Objective: Capmatinib and tepotinib, two recently FDA-approved and highly specific small-molecule inhibitors of c-MET exon 14 skipping mutations are new and important therapeutic options for the treatment of NSCLC patients harbouring c-MET alterations. However, the precise role of these molecules as a new treatment option is still not fully defined. Methods: In an attempt to further evaluate the contributions of c-MET inhibitors to the armamentarium of treatment options for advanced and metastatic NSCLCs, relevant phase II and III studies were retrospectively analyzed in terms of ORR and mPFS (mOS numbers are still not available for current c-MET trials and therefore not considered for statistical purposes). Results: Treatment of advanced and metastatic NSCLC patients harbouring c-MET exon 14 skipping mutations with the novel and highly selective c-MET inhibitors is significantly superior (p < 0.0001) when compared with standard chemotherapy. However, when c-MET inhibitors are compared with immunotherapy or the combination of immunotherapy and chemotherapy, no significant differences in terms of ORR and PFS were found, but treatment with c-MET reported be much more tolerable. Conclusion: The novel and highly selective c-MET inhibitors capmatinib and tepotinib are promising novel treatment options for patients with c-MET-dysregulated NSCLC primarily in the first-line setting, albeit a clear mOS benefit has not yet been established. Since immunotherapy did not appear to be particularly effective in NSCLC patients harbouring c-MET alterations, the vast majority of these patients are treated with immunotherapy plus chemotherapy. C-Met inhibitors appear to be equally effective and thereby sparing patients from the toxic effects of the chemotherapy. The routine testing of c-MET exon 14 skipping mutations should be performed as the GEOMETRY mono-1 data clearly showed higher response rates with capmatinib in treatment-naive than in pretreated patients, indicating that c-MET exon 14 skipping mutations should preferably be molecularly assessed at baseline. C-MET exon 14 skipping mutations are, therefore, clear biomarkers of response to c-MET inhibitors.
Luckson, L.N., Larkins, E., Akinboro, O., Roy, P., Amatya, A.K., Fiero, M.H., Mishra-Kalyani, P.S., Helms, W.S., Myers, C.E., Skinner, A.M., Aungst, S., Jin, R., Zhao H., Xia, H., Zirkelbach, J.F., Bi, Y., Li, Y., Liu, J., Grimstein, M., Zhang, X., Woods, S., Reece, K., Abukhdeir AM, Ghosh, S., Philip, R., Tang, S., Goldberg, K.B., Pazdur, R., Beaver, J.A. and Singh, H. (2022) FDA Approval Summary: Capmatinib and Tepotinib for the Treatment of Metastatic NSCLC Harboring MET Exon 14 Skipping Mutations or Alterations. Clinical Cancer Research, 28, 249-254. https://doi.org/10.1158/1078-0432.CCR-21-1566
[3]
Wolf, J., Seto, T, Han, J.Y., Reguart, N., Garon, E.B., Groen, H.J.M., Tan, D.S.W., Hida, T., de Jonge, M., Orlov, S.V., Smit, E.F., Souquet, P.J., Vansteenkiste, J., Hochmair, M., Felip, E., Nisho, M., Thomas, M., Ohashi, K., Toyozawa, R., Overbeck, T.R., de Marinis, F., Kim, T.M., Laack, E., Robeva, A., Le Mouhaer, S., Waldron-Lynch, M., Sankaran, B., Balbin, OA, Cui, X., Giovannini, M., Akimov, M. and Heist, R.S. (2020) Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. New England Journal of Medicine, 383, 944-957. https://doi.org/10.1056/NEJMoa2002787
[4]
Paik, P.K., Felip, E., Veillon, R., Sakai, H., Cortot, A.B., Garassino, M.C., Mazieres, J., Viteri, S., Senellart, H., van Meerbeeck, J., Raskin, J., Reinmuth, N., Conto, P., Kowalski, D., Cho, B.C., Patel, J.D., Horn, L., Griesinger, F., Han, J.Y., Kim, Y.C., Chang, G.C., Tsai, C.L., Yang, J.C.H., Chen, Y.M., Smit, E.F., van der Wekken, A.J., Kato, T., Juraeva, D., Stroh, C., Bruns, R., Straub, J., Johne, A., Scheele, J., Heymach, J.V. and Le, X. (2020) Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. New England Journal of Medicine, 383, 931-943. https://doi.org/10.1056/NEJMoa2004407
