Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice

Xiuning Le; Hiroshi Sakai; Enriqueta Felip; Remi Veillon; Marina Chiara Garassino; Jo Raskin; Alexis B. Cortot; Santiago Viteri; Julien Mazieres; Egbert F. Smit; Michael Thomas; Wade T. Iams; Byoung Chul Cho; Hye Ryun Kim; James Chih Hsin Yang; Yuh Min Chen; Jyoti D. Patel; Christine M. Bestvina; Keunchil Park; Frank Griesinger; Melissa Johnson; Maya Gottfried; Christian Britschgi; John Heymach; Elif Sikoglu; Karin Berghoff; Karl Maria Schumacher; Rolf Bruns; Gordon Otto; Paul K. Paik

doi:10.1158/1078-0432.CCR-21-2733

Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice

Xiuning Le, Hiroshi Sakai, Enriqueta Felip, Remi Veillon, Marina Chiara Garassino, Jo Raskin, Alexis B. Cortot, Santiago Viteri, Julien Mazieres, Egbert F. Smit, Michael Thomas, Wade T. Iams, Byoung Chul Cho, Hye Ryun Kim, James Chih Hsin Yang, Yuh Min Chen, Jyoti D. Patel, Christine M. Bestvina, Keunchil Park, Frank GriesingerMelissa Johnson, Maya Gottfried, Christian Britschgi, John Heymach, Elif Sikoglu, Karin Berghoff, Karl Maria Schumacher, Rolf Bruns, Gordon Otto, Paul K. Paik

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

Abstract

Purpose: Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non–small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups. Patients and Methods: This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity. Results: 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7–53.0]. Patients aged <75 (n ¼ 84) and ≥75 (n ¼ 68) had ORRs of 48.8% (95% CI: 37.7–60.0) and 39.7% (95% CI: 28.0–52.3), respectively. Treatment-naïve (n ¼ 69) versus previously treated (n ¼ 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9–57.4) vs. 44.6% (33.7–55.9); median duration of response (95% CI): 10.8 (6.9–not estimable) vs. 11.1 (9.5–18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies. Conclusions: Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations.

Original language	English
Pages (from-to)	1117-1126
Number of pages	10
Journal	Clinical Cancer Research
Volume	28
Issue number	6
DOIs	https://doi.org/10.1158/1078-0432.CCR-21-2733
Publication status	Published - 2022 Mar 15

