Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLC
Introduction: MET amplification is a known resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant NSCLC. Dual EGFR-MET inhibition has been reported with success in overcoming such resistance and inducing clinical benefit. Resistance mechanisms to dual EGFR-MET inhibiti...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | JTO Clinical and Research Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666364323000723 |
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| author | Kaiwen Wang, PharmD Robyn Du, BS Sinchita Roy-Chowdhuri, MD Ziping T. Li, MD Lingzhi Hong, MD Natalie Vokes, MD Yasir Y. Elamin, MD Celyne Bueno Hume, MD Ferdinandos Skoulidis, MD, PhD Carl M. Gay, MD, PhD George Blumenschein, MD Frank V. Fossella, MD Anne Tsao, MD Jianjun Zhang, MD, PhD Niki Karachaliou, MD Aurora O’Brate, PhD Claudia-Nanette Gann, MD Jeff Lewis, MS Waree Rinsurongkawong, PhD J. Jack Lee, PhD, MS, DDS Don Lynn Gibbons, MD, PhD Ara A. Vaporciyan, MD John V. Heymach, MD, PhD Mehmet Altan, MD Xiuning Le, MD, PhD |
| author_facet | Kaiwen Wang, PharmD Robyn Du, BS Sinchita Roy-Chowdhuri, MD Ziping T. Li, MD Lingzhi Hong, MD Natalie Vokes, MD Yasir Y. Elamin, MD Celyne Bueno Hume, MD Ferdinandos Skoulidis, MD, PhD Carl M. Gay, MD, PhD George Blumenschein, MD Frank V. Fossella, MD Anne Tsao, MD Jianjun Zhang, MD, PhD Niki Karachaliou, MD Aurora O’Brate, PhD Claudia-Nanette Gann, MD Jeff Lewis, MS Waree Rinsurongkawong, PhD J. Jack Lee, PhD, MS, DDS Don Lynn Gibbons, MD, PhD Ara A. Vaporciyan, MD John V. Heymach, MD, PhD Mehmet Altan, MD Xiuning Le, MD, PhD |
| author_sort | Kaiwen Wang, PharmD |
| collection | DOAJ |
| description | Introduction: MET amplification is a known resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant NSCLC. Dual EGFR-MET inhibition has been reported with success in overcoming such resistance and inducing clinical benefit. Resistance mechanisms to dual EGFR-MET inhibition require further investigation and characterization. Methods: Patients with NSCLC with both MET amplification and EGFR mutation who have received crizotinib, capmatinib, savolitinib, or tepotinib plus osimertinib (OSI) after progression on OSI at MD Anderson Cancer Center were included in this study. Molecular profiling was completed by means of fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). Radiological response was assessed on the basis of Response Evaluation Criteria in Solid Tumors version 1.1. Results: From March 2016 to March 2022, 23 treatments with dual MET inhibitor and osi were identified with a total of 20 patients included. Three patients received capmatinib plus OSI after progression on crizotinib plus OSI. Median age was 64 (38–89) years old and 75% were female. MET amplification was detected by FISH in 14 patients in the tissue, NGS in 10 patients, and circulating tumor DNA in three patients. Median MET gene copy number was 13.6 (6.4–20). Overall response rate was 34.8% (eight of 23). In assessable patients, tumor shrinkage was observed in 82.4% (14 of 17). Median time on treatment was 27 months. Two of three patients responded to capmatinib plus OSI after progression on crizotinib plus OSI. Dual EGFR-MET inhibition was overall well tolerated. Two patients on crizotinib plus OSI and one pt on capmatinib plus OSI discontinued therapy due to pneumonitis. One pt discontinued crizotinib plus OSI due to gastrointestinal toxicity. Six patients were still on double TKI treatment. At disease progression to dual EGFR-MET inhibition, FISH and NGS on tumor and plasma were completed in six patients. Notable resistance mechanisms observed include acquired MET D1246H (n = 1), acquired EGFR C797S (n = 2), FGFR2 fusion (n = 1, concurrent with C797S), and EGFR G796S (n = 1, concurrent with C797S). Four patients lost MET amplification. Conclusions: Dual EGFR and MET inhibition yielded high clinical response rate after progression on OSI. Resistance mechanisms to EGFR-MET double TKI inhibition include MET secondary mutation, EGFR secondary mutation, or loss of MET amplification. |
| first_indexed | 2024-03-12T13:27:44Z |
| format | Article |
| id | doaj.art-abe6440483814bd08d4c9b73ab459684 |
| institution | Directory Open Access Journal |
| issn | 2666-3643 |
| language | English |
| last_indexed | 2024-03-12T13:27:44Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JTO Clinical and Research Reports |