[5]
Vuong, H.G., Ho, A.T.N., Altibi, A.M.A., Nakazawa, T., Katoh, R. and Kondo, T. (2018) Clinicopathological Implications of MET Exon 14 Mutations in Non-Small Cell Lung Cancer—A Systematic Review and Meta-Analysis. Lung Cancer, 123, 76-82. https://doi.org/10.1016/j.lungcan.2018.07.006
[6]
Ahn, H.K., Kim, S., Kwon, D., Koh, J., Kim, YA, Kim, K., Chung, D.H. and Jeon, Y.K. (2019) MET Receptor Tyrosine Kinase Regulates the Expression of Co-Sti-mulatory and Co-Inhibitory Molecules in Tumor Cells and Contributes to PD-L1-Mediated Suppression of Immune Cell Function. International Journal of Molecular Science, 20, Article No. 4287. https://doi.org/10.3390/ijms20174287
[7]
Dempke, W.C.M. and Fenchel, K. (2021) Has Programmed Cell Death Ligand-1 MET an Accomplice in Non-Small Cell Lung Cancer—A Narrative Review. Translational Lung Cancer Research, 10, 2667-2682. https://doi.org/10.21037/tlcr-21-124
[8]
Benkhoucha, M., Santiago-Raber, M.L., Schneiter, G., Chofflon, M., Funakoshi, H., Nakamura, T. and Lalive, P.H. (2010) Hepatocyte Growth Factor Inhibits CNS Autoimmunity by Inducing Tolerogenic Dendritic Cells and CD25+Foxp3+ Regulatory T Cells. Proceedings of the National Academy of Sciences of the United States of America, 107, 6424-6429. https://doi.org/10.1073/pnas.0912437107
[9]
Glodde, N., Bald, T., van den Boorn-Konijnenberg, D., Nakamura, K., O’Donnell, J.S., Szczepanski, S., Brandes, M., Eickhoff, S., Das, I., Shridhar, N., Hinze, D., Rogava, M., van der Sluis, T.C., Ruotsalainen, J.J., Gaffal, E., Landsberg, J., Ludwig, K.U., Wilhelm, C., Riek-Burchardt, M., Müller, A.J., Gebhardt, C., Scolyer, R.A., Long, G.V., Janzen, V., Teng, M.W.L., Kastenmüller, W., Mazzone, M., Smyth, M.J., Tüting, T. and Hölzel, M. (2017) Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy. Immunity, 47, 789-802.e9. https://doi.org/10.1016/j.immuni.2017.09.012
[10]
Mazieres, J., Drilon, A., Lusque, A., Mhanna, L., Cortot, A.B., Mezquita, L., Thai, A.A., Mascaux, C., Couraud, S., Veillon, R., van den Heuvel, M., Neal, J., Peled, N., Früh, M., Ng, T.L., Gounant, V., Popat, S., Diebold, J., Sabari, J., Zhu, V.W., Rothschild, S.I., Bironzo, P., Martinez-Marti, A., Curioni-Fontecedro, A., Rosell, R., Lattuca-Truc, M., Wiesweg, M., Besse, B., Solomon, B., Barlesci, F., Schouten, R.D., Wakelee, H., Camidge, D.R., Zalcman, G., Novello, S., Ou, S.I., Milia, J. and Gautschi, O. (2019) Immune Checkpoint Inhibitors for Patients with Advanced lung Cancer and Oncogenic Driver Alterations: Results from the IMMUNOTARGET Registry. Annuals of Oncology, 30, 1321-1328. https://doi.org/10.1093/annonc/mdz167
[11]
Schiller, J.H., Harrington, D., Belani, C.P., Langer, C., Sandler, A., Krook, J., Zhu, J. and Johnson, D.H. (2002) Comparison of Four Chemotherapy Regimens for Advanced Non-Small-Cell Lung Cancer. New England Journal of Medicine, 346, 92-98. https://doi.org/10.1056/NEJMoa011954
[12]
Scagliotti, G.V., de Marinis, F., Rinaldi, M., Crinò, L., Gridelli, C., Ricci, S., Matano, E., Boni, C., Marangolo, M., Failla, G., Altavilla, G., Adamo, V., Ceribelli, A., Clerici, A., Di Costanzo, F., Frontini, L. and Tonato, M. (2002) Phase III Randomized Trial Comparing Three Platinum-Based Doublets in Advanced Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 20, 4285-4291. https://doi.org/10.1200/JCO.2002.02.068
[13]