Bibliographical note

Funding Information:
financial support from Novartis and Roche; grants and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany; personal fees from Johnson & Johnson; and personal fees and non-financial support from Takeda outside the submitted work. S. Viteri reports personal fees from Takeda, the healthcare business of Merck KGaA, Darmstadt, Germany, BMS, Merck & Co., Janssen, Puma, AstraZeneca, and Roche outside the submitted work. J. Mazieres reports personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as personal fees from Roche, AstraZeneca, BMS, Merck & Co., Takeda, and Novartis; grants from Pierre Fabre; and personal fees from Daiichi Sankyo outside the submitted work. E.F. Smit reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study. M. Thomas reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Roche, and Takeda and personal fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Chugai Pharma, Janssen Oncology, Eli Lilly and Company, Mirati Therapeutics, Bristol-Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Leads Biolabs, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck & Co., Novartis, and Pfizer outside the submitted work. W.T. Iams reports personal fees from Genentech, Jazz Pharma, G1 Therapeutics, Mirati, OncLive, Clinical Care Options, Chardan, Outcomes Insights, Cello Health, and Curio Science outside the submitted work. B.C. Cho reports grants from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck & Co., AbbVie, Medpacto, GIInnovation, Eli Lilly and Company, Blueprint Medicines, and Interpark Bio Convergence Corp.; personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly and Company, Janssen, Takeda, Merck & Co., Medpacto, Blueprint Medicines, TheraCanVac Inc., Gencurix Inc., Bridgebio Therapeutics, KANAPH Therapeutic Inc., Cyrus Therapeutics, Inter-park Bio Convergence Corp., Guardant Health, Joseah BIO, and Champions Oncology; and other support from DAAN Biotherapeutics outside the submitted work. J.C.-H. Yang reports other support from Amgen, Eli Lilly and Company, JNJ, and GSK; grants, personal fees, and other support from AstraZeneca; personal fees and other support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, the healthcare business of Merck KGaA, Darm-stadt, Germany, Merck & Co., Novartis, Roche/Genentech, Takeda Oncology, and Yuhan Pharmaceutical; personal fees from Ono Pharmaceutical and Pfizer; and other support from Puma Technology outside the submitted work. J.D. Patel reports other support from AstraZeneca, Takeda, and Eli Lilly and Company outside the submitted work. C.M. Bestvina reports other support from EMD Serono during the conduct of the study as well as personal fees from AstraZeneca, Genentech, JNJ, Novartis, Pfizer, Seattle Genetics, and Takeda; grants and personal fees from BMS; and personal fees from Jazz Pharmaceuticals outside the submitted work. K. Park reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, outside the submitted work. F. Griesinger reports personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as grants and personal fees from AstraZeneca, Boehringer Ingelheim, BMS, Merck & Co., Novartis, Pfizer, Roche, GSK, Siemens, Amgen, and Takeda; grants from Eli Lilly and Company; and personal fees from AbbVie outside the submitted work. M. Johnson reports grants and other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as grants and other support from Mirati Therapeutics, AbbVie, Amgen, AstraZeneca, Atreca, Calithera Biosciences, Checkpoint Therapeutics, CytomX, Daiichi Sankyo, Eli Lilly and Company, EMD Serono, Genentech/Roche, Genmab, GlaxoSmithKline, Gritstone Oncology, Guardant Health, IDEAYA Biosciences, Incyte, Janssen, Loxo Oncology, Novartis, Pfizer, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi, Turning Point Therapeutics, and WindMIL; grants from Acerta, Adaptimmune, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, BeiGene, BioA-tla, Corvus Pharmaceuticals, Curis, Dracen Pharmaceuticals, Dynavax, Elicio Therapeutics, Erasca, Genocea Biosciences, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IGM Biosciences, Immunocore, Jounce Therapeutics, Kadmon Pharmaceuticals, Lycera, Memorial Sloan-Kettering, NeoImmune Tech, Neovia Oncology, Numab Therapeutics, OncoMed Pharmaceuticals, PMV Pharmaceuticals, RasCal Therapeutics, Relay Therapeutics, Revolution Medicines, Rubius Therapetics, Seven and Eight Biopharmaceuticals/ Birdie Biopharmaceuticals, Shattuck Labs, Sillicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, University of Michigan, Vyriad, and y-mAbs Therapeutics; and other support from Boehringer Ingelheim, Achilles Therapeutics, Axelia Oncology, Black Diamond, Bris- tol-Myers Squibb, EcoR1, Editas Medicine, Eisai, G1 Therapeutics, ITeos, and Oncorus outside the submitted work. C. Britschgi reports personal fees and nonfinancial support from AstraZeneca and Takeda and personal fees from Pfizer, Roche, Janssen-Cilag, and Boehringer Ingelheim outside the submitted work. J. Heymach reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Takeda Pharmaceuticals; personal fees from Genentech, Catalyst, Guardant Health, Foundation Medicine, Hengrui, Eli Lilly and Company, Novartis, Sanofi, Mirati Therapeutics, Bristol-Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, and Leads Biolabs; grants, personal fees, and other support from Spectrum; and personal fees from RefleXion outside the submitted work. E. Sikoglu reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study. K. Berghoff and K.-M. Schumacher are employees of the healthcare business of Merck KGaA, Darmstadt, Germany. R. Bruns is an employee and stockholder of the healthcare business of Merck KGaA, Darmstadt, Germany. G. Otto is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stocks with Novartis. P.K. Paik reports personal fees and other support from EMD Serono during the conduct of the study; personal fees and other support from Calithera; personal fees from Takeda and Xencor; other support from Boehringer Ingelheim; and personal fees and other support from Bicara outside the submitted work. No disclosures were reported by the other authors.

