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

Istituto Oncologico Veneto

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

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	The New England journal of medicine
Volume	383
Issue number	10
DOIs	https://doi.org/10.1056/NEJMoa2004407
Publication status	Published - Sep 3 2020

Keywords

Adult
Aged
Aged, 80 and over
Antineoplastic Agents/adverse effects
Carcinoma, Non-Small-Cell Lung/drug therapy
Edema/chemically induced
Exons
Female
Humans
Lung Neoplasms/drug therapy
Male
Middle Aged
Mutation
Piperidines/adverse effects
Protein Kinase Inhibitors/adverse effects
Proto-Oncogene Proteins c-met/antagonists & inhibitors
Pyridazines/adverse effects
Pyrimidines/adverse effects

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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. The New England journal of medicine, 383(10), 931-943. https://doi.org/10.1056/NEJMoa2004407

Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. / Paik, Paul K; Felip, Enriqueta; Veillon, Remi; Sakai, Hiroshi; Cortot, Alexis B; Garassino, Marina C; Mazieres, Julien; Viteri, Santiago; Senellart, Helene; Van Meerbeeck, Jan; Raskin, Jo; Reinmuth, Niels; Conte, Pierfranco; Kowalski, Dariusz; Cho, Byoung Chul; Patel, Jyoti D; Horn, Leora; Griesinger, Frank; Han, Ji-Youn; Kim, Young-Chul; Chang, Gee-Chen; Tsai, Chen-Liang; Yang, James C-H; Chen, Yuh-Min; Smit, Egbert F; van der Wekken, Anthonie J; Kato, Terufumi; Juraeva, Dilafruz; Stroh, Christopher; Bruns, Rolf; Straub, Josef; Johne, Andreas; Scheele, Jürgen; Heymach, John V; Le, Xiuning.

In: The New England journal of medicine, Vol. 383, No. 10, 03.09.2020, p. 931-943.

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

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, J-Y, Kim, Y-C, Chang, G-C, Tsai, C-L, Yang, JC-H, Chen, Y-M, 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', The New England journal of medicine, vol. 383, no. 10, pp. 931-943. https://doi.org/10.1056/NEJMoa2004407

Paik, Paul K ; Felip, Enriqueta ; Veillon, Remi ; Sakai, Hiroshi ; Cortot, Alexis B ; Garassino, Marina C ; Mazieres, Julien ; Viteri, Santiago ; Senellart, Helene ; Van Meerbeeck, Jan ; Raskin, Jo ; Reinmuth, Niels ; Conte, Pierfranco ; Kowalski, Dariusz ; Cho, Byoung Chul ; Patel, Jyoti D ; Horn, Leora ; Griesinger, Frank ; Han, Ji-Youn ; Kim, Young-Chul ; Chang, Gee-Chen ; Tsai, Chen-Liang ; Yang, James C-H ; Chen, Yuh-Min ; Smit, Egbert F ; van der Wekken, Anthonie J ; Kato, Terufumi ; Juraeva, Dilafruz ; Stroh, Christopher ; Bruns, Rolf ; Straub, Josef ; Johne, Andreas ; Scheele, Jürgen ; Heymach, John V ; Le, Xiuning. / Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. In: The New England journal of medicine. 2020 ; Vol. 383, No. 10. pp. 931-943.

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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.).",

keywords = "Adult, Aged, Aged, 80 and over, Antineoplastic Agents/adverse effects, Carcinoma, Non-Small-Cell Lung/drug therapy, Edema/chemically induced, Exons, Female, Humans, Lung Neoplasms/drug therapy, Male, Middle Aged, Mutation, Piperidines/adverse effects, Protein Kinase Inhibitors/adverse effects, Proto-Oncogene Proteins c-met/antagonists & inhibitors, Pyridazines/adverse effects, Pyrimidines/adverse effects",

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 Ji-Youn Han and Young-Chul Kim and Gee-Chen Chang and Chen-Liang Tsai and Yang, {James C-H} and Yuh-Min Chen 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 = "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",

}

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

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.).

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Agents/adverse effects

KW - Carcinoma, Non-Small-Cell Lung/drug therapy

KW - Edema/chemically induced

KW - Exons

KW - Female

KW - Humans

KW - Lung Neoplasms/drug therapy

KW - Male

KW - Middle Aged

KW - Mutation

KW - Piperidines/adverse effects

KW - Protein Kinase Inhibitors/adverse effects

KW - Proto-Oncogene Proteins c-met/antagonists & inhibitors

KW - Pyridazines/adverse effects

KW - Pyrimidines/adverse effects

U2 - 10.1056/NEJMoa2004407

DO - 10.1056/NEJMoa2004407

M3 - Article

C2 - 32469185

VL - 383

SP - 931

EP - 943

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 10

ER -