| spelling | doaj.art-abe6440483814bd08d4c9b73ab4596842023-08-25T04:24:47ZengElsevierJTO Clinical and Research Reports2666-36432023-08-0148100533Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLCKaiwen Wang, PharmD0Robyn Du, BS1Sinchita Roy-Chowdhuri, MD2Ziping T. Li, MD3Lingzhi Hong, MD4Natalie Vokes, MD5Yasir Y. Elamin, MD6Celyne Bueno Hume, MD7Ferdinandos Skoulidis, MD, PhD8Carl M. Gay, MD, PhD9George Blumenschein, MD10Frank V. Fossella, MD11Anne Tsao, MD12Jianjun Zhang, MD, PhD13Niki Karachaliou, MD14Aurora O’Brate, PhD15Claudia-Nanette Gann, MD16Jeff Lewis, MS17Waree Rinsurongkawong, PhD18J. Jack Lee, PhD, MS, DDS19Don Lynn Gibbons, MD, PhD20Ara A. Vaporciyan, MD21John V. Heymach, MD, PhD22Mehmet Altan, MD23Xiuning Le, MD, PhD24Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasThe Healthcare Business of Merck KGaA, Darmstadt, GermanyThe Healthcare Business of Merck KGaA, Darmstadt, GermanyThe Healthcare Business of Merck KGaA, Darmstadt, GermanyDepartment of Quantitative Research Computing, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Quantitative Research Computing, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic & Cardiovasc Surgery, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TexasDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Corresponding author. Address for correspondence: Xiuning Le, MD, PhD, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030.Introduction: MET amplification is a known resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant NSCLC. Dual EGFR-MET inhibition has been reported with success in overcoming such resistance and inducing clinical benefit. Resistance mechanisms to dual EGFR-MET inhibition require further investigation and characterization. Methods: Patients with NSCLC with both MET amplification and EGFR mutation who have received crizotinib, capmatinib, savolitinib, or tepotinib plus osimertinib (OSI) after progression on OSI at MD Anderson Cancer Center were included in this study. Molecular profiling was completed by means of fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). Radiological response was assessed on the basis of Response Evaluation Criteria in Solid Tumors version 1.1. Results: From March 2016 to March 2022, 23 treatments with dual MET inhibitor and osi were identified with a total of 20 patients included. Three patients received capmatinib plus OSI after progression on crizotinib plus OSI. Median age was 64 (38–89) years old and 75% were female. MET amplification was detected by FISH in 14 patients in the tissue, NGS in 10 patients, and circulating tumor DNA in three patients. Median MET gene copy number was 13.6 (6.4–20). Overall response rate was 34.8% (eight of 23). In assessable patients, tumor shrinkage was observed in 82.4% (14 of 17). Median time on treatment was 27 months. Two of three patients responded to capmatinib plus OSI after progression on crizotinib plus OSI. Dual EGFR-MET inhibition was overall well tolerated. Two patients on crizotinib plus OSI and one pt on capmatinib plus OSI discontinued therapy due to pneumonitis. One pt discontinued crizotinib plus OSI due to gastrointestinal toxicity. Six patients were still on double TKI treatment. At disease progression to dual EGFR-MET inhibition, FISH and NGS on tumor and plasma were completed in six patients. Notable resistance mechanisms observed include acquired MET D1246H (n = 1), acquired EGFR C797S (n = 2), FGFR2 fusion (n = 1, concurrent with C797S), and EGFR G796S (n = 1, concurrent with C797S). Four patients lost MET amplification. Conclusions: Dual EGFR and MET inhibition yielded high clinical response rate after progression on OSI. Resistance mechanisms to EGFR-MET double TKI inhibition include MET secondary mutation, EGFR secondary mutation, or loss of MET amplification.http://www.sciencedirect.com/science/article/pii/S2666364323000723Resistance mechanismsMETEGFRNSCLC |
| spellingShingle | Kaiwen Wang, PharmD Robyn Du, BS Sinchita Roy-Chowdhuri, MD Ziping T. Li, MD Lingzhi Hong, MD Natalie Vokes, MD Yasir Y. Elamin, MD Celyne Bueno Hume, MD Ferdinandos Skoulidis, MD, PhD Carl M. Gay, MD, PhD George Blumenschein, MD Frank V. Fossella, MD Anne Tsao, MD Jianjun Zhang, MD, PhD Niki Karachaliou, MD Aurora O’Brate, PhD Claudia-Nanette Gann, MD Jeff Lewis, MS Waree Rinsurongkawong, PhD J. Jack Lee, PhD, MS, DDS Don Lynn Gibbons, MD, PhD Ara A. Vaporciyan, MD John V. Heymach, MD, PhD Mehmet Altan, MD Xiuning Le, MD, PhD Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLC JTO Clinical and Research Reports Resistance mechanisms MET EGFR NSCLC |
| title | Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLC |
| title_full | Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLC |
| title_fullStr | Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLC |
| title_full_unstemmed | Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLC |
| title_short | Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLC |
| title_sort | brief report clinical response toxicity and resistance mechanisms to osimertinib plus met inhibitors in patients with egfr mutant met amplified nsclc |
| topic | Resistance mechanisms MET EGFR NSCLC |
| url | http://www.sciencedirect.com/science/article/pii/S2666364323000723 |
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