Funding Information:
X. Le reports grants and personal fees from EMD Serono and Eli Lilly and Company; personal fees from AstraZeneca, Hengrui Therapeutics, Daiichi Sanyko, Janssen, Novartis, AbbVie, and Spectrum Pharmaceutics; and grants and personal fees from Boehringer Ingelheim outside the submitted work. H. Sakai reports grants and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as personal fees from Ono Pharmaceutical Co., Bristol-Myers Squibb, AstraZeneca, Chugai Pharmaceutical Co., and Taiho Pharmaceutical Co. outside the submitted work. R. Veillon reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as personal fees from Roche, AstraZeneca, BMS, Janssen, and Merck & Co. outside the submitted work. M.C. Garassino reports grants and personal fees from AstraZeneca and the healthcare business of Merck KGaA, Darmstadt, Germany, and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, BMS, Roche, Daiichi Sankyo, Celgene, GSK, Eli Lilly and Company, Novartis, Regeneron, and Gilead during the conduct of the study as well as personal fees from AstraZeneca, Roche, Gilead, Merck & Co., BMS, Eli Lilly and Company, GSK, Regeneron, Novartis, and Celgene outside the submitted work. J. Raskin reports personal fees from Boehringer Ingelheim, Eli Lilly and Company, and Pfizer; non-financial support from Roche; and personal fees from BMS outside the submitted work. A.B. Cortot reports personal fees and non-financial support from AstraZeneca, Bristol-Myers Squibb, Merck & Co., and Pfizer; grants, personal fees, and non-

Publisher Copyright:
2021 The Authors; Published by the American Association for Cancer Research

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/1078-0432.CCR-21-2733

Cite this

Le, X., Sakai, H., Felip, E., Veillon, R., Garassino, M. C., Raskin, J., Cortot, A. B., Viteri, S., Mazieres, J., Smit, E. F., Thomas, M., Iams, W. T., Cho, B. C., Kim, H. R., Yang, J. C. H., Chen, Y. M., Patel, J. D., Bestvina, C. M., Park, K., ... Paik, P. K. (2022). Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice. Clinical Cancer Research, 28(6), 1117-1126. https://doi.org/10.1158/1078-0432.CCR-21-2733

@article{25eef7d09ea34eff8fc806ea62104e1f,

title = "Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice",

abstract = "Purpose: Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non–small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups. Patients and Methods: This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity. Results: 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7–53.0]. Patients aged <75 (n ¼ 84) and ≥75 (n ¼ 68) had ORRs of 48.8% (95% CI: 37.7–60.0) and 39.7% (95% CI: 28.0–52.3), respectively. Treatment-na{\"i}ve (n ¼ 69) versus previously treated (n ¼ 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9–57.4) vs. 44.6% (33.7–55.9); median duration of response (95% CI): 10.8 (6.9–not estimable) vs. 11.1 (9.5–18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies. Conclusions: Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations.",

author = "Xiuning Le and Hiroshi Sakai and Enriqueta Felip and Remi Veillon and Garassino, {Marina Chiara} and Jo Raskin and Cortot, {Alexis B.} and Santiago Viteri and Julien Mazieres and Smit, {Egbert F.} and Michael Thomas and Iams, {Wade T.} and Cho, {Byoung Chul} and Kim, {Hye Ryun} and Yang, {James Chih Hsin} and Chen, {Yuh Min} and Patel, {Jyoti D.} and Bestvina, {Christine M.} and Keunchil Park and Frank Griesinger and Melissa Johnson and Maya Gottfried and Christian Britschgi and John Heymach and Elif Sikoglu and Karin Berghoff and Schumacher, {Karl Maria} and Rolf Bruns and Gordon Otto and Paik, {Paul K.}",