Dempke, W.C.M., Fenchel, K. and Dale, S.P. (2018) Programmed Cell Death Ligand-1 (PD-L1) as a Biomarker for Non-Small Cell Lung Cancer (NSCLC) Treatment—Are We Barking up the Wrong Tree? Translational Lung Cancer Research, 7, S275-S279. https://doi.org/10.21037/tlcr.2018.04.18
[14]
Herbst, R.S., Giaccone, G., de Marinis, F., Reinmuth, N., Vergnenegre A, Barrois, C.H., Morise, M., Felip, E., Andric, Z., Geater, S., Özgüroglu, M., Zou, W., Sandler, A., Enquist, I., Komatsubara, K., Deng, Y., Kuriki, H., Wen, X., McCleland, M., Mocci, S., Jassem, J. and Spigel, D.R. (2020) Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. New England Journal of Medicine, 383, 1328-1339. https://doi.org/10.1056/NEJMoa1917346
[15]
Reck, M., Rodrígez-Abreu, D., Robinson, A.G., Hui, R., Csószi, T., Fülöp, A., Got-tminenza, E., Wrangle, J.M., Rodrigezfreid, M., Peled, N., Tafreshi, A., Cuffe, S., O’Brien, M., Rao, S., Hotta, K., Leiby, M.A., Lubiniecki, G.M., Shentu, Y., Rangwala R. and Brahmer, J. (2016) Pembrolizumab versus Chemotherapy for PD-L1-Positive non-small-cell lung cancer. New England Journal of Medicine, 375, 1823-1833. https://doi.org/10.1056/NEJMoa1606774
[16]
Carbone, D.P., Reck, M., Paz-Ares, L., Creelan, B., Horn, L., Steins, M., Felip, E., van den Heuvel, M.M., Ciuleanu, T.E., Badin, F., Ready, N., Hiltermann, T.J.N., Nair, S., Juergens, R., Peters, S., Minenza, E., Wrangle, J.M., Rodriguez-Abreu, D., Borghaei, H., Blumenschein, G.R., Villaruz, L.C., Havel, L., Krejci, J., Jaime, J.C., Chang, H., Geese, W.J., Bhagavatheeswaran, P., Chen, A.C. and Socinski, M.A (2017) First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. New England Journal of Medicine, 376, 2415-2426. https://doi.org/10.1056/NEJMoa1613493
[17]
Rizvi, N.A., Cho, B.C., Reinmuth, N., Lee, K.H., Luft, A., Ahn, M.J., van den Heuvel, M.M., Cobo, M., Vicente, D., Smolin, A., Moiseyenko, V., Antonia, S.J., Le Moulec, S., Robinet, G., Natale, R., Schneider, J., Shephard, F.A., Geater, S.L., Garon, E.B., Kim, E.S., Goldberg, S.B., Nakagawa, K., Raja, R., Higgs, B.W., Boothman, A.M., Zhao, L., Scheurig, U., Stockman, P.K., Chand, V.K. and Peters, S. (2020) Durvalumab with or without Tremelimumab vs Standard Chemotherapy in First-Line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. Journal of the American Medical Association Oncology, 6, 661-674. https://doi.org/10.1001/jamaoncol.2020.0237
[18]
Jotte, R., Cappuzzo, F., Vynnychenko, I., Stroyakovsky, D., Rodríguez-Abreu, D., Hussein, M., Soo, H., Conter, H.J., Kozuki, T., Huang, K.C., Graupner, V., Sun, S.W., Hoang, T., Jessop, H., McCleland, M., Ballinger, M., Sandler, A. and Socineski, M.A. (2020) Atezolizumab in Combination with Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (Impower131): RESULTS from a Randomized Phase III Trial. Journal of Thoracic Oncology, 15, 1351-1360. https://doi.org/10.1016/j.jtho.2020.03.028
[19]
Socienski, M.A., Jotte, R.M., Cappuzzo, F., Orlandi, F., Stroyakovsky, D., Nogami, N., Rodriguez-Abreu, D., Moro-Sibilot, D., Thomas, C.A., Barlesi, F., Finley, G., Kelsch, C., Lee, A., Coleman, S., Deng, Y., Shen, Y., Kowanetz, M., Lopez-Chavez, A., Sandler, A. and Reck, M. (2018) Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. New England Journal of Medicine, 378, 2288-2301. https://doi.org/10.1056/NEJMoa1716948
[20]
Paz-Ares, L., Luft A., Vicente, D., Tafreshi, A., Gümüs, M., Mazières, J., Hermes, B., Senler, F.C., Csószi, T., Fülöp, A., Rodriguez-Cid, J., Wilson, J., Sugawara, S., Kato, T., Lee, K.H., Cheng, Y., Novello, S., Halmos, B., Li, X., Lubiniecki, G.M., Piperdi, B. and Kowalski, D.M. (2018) Pembrolizumab Plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. New England Journal of Medicine, 379, 2040-2051. https://doi.org/10.1056/NEJMoa1810865
[21]
Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., DeAngelis, F., Domine, M., Clingan, P., Hochmair, M.J., Powell, S.F., Cheng, S.Y.S., Bischoff, H.G, Peled, N., Grossi, F., Jennens, R.R., Reck, M., Hui, R., Garon, E.B., Boyer, M., Rubio-Viqueira, B., Novello, S., Kurata, T., Gray, J.E., Vida, J., Wei, Z., Yang, J., Raftopoulos, H., Pietanza, M.C. and Garassino, M.C. (2018) Pembrolizumab Plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. New England Journal of Medicine, 378, 2078-2092. https://doi.org/10.1056/NEJMoa1801005
[22]
Johnson, M.L., Cho, B.C., Luft, A., Alatorre-Alexander, J., Geater, S.L., Laktionov, K., Vasiliev, A., et al. (2021) PL02.01. Durvalumab ± Tremelimumab + Chemotherapy as First-Line Treatment for mNSCLC: Results from the Phase 3 POSEIDON Study. Journal of Thoracic Oncology, 16, S844. https://doi.org/10.1016/j.jtho.2021.08.029
[23]
Mazieres, J., Paik, P., Felip, E., Veillon, R., Sakai, H., Cortot, A., Viteri, S., Garassino, M., van Merbeeck, J., Raskin, J., Thomas, M., Morise, M., Cho, B.C., Bruns, R., Demuth, t., Schumacher, K.M. and Le, X. (2021) OA05.03 Tepotinib in Patients with Advanced NSCLC with MET Exon 14 (METex14) Skipping: Overall Efficacy Results from VISION Cohort A. Journal of Thoracic Oncology, 16, S5. https://doi.org/10.1016/j.jtho.2020.10.028
[24]
Sabari, J.K., Leonardi, G.C., Shu, C.A., Umeton, R., Montecalvo, J., Ni, A., Chen, R., Dienstag, J., Mrad, C., Bergagnini, I., Lai, W.V., Offin, M., Arbour, K.C., Plodkowski, A.J., Halpenny, D.F., Paik, P.K., Li, B.T., Riely, G.J., Kris, M.G., Rudin, C.M., Sholl, L.M., Nishino, M., Hellmann, M.D., Rekhtman, N., Awad, M.M. and Drilon, A. (2018) PD-L1 Expression, Tumor Mutational Burden, and Response to Immunotherapy in Patients with MET Exon 14 Altered Lung Cancers. Annuals of Oncology, 29, 2085-2091. https://doi.org/10.1093/annonc/mdy334
[25]
Baba, K., Tanaka, H., Sakamoto, H., Shiratori, T., Tsuchiya, J., Ishioka, Y., Itoga, M., Taima, K. and Tasaka, S. (2019) Efficacy of Pembrolizumab for Patients with Both High PD-L1 Expression and an MET Exon 14 Skipping Mutation. A Case Report. Thoracic Cancer, 10, 369-372. https://doi.org/10.1111/1759-7714.12939
[26]
Reis, H., Metzenmacher, M., Goetz, M., Savvidou, N., Darwiche, K., Aigner, C., Herold, T., Eberhardt, W.E., Skiba, C., Hense, J., Virchow, I., Westerwick, D., Bogner, S., Ting,S., Kasper, S., Stuschke, M., Nensa, F., Herrmann, K., Hager, T., Schmid, K.W., Schuler, M. and Wiesweg, M. (2018) MET Expression in Advanced Non-Small-Cell Lung Cancer: Effect on Clinical Outcomes of Chemotherapy, Targeted Therapy, and Immunotherapy. Clinical Lung Cancer, 19, E441-E463. https://doi.org/10.1016/j.cllc.2018.03.010
[27]
Digumarthy, S.R., Mendoza, D.P., Zhang, E.W., Lennerz, J.K. and Heist, R.S. (2019) Clinicopathologic and Imaging Features of Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. Cancers, 12, Article No. 2033. https://doi.org/10.3390/cancers11122033
[28]
Awad, M.M., Leonardi, G.C., Kravets, S., Dahlberg, S.E., Drilon, A., Noonan, S.A., Camidge, D.R., Ou, S.H.I., Costa, D.B., Gadgeel, S.M., Steuer, C.E., Forde, P.M., Zhu, V.W., Fukuda, Y., Clark, J.W., Jänne, P.A., Mok, T., Sholl, L.M. and Hesit, R.S. (2019) Impact of MET Inhibitors on Survival among Patients with Non-Small Cell Lung Cancer Harboring MET Exon 14 Mutations: A Retrospective Analysis. Lung Cancer, 133, 96-102. https://doi.org/10.1016/j.lungcan.2019.05.011
[29]
Xu, Z., Li, H., Dong, Y., Cheng, P., Luo, F., Fu, S., Gao, M., Kong, L. and Che, N. (2020) Incidence and PD-L1 Expression of MET 14 Skipping in Chinese Population: A Non-Selective NSCLC Cohort Study Using RNA-Based Sequencing. Oncology Targets and Therapy, 13, 6245-6253. https://doi.org/10.2147/OTT.S241231
