Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With EGFR -Mutated, MET Factor–Dysregulated Non–Small-Cell Lung Cancer
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Purpose: MET dysregulation occurs in up to 26% of non–small-cell lung cancers (NSCLCs) after epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) treatment. Capmatinib (INC280) is a potent and selective MET inhibitor with preclinical activity in combination with gefitinib in EGFR-mutant, MET-amplified/overexpressing models of acquired EGFR-TKI resistance. This phase Ib/II study investigated the safety and efficacy of capmatinib plus gefitinib in patients with EGFR-mutated, MET-dysregulated (amplified/overexpressing) NSCLC who experienced disease progression while receiving EGFR-TKI treatment. Methods: Patients in phase Ib received capmatinib 100- to 800-mg capsules once per day or 200- to 600-mg capsules or tablets twice per day, plus gefitinib 250 mg once per day. Patients in phase II received the recommended phase II dose. The primary end point was the overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Sixty-one patients were treated in phase Ib, and 100 were treated in phase II. The recommended phase II dose was capmatinib 400 mg twice per day plus gefitinib 250 mg once per day. Preliminary clinical activity was observed, with an ORR across phase Ib/II of 27%. Increased activity was seen in patients with high MET-amplified tumors, with a phase II ORR of 47% in patients with a MET gene copy number ≥ 6. Across phases Ib and II, the most common drug-related adverse events were nausea (28%), peripheral edema (22%), decreased appetite (21%), and rash (20%); the most common drug-related grade 3/4 adverse events were increased amylase and lipase levels (both 6%). No significant drug-drug interactions between capmatinib and gefitinib were evident. Conclusion: This study, focused on a predominant EGFR-TKI resistance mechanism in patients with EGFR-mutated NSCLC, shows that the combination of capmatinib with gefitinib is a promising treatment for patients with EGFR-mutated, MET-dysregulated NSCLC, particularly MET-amplified disease.
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The phase II multicentre, multicohort GEOMETRY mono-1 clinical study showed that the combination of capmatinib with gefitinib had a good overall response rate in EGFR-TKI-resistant patients, particularly those with MET-amplified disease.
“At the American Society of Clinical Oncology (ASCO) 2019, the phase II multicentre, multicohort GEOMETRY mono-1 clinical study showed that the combination of capmatinib (a c-MET inhibitor) with gefitinib (EGFR-TKI) had a good overall response rate in EGFR-TKI-resistant patients, particularly those with MET-amplified disease [34].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [34]
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<i>MET</i> Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., et al. (2007) · Science · doi:10.1126/science.1141478 · Cited by 4,496 · see citing works
<i>EGFR</i> Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Kobayashi, S., Boggon, T. J., Dayaram, T., Jänne, P. A., Kocher, O., Meyerson, M., Johnson, B. E., Eck, M. J., Tenen, D. G., & Halmos, B. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa044238 · Cited by 3,964 · see citing works
Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P., Bergethon, K., Shaw, A. T., Gettinger, S., Cosper, A. K., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002003 · Cited by 3,499 · see citing works
Yu, H. A., Arcila, M. E., Rekhtman, N., Sima, C. S., Zakowski, M. F., Pao, W., Kris, M. G., Miller, V. A., Ladanyi, M., & Riely, G. J. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-2246 · Cited by 2,454 · see citing works
Bean, J., Brennan, C., Shih, J.-Y., Riely, G., Viale, A., Wang, L., Chitale, D., Motoi, N., Szoke, J., Broderick, S., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710370104 · Cited by 1,598 · see citing works
Frampton, G. M., Ali, S. M., Rosenzweig, M., Chmielecki, J., Lu, X., Bauer, T. M., Akimov, M., Bufill, J. A., Lee, C., Jentz, D., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0285 · Cited by 796 · see citing works
Self-citationJackman, D., Pao, W., Riely, G. J., Engelman, J. A., Kris, M. G., Jänne, P. A., Lynch, T., Johnson, B. E., & Miller, V. A. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.24.7049 · Cited by 793 · see citing works
Spigel, D. R., Ervin, T. J., Ramlau, R., Daniel, D. B., Goldschmidt, J. H., Blumenschein, G. R., Krzakowski, M. J., Robinet, G., Godbert, B., Barlési, F., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.47.4189 · Cited by 479 · see citing works
Critical aspects of the Bayesian approach to phase I cancer trials
Neuenschwander, B. E., Branson, M., & Gsponer, T. (2008) · Statistics in Medicine · doi:10.1002/sim.3230 · Cited by 443 · see citing works