note = "Funding Information: financial support from Novartis and Roche; grants and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany; personal fees from Johnson & Johnson; and personal fees and non-financial support from Takeda outside the submitted work. S. Viteri reports personal fees from Takeda, the healthcare business of Merck KGaA, Darmstadt, Germany, BMS, Merck & Co., Janssen, Puma, AstraZeneca, and Roche outside the submitted work. J. Mazieres reports personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as personal fees from Roche, AstraZeneca, BMS, Merck & Co., Takeda, and Novartis; grants from Pierre Fabre; and personal fees from Daiichi Sankyo outside the submitted work. E.F. Smit reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study. M. Thomas reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Roche, and Takeda and personal fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Chugai Pharma, Janssen Oncology, Eli Lilly and Company, Mirati Therapeutics, Bristol-Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Leads Biolabs, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck & Co., Novartis, and Pfizer outside the submitted work. W.T. Iams reports personal fees from Genentech, Jazz Pharma, G1 Therapeutics, Mirati, OncLive, Clinical Care Options, Chardan, Outcomes Insights, Cello Health, and Curio Science outside the submitted work. B.C. Cho reports grants from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck & Co., AbbVie, Medpacto, GIInnovation, Eli Lilly and Company, Blueprint Medicines, and Interpark Bio Convergence Corp.; personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly and Company, Janssen, Takeda, Merck & Co., Medpacto, Blueprint Medicines, TheraCanVac Inc., Gencurix Inc., Bridgebio Therapeutics, KANAPH Therapeutic Inc., Cyrus Therapeutics, Inter-park Bio Convergence Corp., Guardant Health, Joseah BIO, and Champions Oncology; and other support from DAAN Biotherapeutics outside the submitted work. J.C.-H. Yang reports other support from Amgen, Eli Lilly and Company, JNJ, and GSK; grants, personal fees, and other support from AstraZeneca; personal fees and other support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, the healthcare business of Merck KGaA, Darm-stadt, Germany, Merck & Co., Novartis, Roche/Genentech, Takeda Oncology, and Yuhan Pharmaceutical; personal fees from Ono Pharmaceutical and Pfizer; and other support from Puma Technology outside the submitted work. J.D. Patel reports other support from AstraZeneca, Takeda, and Eli Lilly and Company outside the submitted work. C.M. Bestvina reports other support from EMD Serono during the conduct of the study as well as personal fees from AstraZeneca, Genentech, JNJ, Novartis, Pfizer, Seattle Genetics, and Takeda; grants and personal fees from BMS; and personal fees from Jazz Pharmaceuticals outside the submitted work. K. Park reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, outside the submitted work. F. Griesinger reports personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as grants and personal fees from AstraZeneca, Boehringer Ingelheim, BMS, Merck & Co., Novartis, Pfizer, Roche, GSK, Siemens, Amgen, and Takeda; grants from Eli Lilly and Company; and personal fees from AbbVie outside the submitted work. M. Johnson reports grants and other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as grants and other support from Mirati Therapeutics, AbbVie, Amgen, AstraZeneca, Atreca, Calithera Biosciences, Checkpoint Therapeutics, CytomX, Daiichi Sankyo, Eli Lilly and Company, EMD Serono, Genentech/Roche, Genmab, GlaxoSmithKline, Gritstone Oncology, Guardant Health, IDEAYA Biosciences, Incyte, Janssen, Loxo Oncology, Novartis, Pfizer, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi, Turning Point Therapeutics, and WindMIL; grants from Acerta, Adaptimmune, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, BeiGene, BioA-tla, Corvus Pharmaceuticals, Curis, Dracen Pharmaceuticals, Dynavax, Elicio Therapeutics, Erasca, Genocea Biosciences, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IGM Biosciences, Immunocore, Jounce Therapeutics, Kadmon Pharmaceuticals, Lycera, Memorial Sloan-Kettering, NeoImmune Tech, Neovia Oncology, Numab Therapeutics, OncoMed Pharmaceuticals, PMV Pharmaceuticals, RasCal Therapeutics, Relay Therapeutics, Revolution Medicines, Rubius Therapetics, Seven and Eight Biopharmaceuticals/ Birdie Biopharmaceuticals, Shattuck Labs, Sillicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, University of Michigan, Vyriad, and y-mAbs Therapeutics; and other support from Boehringer Ingelheim, Achilles Therapeutics, Axelia Oncology, Black Diamond, Bris- tol-Myers Squibb, EcoR1, Editas Medicine, Eisai, G1 Therapeutics, ITeos, and Oncorus outside the submitted work. C. Britschgi reports personal fees and nonfinancial support from AstraZeneca and Takeda and personal fees from Pfizer, Roche, Janssen-Cilag, and Boehringer Ingelheim outside the submitted work. J. Heymach reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Takeda Pharmaceuticals; personal fees from Genentech, Catalyst, Guardant Health, Foundation Medicine, Hengrui, Eli Lilly and Company, Novartis, Sanofi, Mirati Therapeutics, Bristol-Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, and Leads Biolabs; grants, personal fees, and other support from Spectrum; and personal fees from RefleXion outside the submitted work. E. Sikoglu reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study. K. Berghoff and K.-M. Schumacher are employees of the healthcare business of Merck KGaA, Darmstadt, Germany. R. Bruns is an employee and stockholder of the healthcare business of Merck KGaA, Darmstadt, Germany. G. Otto is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stocks with Novartis. P.K. Paik reports personal fees and other support from EMD Serono during the conduct of the study; personal fees and other support from Calithera; personal fees from Takeda and Xencor; other support from Boehringer Ingelheim; and personal fees and other support from Bicara outside the submitted work. No disclosures were reported by the other authors. Funding Information: X. Le reports grants and personal fees from EMD Serono and Eli Lilly and Company; personal fees from AstraZeneca, Hengrui Therapeutics, Daiichi Sanyko, Janssen, Novartis, AbbVie, and Spectrum Pharmaceutics; and grants and personal fees from Boehringer Ingelheim outside the submitted work. H. Sakai reports grants and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as personal fees from Ono Pharmaceutical Co., Bristol-Myers Squibb, AstraZeneca, Chugai Pharmaceutical Co., and Taiho Pharmaceutical Co. outside the submitted work. R. Veillon reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as personal fees from Roche, AstraZeneca, BMS, Janssen, and Merck & Co. outside the submitted work. M.C. Garassino reports grants and personal fees from AstraZeneca and the healthcare business of Merck KGaA, Darmstadt, Germany, and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, BMS, Roche, Daiichi Sankyo, Celgene, GSK, Eli Lilly and Company, Novartis, Regeneron, and Gilead during the conduct of the study as well as personal fees from AstraZeneca, Roche, Gilead, Merck & Co., BMS, Eli Lilly and Company, GSK, Regeneron, Novartis, and Celgene outside the submitted work. J. Raskin reports personal fees from Boehringer Ingelheim, Eli Lilly and Company, and Pfizer; non-financial support from Roche; and personal fees from BMS outside the submitted work. A.B. Cortot reports personal fees and non-financial support from AstraZeneca, Bristol-Myers Squibb, Merck & Co., and Pfizer; grants, personal fees, and non- Publisher Copyright: 2021 The Authors; Published by the American Association for Cancer Research",

