruption that triggers alternative splicing of the MET gene product. This, in short, leads to deletion of exon 14 and an in-frame fusion of exons 13 and 15. This is important because exon 14 encodes for a domain that other cellular mechanisms identify to target MET for degradation. When exon 14 is deleted, turnover is impaired leading to stabilization and overexpression of the MET receptor. This mechanism is very different from what we’re used to with other oncogenes, since these MET mutations don’t cause constitutive activation of the receptor.

Is MET exon 14 skipping more common in specific NSCLC histologies or among certain patient subgroups?  Should all patients with NSCLC be screened for MET exon 14 skipping?

All should be screened for MET exon 14 skipping alterations because there’s a chance that any NSCLC tumor might test positive. This includes patients who are diagnosed with squamous cell lung cancers, poorly differentiated NSCLCs, and sarcomatoid carcinomas. The frequency of MET exon 14 skipping mutations is highest in sarcomatoid carcinomas (approximately one-third), followed by adenocarcinomas (3% to 4%) and squamous cell lung cancers (1%).

MET exon 14 skipping has been reported across NSCLC patients with all smoking histories and histologic types.⁶  These alterations do appear to occur primarily in older adults (with a median age of 70 years) — in contrast to other oncogene-driven NSCLC types such as those with ALK and ROS1 rearrangements — and they exist in the absence of other key driver alterations.^6-8 Although MET exon 14 mutations coexist with mutations in KRAS, ROS1, and EGFR, they appear to drive tumors in the absence of other driver oncogenes.

Clinical data support targeting MET exon 14 skipping in NSCLC, but the ability of next-generation sequencing (NGS) assays to identify the diverse set of genetic alterations leading to MET exon 14 varies. What is the best and most reliable method of identifying MET exon 14 skipping in NSCLC?

The best method to test for MET exon 14 skipping alterations, exactly because of what you noted, is NGS, which can be constructed to deeply and broadly cover the flanking intronic sequences around exon 14 in a way that, for example, polymerase chain reaction-based assays cannot. NGS assays can be DNA-based or RNA-based, and both are able to capture exon 14 skipping events. In addition, circulating tumor DNA (ctDNA) NGS assays are available that cover MET exon 14 splice site mutations. The manifold advantages to these liquid biopsies include faster turnaround time and safety. Depending on the amount of ctDNA shed, liquid biopsies can yield false-negative results, however, so they do not supplant tumor testing as a gold standard.

The approval of capmatinib and tepotinib for metastatic NSCLC with MET exon 14 skipping mutations has made MET exon 14 an additional actionable oncogenic driver in NSCLC. Does crizotinib still have a role in this setting? Are there new therapeutics in phase 2 or 3 trials that may be heading for US Food and Drug Administration (FDA) approval?

The role for crizotinib as a treatment for MET exon 14 skipping-positive NSCLC has diminished with the approval of capmatinib and tepotinib, in part because crizotinib has not been approved by the FDA for this indication and in part because cross-trial comparison suggests crizotinib might be less effective than capmatinib and tepotinib, which are more selective MET inhibitors.

Tepotinib was approved earlier this year for adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations based on efficacy demonstrated in VISION (ClinicalTrials.gov Identifier: NCT02864992), a phase 2 study that included 152 patients with advanced or metastatic NSCLC with MET exon 14 skipping alterations.⁷ Among treatment-naive patients, the overall response rate (ORR) was 43%, with a median response duration of 10.8 months. For previously treated patients, the ORR was 43%, and the median response duration was 11.1 months.

The FDA also granted approval to capmatinib last year for the same indication based on results from the phase 2 GEOMETRY mono-1 trial (ClinicalTrials.gov Identifier: NCT02414139).⁸ The cohort included 97 patients with metastatic NSCLC with confirmed MET exon 14 skipping. Among treatment-naive patients, the ORR was 68%, with a response duration of 12.6 months. For previously treated patients, the ORR was 41%, with a response duration of 9.7 months.

Although the selective MET tyrosine kinase inhibitors capmatinib and tepotinib have demonstrated unprecedented activity in lung cancers with altered MET exon 14, the reported response rates are still modest relative to those observed with targeted therapies in other oncogene-driven lung cancers. There are new therapeutic concepts in this space, with most of the activity seen in early-phase trials using antibody-based therapies that could complement the current use of TKIs. At this point, trying to boost the activity of up-front MET inhibition for these patients or, alternatively, circumventing resistance are important next-step endeavors for improving the care of patients with MET exon 14 skipping NSCLC.