Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations

Paul K. Paik; Enriqueta Felip; Remi Veillon; Hiroshi Sakai; Alexis B. Cortot; Marina C. Garassino; Julien Mazieres; Santiago Viteri; Helene Senellart; Jan van Meerbeeck; Jo Raskin; Niels Reinmuth; Pierfranco Conte; Dariusz Kowalski; Byoung Chul Cho; Jyoti D. Patel; Leora Horn; Frank Griesinger; Ji Youn Han; Young Chul Kim; Gee Chen Chang; Chen Liang Tsai; James C.H. Yang; Yuh Min Chen; Egbert F. Smit; Anthonie J. van der Wekken; Terufumi Kato; Dilafruz Juraeva; Christopher Stroh; Rolf Bruns; Josef Straub; Andreas Johne; Jürgen Scheele; John V. Heymach; Xiuning Le

doi:10.1056/NEJMoa2004407

Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations

Paul K. Paik, Enriqueta Felip, Remi Veillon, Hiroshi Sakai, Alexis B. Cortot, Marina C. Garassino, Julien Mazieres, Santiago Viteri, Helene Senellart, Jan van Meerbeeck, Jo Raskin, Niels Reinmuth, Pierfranco Conte, Dariusz Kowalski, Byoung Chul Cho, Jyoti D. Patel, Leora Horn, Frank Griesinger, Ji Youn Han, Young Chul KimGee Chen Chang, Chen Liang Tsai, James C.H. Yang, Yuh Min Chen, Egbert F. Smit, Anthonie J. van der Wekken, Terufumi Kato, Dilafruz Juraeva, Christopher Stroh, Rolf Bruns, Josef Straub, Andreas Johne, Jürgen Scheele, John V. Heymach, Xiuning Le

Department of Internal Medicine

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

317 Citations (Scopus)

Abstract

BACKGROUND A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

Original language	English
Pages (from-to)	931-943
Number of pages	13
Journal	New England Journal of Medicine
Volume	383
Issue number	10
DOIs	https://doi.org/10.1056/NEJMoa2004407
Publication status	Published - 2020 Sept 3

Bibliographical note

Funding Information:
We thank the patients who participated in this trial and their families; the investigators, coinvestigators, and study teams at all the participating centers; representatives of Merck in Darmstadt, Germany; Bruce Gaumond and the rest of the Merck Global Clinical Operations team; representatives of contract research organization IQVIA for their contribution to study recruitment, conduct of the study, and data analysis; and Jack Eaton and Suzanne Patel of Syneos Health for editorial assistance with a previous version of the manuscript.

Funding Information:
The study was performed in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council on Harmonisation, local laws, and applicable regulatory requirements. The study was designed and funded by Merck (Darmstadt, Germany), and representatives of the sponsor were responsible for the collection and analysis of the data. The first author had full access to the data, and all the authors were involved in the data analysis and manuscript preparation and vouch for the completeness and accuracy of the data and the adherence of the study to the protocol, which is available at NEJM.org. Editorial support, including cowriting of the first draft of the manuscript with the first author, was provided by a medical writer employed by Syneos Health with funding from the sponsor.

Publisher Copyright:
Copyright © 2020 Massachusetts Medical Society.

All Science Journal Classification (ASJC) codes

Medicine(all)

UN SDGs

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

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10.1056/NEJMoa2004407

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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., Conte, P., Kowalski, D., Cho, B. C., Patel, J. D., Horn, L., Griesinger, F., Han, J. Y., ... Le, X. (2020). Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. New England Journal of Medicine, 383(10), 931-943. https://doi.org/10.1056/NEJMoa2004407

@article{db2e4a18e5424bf5b37d6f1aabbb7fac,

title = "Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations",

abstract = "BACKGROUND A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).",

author = "Paik, {Paul K.} and Enriqueta Felip and Remi Veillon and Hiroshi Sakai and Cortot, {Alexis B.} and Garassino, {Marina C.} and Julien Mazieres and Santiago Viteri and Helene Senellart and {van Meerbeeck}, Jan and Jo Raskin and Niels Reinmuth and Pierfranco Conte and Dariusz Kowalski and Cho, {Byoung Chul} and Patel, {Jyoti D.} and Leora Horn and Frank Griesinger and Han, {Ji Youn} and Kim, {Young Chul} and Chang, {Gee Chen} and Tsai, {Chen Liang} and Yang, {James C.H.} and Chen, {Yuh Min} and Smit, {Egbert F.} and {van der Wekken}, {Anthonie J.} and Terufumi Kato and Dilafruz Juraeva and Christopher Stroh and Rolf Bruns and Josef Straub and Andreas Johne and J{\"u}rgen Scheele and Heymach, {John V.} and Xiuning Le",