year = "2022",

month = mar,

day = "15",

doi = "10.1158/1078-0432.CCR-21-2733",

language = "English",

volume = "28",

pages = "1117--1126",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "6",

}

Le, X, Sakai, H, Felip, E, Veillon, R, Garassino, MC, Raskin, J, Cortot, AB, Viteri, S, Mazieres, J, Smit, EF, Thomas, M, Iams, WT, Cho, BC, Kim, HR, Yang, JCH, Chen, YM, Patel, JD, Bestvina, CM, Park, K, Griesinger, F, Johnson, M, Gottfried, M, Britschgi, C, Heymach, J, Sikoglu, E, Berghoff, K, Schumacher, KM, Bruns, R, Otto, G & Paik, PK 2022, 'Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice', Clinical Cancer Research, vol. 28, no. 6, pp. 1117-1126. https://doi.org/10.1158/1078-0432.CCR-21-2733

TY - JOUR

T1 - Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC

T2 - Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice

AU - Le, Xiuning

AU - Sakai, Hiroshi

AU - Felip, Enriqueta

AU - Veillon, Remi

AU - Garassino, Marina Chiara

AU - Raskin, Jo

AU - Cortot, Alexis B.

AU - Viteri, Santiago

AU - Mazieres, Julien

AU - Smit, Egbert F.

AU - Thomas, Michael

AU - Iams, Wade T.

AU - Cho, Byoung Chul

AU - Kim, Hye Ryun

AU - Yang, James Chih Hsin

AU - Chen, Yuh Min

AU - Patel, Jyoti D.

AU - Bestvina, Christine M.

AU - Park, Keunchil

AU - Griesinger, Frank

AU - Johnson, Melissa

AU - Gottfried, Maya

AU - Britschgi, Christian

AU - Heymach, John

AU - Sikoglu, Elif

AU - Berghoff, Karin

AU - Schumacher, Karl Maria

AU - Bruns, Rolf

AU - Otto, Gordon

AU - Paik, Paul K.

