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      Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations

      Author(s): 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1
      Publication date (Electronic):
      Journal: New England Journal of Medicine
      Publisher: Massachusetts Medical Society

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          Abstract

          <p class="first" id="d17226341e328">A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. </p>

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          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.

          Mark M Awad, Geoffrey R Oxnard, David M. Jackman … (2016)
          Non-small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations.
          Article 0 comments Cited 232 times – based on 0 reviews     Review now
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            Antitumor Activity of Crizotinib in Lung Cancers Harboring a MET Exon 14 Alteration

            Alexander Drilon, Jeffrey W Clark, Jared Weiss … (2020)
            MET exon 14 alterations are oncogenic drivers of non-small cell lung cancers (NSCLCs). 1 These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition. 2 Crizotinib is a multikinase inhibitor with potent activity against MET. 3 The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations in an expansion cohort of an open-label phase 1 study of crizotinib ( NCT00585195 ). The confirmed objective response rate was 32% (95% confidence interval [CI], 21–45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by MET exon 14 alteration splice site region and mutation type, concurrent increased MET copy number, or the detection of a MET exon 14 alteration in ctDNA. The median duration of response was 9.1 months (95% CI, 6.4–12.7). The median progression-free survival was 7.3 months (95% CI, 5.4–9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in patients with MET exon 14-altered lung cancers and adds to an expanding list of genomically-driven therapies for oncogenic subsets of NSCLC.
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              PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers

              J Sabari, G C Leonardi, C Shu … (2018)
              Background MET exon 14 alterations are actionable oncogenic drivers. Durable responses to MET inhibitors are observed in patients with advanced MET exon 14-altered lung cancers in prospective trials. In contrast, the activity of immunotherapy, PD-L1 expression and tumor mutational burden (TMB) of these tumors and are not well characterized. Patients and methods Patients with MET exon 14-altered lung cancers of any stage treated at two academic institutions were identified. A review of clinicopathologic and molecular features, and an analysis of response to single-agent or combination immune checkpoint inhibition were conducted. PD-L1 immunohistochemistry was carried out and TMB was calculated by estimation from targeted next-generation sequencing panels. Results We identified 147 patients with MET exon 14-altered lung cancers. PD-L1 expression of 0%, 1%–49%, and ≥50% were 37%, 22%, and 41%, respectively, in 111 evaluable tumor samples. The median TMB of MET exon 14-altered lung cancers was lower than that of unselected non-small-cell lung cancers (NSCLCs) in both independently evaluated cohorts: 3.8 versus 5.7 mutations/megabase ( P  < 0.001, n  = 78 versus 1769, cohort A), and 7.3 versus 11.8 mutations/megabase ( P  < 0.001, n  = 62 versus 1100, cohort B). There was no association between PD-L1 expression and TMB (Spearman’s rho=0.18, P  =   0.069). In response-evaluable patients ( n  = 24), the objective response rate was 17% (95% CI 6% to 36%) and the median progression-free survival was 1.9 months (95% CI 1.7–2.7). Responses were not enriched in tumors with PD-L1 expression ≥50% nor high TMB. Conclusion A substantial proportion of MET exon 14-altered lung cancers express PD-L1, but the median TMB is lower compared with unselected NSCLCs. Occasional responses to PD-1 blockade can be achieved, but overall clinical efficacy is modest.
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                Author and article information

                Journal
                Title: New England Journal of Medicine
                Abbreviated Title: N Engl J Med
                Publisher: Massachusetts Medical Society
                ISSN (Print): 0028-4793
                ISSN (Electronic): 1533-4406
                Publication date (Electronic): May 28 2020
                Affiliations
                [1 ]From Memorial Sloan Kettering Cancer Center, New York (P.K.P.); the Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (E.F.), and Dr. Rosell Oncology Institute, Dexeus University Hospital, Quirónsalud Group (S.V.), Barcelona; Centre Hospitaliere Universitaire (CHU) Bordeaux, Service des Maladies Respiratoires, Bordeaux (R.V.), Université de Lille, CHU Lille, Thoracic Oncology Department, Centre National de la Recherche Scientifique, INSERM, Institut Pasteur de...
                Article
                DOI: 10.1056/NEJMoa2004407
                PubMed ID: 32469185
                SO-VID: 18ed5208-c797-40cc-bcf6-42544ec03591
                Copyright © © 2020
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                http://www.nejmgroup.org/legal/terms-of-use.htm

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