Liu, X., Wang, Q., Yang, G., Marando, C. A., Koblish, H. K., Hall, L. M., Fridman, J. S., Behshad, E., Wynn, R., Li, Y., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1157 · Cited by 268 · see citing works
Self-citationMinari, R., Bordi, P., & Tiseo, M. (2016) · Translational Lung Cancer Research · doi:10.21037/tlcr.2016.12.02 · Cited by 186 · see citing works
c-MET/Phospho-MET Protein Expression and MET Gene Copy Number in Non-small Cell Lung Carcinomas
Tsuta, K., Kozu, Y., Mimae, T., Yoshida, A., Kohno, T., Sekine, I., Tamura, T., Asamura, H., Furuta, K., & Tsuda, H. (2011) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318241655f · Cited by 152 · see citing works
Yoshioka, H., Azuma, K., Yamamoto, N., Takahashi, T., Nishio, M., Katakami, N., Ahn, M., Hirashima, T., Maemondo, M., Kim, S. W., et al. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv288 · Cited by 117 · see citing works
Self-citationClinical Pharmacokinetics of Tyrosine Kinase Inhibitors
Scheffler, M., Gion, P. D., Doroshyenko, O., Wolf, J., & Fuhr, U. (2011) · Clinical Pharmacokinetics · doi:10.2165/11587020-000000000-00000 · Cited by 110 · see citing works
Chen, H.-J., Mok, T. S. K., Chen, Z. H., Guo, A., Zhang, X., Su, J., & Wu, Y.-L. L. C. (2009) · Pathology & Oncology Research · doi:10.1007/s12253-009-9167-8 · Cited by 107 · see citing works
Self-citationTargeting MET Amplification as a New Oncogenic Driver
Kawakami, H., Okamoto, I., Okamoto, W., Tanizaki, J., Nakagawa, K., & Nishio, K. (2014) · Cancers · doi:10.3390/cancers6031540 · Cited by 107 · see citing works
Onitsuka, T., Uramoto, H., Ono, K., Takenoyama, M., Hanagiri, T., Oyama, T., Izumi, H., Kohno, K., & Yasumoto, K. (2010) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181d0a4db · Cited by 83 · see citing works
Salgia, R., Patel, P. H., Bothos, J. G., Yu, W., Eppler, S., Hegde, P. S., Bai, S., Kaur, S., Nijem, I., Catenacci, D. V. T., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-2070 · Cited by 66 · see citing works
Calles, A., Kwiatkowski, N. P., Cammarata, B. K., Ercan, D., Gray, N. S., & Janne, P. A. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.08.011 · Cited by 58 · see citing works
Janne, P. A., Shaw, A. T., Camidge, D. R., Giaccone, G., Shreeve, S. M., Tang, Y., Goldberg, Z., Martini, J., Xu, H., James, L. P., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.01.022 · Cited by 56 · see citing works
Ou, S. I., Govindan, R., Eaton, K. D., Otterson, G. A., Gutierrez, M. E., Mita, A. C., Argiris, A. E., Brega, N. M., Usari, T., Tan, W., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.09.131 · Cited by 53 · see citing works
Lara, M. S., Holland, W. S., Chinn, D. C., Burich, R. A., Lara, P. N., Gandara, D. R., Kelly, K. L., & Mack, P. C. (2016) · Clinical Lung Cancer · doi:10.1016/j.cllc.2016.11.006 · Cited by 40 · see citing works
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Xie, Y.-H., Chen, Y.-X., & Fang, J.-Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0116-z · Cited by 1,687 · see citing works
Oxnard, G. R., Yang, J. C.-H., Yu, H., Kim, S.-W., Saka, H., Horn, L., Goto, K., Ohe, Y., Mann, H., Thress, K. S., et al. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2020.01.013 · Cited by 438 · see citing works
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HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence
Fu, J., Su, X., Li, Z., Deng, L., Liu, X., Feng, X., & Peng, J. (2021) · Oncogene · doi:10.1038/s41388-021-01863-w · Cited by 235 · see citing works
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- Authors
- Wu, Y.-L., Zhang, L., Kim, D.-W., Liu, X., Lee, D. H., Yang, J. C.-H., Ahn, M.-J., Vansteenkiste, J. F., Su, W.-C., Felip, E., Chia, V., Glaser, S., Pultar, P., Zhao, S., Peng, B., Akimov, M., & Tan, D. S. W.
- Affiliations
- Guangdong General Hospital (CN)
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People’s Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2018-11-01
- Volume
- 36
- Issue
- 31
- Pages
- 3101-3109
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2889373434
- Cited by
- 333
- References
- 22
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 54 · 2023: 40 · 2022: 51 · 2021: 54 · 2020: 54 · 2019: 32 · 2018: 5
- FWCI
- 27.32
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-01-20)
- Open access
- green
- lirias.kuleuven.be
- Licence
- other-oa
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Sanofi
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- capmatinib, gefitinib, MET amplification, EGFR-mutant non-small cell lung cancer, EGFR tyrosine kinase inhibitor resistance, MET inhibitors, combination therapy, overall response rate, drug safety and tolerability, drug-drug interactions, recommended phase 2 dose, RECIST 1.1
- MeSH terms
- Gefitinib, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Carcinoma, Non-Small-Cell Lung, Female, Humans, Imidazoles, Lung Neoplasms, Male, Middle Aged, Mutation, Triazines, Proto-Oncogene Proteins c-met, Maximum Tolerated Dose, ErbB Receptors
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