N1 - Funding Information: financial support from Novartis and Roche; grants and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany; personal fees from Johnson & Johnson; and personal fees and non-financial support from Takeda outside the submitted work. S. Viteri reports personal fees from Takeda, the healthcare business of Merck KGaA, Darmstadt, Germany, BMS, Merck & Co., Janssen, Puma, AstraZeneca, and Roche outside the submitted work. J. Mazieres reports personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as personal fees from Roche, AstraZeneca, BMS, Merck & Co., Takeda, and Novartis; grants from Pierre Fabre; and personal fees from Daiichi Sankyo outside the submitted work. E.F. Smit reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study. M. Thomas reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Roche, and Takeda and personal fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Chugai Pharma, Janssen Oncology, Eli Lilly and Company, Mirati Therapeutics, Bristol-Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Leads Biolabs, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck & Co., Novartis, and Pfizer outside the submitted work. W.T. Iams reports personal fees from Genentech, Jazz Pharma, G1 Therapeutics, Mirati, OncLive, Clinical Care Options, Chardan, Outcomes Insights, Cello Health, and Curio Science outside the submitted work. B.C. Cho reports grants from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck & Co., AbbVie, Medpacto, GIInnovation, Eli Lilly and Company, Blueprint Medicines, and Interpark Bio Convergence Corp.; personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly and Company, Janssen, Takeda, Merck & Co., Medpacto, Blueprint Medicines, TheraCanVac Inc., Gencurix Inc., Bridgebio Therapeutics, KANAPH Therapeutic Inc., Cyrus Therapeutics, Inter-park Bio Convergence Corp., Guardant Health, Joseah BIO, and Champions Oncology; and other support from DAAN Biotherapeutics outside the submitted work. J.C.-H. Yang reports other support from Amgen, Eli Lilly and Company, JNJ, and GSK; grants, personal fees, and other support from AstraZeneca; personal fees and other support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, the healthcare business of Merck KGaA, Darm-stadt, Germany, Merck & Co., Novartis, Roche/Genentech, Takeda Oncology, and Yuhan Pharmaceutical; personal fees from Ono Pharmaceutical and Pfizer; and other support from Puma Technology outside the submitted work. J.D. Patel reports other support from AstraZeneca, Takeda, and Eli Lilly and Company outside the submitted work. C.M. Bestvina reports other support from EMD Serono during the conduct of the study as well as personal fees from AstraZeneca, Genentech, JNJ, Novartis, Pfizer, Seattle Genetics, and Takeda; grants and personal fees from BMS; and personal fees from Jazz Pharmaceuticals outside the submitted work. K. Park reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, outside the submitted work. F. Griesinger reports personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as grants and personal fees from AstraZeneca, Boehringer Ingelheim, BMS, Merck & Co., Novartis, Pfizer, Roche, GSK, Siemens, Amgen, and Takeda; grants from Eli Lilly and Company; and personal fees from AbbVie outside the submitted work. M. Johnson reports grants and other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as grants and other support from Mirati Therapeutics, AbbVie, Amgen, AstraZeneca, Atreca, Calithera Biosciences, Checkpoint Therapeutics, CytomX, Daiichi Sankyo, Eli Lilly and Company, EMD Serono, Genentech/Roche, Genmab, GlaxoSmithKline, Gritstone Oncology, Guardant Health, IDEAYA Biosciences, Incyte, Janssen, Loxo Oncology, Novartis, Pfizer, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi, Turning Point Therapeutics, and WindMIL; grants from Acerta, Adaptimmune, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, BeiGene, BioA-tla, Corvus Pharmaceuticals, Curis, Dracen Pharmaceuticals, Dynavax, Elicio Therapeutics, Erasca, Genocea Biosciences, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IGM Biosciences, Immunocore, Jounce Therapeutics, Kadmon Pharmaceuticals, Lycera, Memorial Sloan-Kettering, NeoImmune Tech, Neovia Oncology, Numab Therapeutics, OncoMed Pharmaceuticals, PMV Pharmaceuticals, RasCal Therapeutics, Relay Therapeutics, Revolution Medicines, Rubius Therapetics, Seven and Eight Biopharmaceuticals/ Birdie Biopharmaceuticals, Shattuck Labs, Sillicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, University of Michigan, Vyriad, and y-mAbs Therapeutics; and other support from Boehringer Ingelheim, Achilles Therapeutics, Axelia Oncology, Black Diamond, Bris- tol-Myers Squibb, EcoR1, Editas Medicine, Eisai, G1 Therapeutics, ITeos, and Oncorus outside the submitted work. C. Britschgi reports personal fees and nonfinancial support from AstraZeneca and Takeda and personal fees from Pfizer, Roche, Janssen-Cilag, and Boehringer Ingelheim outside the submitted work. J. Heymach reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Takeda Pharmaceuticals; personal fees from Genentech, Catalyst, Guardant Health, Foundation Medicine, Hengrui, Eli Lilly and Company, Novartis, Sanofi, Mirati Therapeutics, Bristol-Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, and Leads Biolabs; grants, personal fees, and other support from Spectrum; and personal fees from RefleXion outside the submitted work. E. Sikoglu reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study. K. Berghoff and K.-M. Schumacher are employees of the healthcare business of Merck KGaA, Darmstadt, Germany. R. Bruns is an employee and stockholder of the healthcare business of Merck KGaA, Darmstadt, Germany. G. Otto is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stocks with Novartis. P.K. Paik reports personal fees and other support from EMD Serono during the conduct of the study; personal fees and other support from Calithera; personal fees from Takeda and Xencor; other support from Boehringer Ingelheim; and personal fees and other support from Bicara outside the submitted work. No disclosures were reported by the other authors. Funding Information: X. Le reports grants and personal fees from EMD Serono and Eli Lilly and Company; personal fees from AstraZeneca, Hengrui Therapeutics, Daiichi Sanyko, Janssen, Novartis, AbbVie, and Spectrum Pharmaceutics; and grants and personal fees from Boehringer Ingelheim outside the submitted work. H. Sakai reports grants and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as personal fees from Ono Pharmaceutical Co., Bristol-Myers Squibb, AstraZeneca, Chugai Pharmaceutical Co., and Taiho Pharmaceutical Co. outside the submitted work. R. Veillon reports other support from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study as well as personal fees from Roche, AstraZeneca, BMS, Janssen, and Merck & Co. outside the submitted work. M.C. Garassino reports grants and personal fees from AstraZeneca and the healthcare business of Merck KGaA, Darmstadt, Germany, and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, BMS, Roche, Daiichi Sankyo, Celgene, GSK, Eli Lilly and Company, Novartis, Regeneron, and Gilead during the conduct of the study as well as personal fees from AstraZeneca, Roche, Gilead, Merck & Co., BMS, Eli Lilly and Company, GSK, Regeneron, Novartis, and Celgene outside the submitted work. J. Raskin reports personal fees from Boehringer Ingelheim, Eli Lilly and Company, and Pfizer; non-financial support from Roche; and personal fees from BMS outside the submitted work. A.B. Cortot reports personal fees and non-financial support from AstraZeneca, Bristol-Myers Squibb, Merck & Co., and Pfizer; grants, personal fees, and non- Publisher Copyright: 2021 The Authors; Published by the American Association for Cancer Research

