Co-alteration of c-Met and ROS1 in Advanced NSCLC: ROS1 Wins.

The identification of key oncogenic driver alterations in NSCLC has led to the development of tailored treatments. ROS1 rearrangements occur in 1% to 2% of NSCLC.1Shaw A.T. Ou S.-H.I. Bang Y.-J. et al.Crizotinib in ROS1-rearranged non–small-cell lung cancer.N Engl J Med. 2014; 371: 1963-1971Crossref PubMed Scopus (1410) Google Scholar Dysregulation of MNNG HOS Transforming gene (MET) signaling through MET exon 14 skipping mutations or MET amplification has been reported in 3% to 4% and 2% to 5% of adenocarcinomas, respectively.2Drilon A. Cappuzzo F. Ou S.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 To our knowledge, co-alteration of c-MET and ROS1 or ALK tyrosine kinase receptor gene (ALK) have not been described yet and the optimal management of this clinical condition is unknown. We report the case of a 42-year-old female never-smoker who was referred to our clinic with lung adenocarcinoma with laterocervical lymph nodes metastases, pleuropericardial effusion, and pulmonary lymphangitis. The patient had progressed during first-line chemotherapy with carboplatin plus pemetrexed and was symptomatic for dyspnea on exertion and cough. Molecular characterization was performed and showed a high polysomy of MET2Drilon A. Cappuzzo F. Ou S.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 (gene copy number [GCN] 8.2) and a ROS1 rearrangement (Figs. 1 and 2). On the basis of these results, she was enrolled on a phase II trial with capmatinib, 400 mg twice daily. After 1 week of treatment she underwent a pericardial window and a pleural drainage. A chest-abdomen computed tomography scan performed after 6 and 12 weeks of treatment showed an overall stable disease. However, after 16 weeks, the patient permanently stopped taking capmatinib because of clinical deterioration and worsening of effusions. She then began receiving crizotinib, 250 mg twice daily, with a rapid improvement in her overall conditions and a partial response on the radiological assessment performed after 8 weeks. The patient is currently still taking crizotinib, which she has been receiving now for 11 months with a confirmed partial remission of the disease (Fig. 3).Figure 2ROS1 rearrangement (positive fluorescence in situ break-apart test, with split red and green signifying the presence of ROS1 rearrangement).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3(left to right) Left lower lobe nodule (red arrow), mediastinal lymphadenopathies (red arrow), and prevascular lymphadenopathy (red arrow). (A) Tumor extension at baseline for capmatinib showing progression of disease after 16 weeks of capmatinib and baseline for crizotinib (B). (C) Partial response after 8 weeks of treatment with crizotinib.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Our patient was initially treated with capmatinib, which selectively inhibits mesenchymal-epithelial transition factor (c-MET) (concentration that inhibits 50% [IC50] 0.13 nM) but has negligible activity on ROS1.3Liu X. Wang Q. Yang G. et al.A novel kinase inhibitor, INCB28060, blocks c-MET–dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3.Clin Cancer Res. 2011; 17: 7127-7138Crossref PubMed Scopus (171) Google Scholar Preliminary results of a phase I trial showed an overall response rate of 63% in patients with a GCN of 5 or higher.4Schuler M.H. Berardi R. Lim W. et al.Phase I study of the safety and efficacy of the cMET inhibitor capmatinib (INC280) in patients with advanced cMET+ non-small cell lung cancer (NSCLC).J Clin Oncol. 2016; 34 ([abstract]): 9067Google Scholar Our patient did not respond to capmatinib; however, she achieved rapid tumor shrinkage after starting to take crizotinib, a potent inhibitor of the proteins anaplastic lymphoma kinase and ROS1 as well MET kinases (IC50 for anaplastic lymphoma kinase and ROS1 40 to 60 nM; IC50 for MET 11nM).1Shaw A.T. Ou S.-H.I. Bang Y.-J. et al.Crizotinib in ROS1-rearranged non–small-cell lung cancer.N Engl J Med. 2014; 371: 1963-1971Crossref PubMed Scopus (1410) Google Scholar This sequential approach allowed us to exclude the role of c-MET amplification as a crucial driver mutation in this case, with ROS1 being the most biologically relevant alteration accountable for tumor progression. If the patient had been treated only with crizotinib, we could have argued that both molecular aberrations were relevant in driving tumor progression. Indeed, in a phase I trial, four out of six patients with advanced NSCLC with high MET amplification (MET-to-CEP7 ratio ≥5) responded to crizotinib (three partial responses and one complete response).5Camidge D.R. Ou S.-H.I. Shapiro G. et al.Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC).J Clin Oncol. 2014; 32 ([abstract]): 8001Crossref Google Scholar To our knowledge, this is the first case of lung adenocarcinoma with concurrent ROS1 rearrangement and MET amplification. This report suggests that ROS1 rearrangements are more relevant than a c-MET high GCN in terms of NSCLC biology and that similar cases should be preferentially approached upfront with a ROS1 inhibitor.