note = "Funding Information: We thank the patients who participated in this trial and their families; the investigators, coinvestigators, and study teams at all the participating centers; representatives of Merck in Darmstadt, Germany; Bruce Gaumond and the rest of the Merck Global Clinical Operations team; representatives of contract research organization IQVIA for their contribution to study recruitment, conduct of the study, and data analysis; and Jack Eaton and Suzanne Patel of Syneos Health for editorial assistance with a previous version of the manuscript. Funding Information: The study was performed in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council on Harmonisation, local laws, and applicable regulatory requirements. The study was designed and funded by Merck (Darmstadt, Germany), and representatives of the sponsor were responsible for the collection and analysis of the data. The first author had full access to the data, and all the authors were involved in the data analysis and manuscript preparation and vouch for the completeness and accuracy of the data and the adherence of the study to the protocol, which is available at NEJM.org. Editorial support, including cowriting of the first draft of the manuscript with the first author, was provided by a medical writer employed by Syneos Health with funding from the sponsor. Publisher Copyright: Copyright {\textcopyright} 2020 Massachusetts Medical Society.",

year = "2020",

month = sep,

day = "3",

doi = "10.1056/NEJMoa2004407",

language = "English",

volume = "383",

pages = "931--943",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "10",

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Paik, PK, Felip, E, Veillon, R, Sakai, H, Cortot, AB, Garassino, MC, Mazieres, J, Viteri, S, Senellart, H, van Meerbeeck, J, Raskin, J, Reinmuth, N, Conte, P, Kowalski, D, Cho, BC, Patel, JD, Horn, L, Griesinger, F, Han, JY, Kim, YC, Chang, GC, Tsai, CL, Yang, JCH, Chen, YM, Smit, EF, van der Wekken, AJ, Kato, T, Juraeva, D, Stroh, C, Bruns, R, Straub, J, Johne, A, Scheele, J, Heymach, JV & Le, X 2020, 'Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations', New England Journal of Medicine, vol. 383, no. 10, pp. 931-943. https://doi.org/10.1056/NEJMoa2004407

TY - JOUR

T1 - Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations

AU - Paik, Paul K.

AU - Felip, Enriqueta

AU - Veillon, Remi

AU - Sakai, Hiroshi

AU - Cortot, Alexis B.

AU - Garassino, Marina C.

AU - Mazieres, Julien

AU - Viteri, Santiago

AU - Senellart, Helene

AU - van Meerbeeck, Jan

AU - Raskin, Jo

AU - Reinmuth, Niels

AU - Conte, Pierfranco

AU - Kowalski, Dariusz

AU - Cho, Byoung Chul

AU - Patel, Jyoti D.

AU - Horn, Leora

AU - Griesinger, Frank

AU - Han, Ji Youn

AU - Kim, Young Chul

AU - Chang, Gee Chen

AU - Tsai, Chen Liang

AU - Yang, James C.H.

AU - Chen, Yuh Min

AU - Smit, Egbert F.

AU - van der Wekken, Anthonie J.

AU - Kato, Terufumi

AU - Juraeva, Dilafruz

AU - Stroh, Christopher

AU - Bruns, Rolf

AU - Straub, Josef

AU - Johne, Andreas

AU - Scheele, Jürgen

AU - Heymach, John V.

AU - Le, Xiuning

N1 - Funding Information: We thank the patients who participated in this trial and their families; the investigators, coinvestigators, and study teams at all the participating centers; representatives of Merck in Darmstadt, Germany; Bruce Gaumond and the rest of the Merck Global Clinical Operations team; representatives of contract research organization IQVIA for their contribution to study recruitment, conduct of the study, and data analysis; and Jack Eaton and Suzanne Patel of Syneos Health for editorial assistance with a previous version of the manuscript. Funding Information: The study was performed in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council on Harmonisation, local laws, and applicable regulatory requirements. The study was designed and funded by Merck (Darmstadt, Germany), and representatives of the sponsor were responsible for the collection and analysis of the data. The first author had full access to the data, and all the authors were involved in the data analysis and manuscript preparation and vouch for the completeness and accuracy of the data and the adherence of the study to the protocol, which is available at NEJM.org. Editorial support, including cowriting of the first draft of the manuscript with the first author, was provided by a medical writer employed by Syneos Health with funding from the sponsor. Publisher Copyright: Copyright © 2020 Massachusetts Medical Society.

PY - 2020/9/3

Y1 - 2020/9/3

N2 - BACKGROUND A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

AB - BACKGROUND A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

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U2 - 10.1056/NEJMoa2004407

DO - 10.1056/NEJMoa2004407

M3 - Article

C2 - 32469185

AN - SCOPUS:85089665538

SN - 0028-4793

VL - 383

SP - 931

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JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 10

ER -

Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations

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