PY - 2022/3/15

Y1 - 2022/3/15

N2 - Purpose: Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non–small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups. Patients and Methods: This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity. Results: 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7–53.0]. Patients aged <75 (n ¼ 84) and ≥75 (n ¼ 68) had ORRs of 48.8% (95% CI: 37.7–60.0) and 39.7% (95% CI: 28.0–52.3), respectively. Treatment-naïve (n ¼ 69) versus previously treated (n ¼ 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9–57.4) vs. 44.6% (33.7–55.9); median duration of response (95% CI): 10.8 (6.9–not estimable) vs. 11.1 (9.5–18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies. Conclusions: Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations.

AB - Purpose: Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non–small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups. Patients and Methods: This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity. Results: 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7–53.0]. Patients aged <75 (n ¼ 84) and ≥75 (n ¼ 68) had ORRs of 48.8% (95% CI: 37.7–60.0) and 39.7% (95% CI: 28.0–52.3), respectively. Treatment-naïve (n ¼ 69) versus previously treated (n ¼ 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9–57.4) vs. 44.6% (33.7–55.9); median duration of response (95% CI): 10.8 (6.9–not estimable) vs. 11.1 (9.5–18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies. Conclusions: Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations.

UR - http://www.scopus.com/inward/record.url?scp=85121458417&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85121458417&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-21-2733

DO - 10.1158/1078-0432.CCR-21-2733

M3 - Article

C2 - 34789481

AN - SCOPUS:85121458417

SN - 1078-0432

VL - 28

SP - 1117

EP - 1126

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 6

ER -

Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice

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