Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations

被引：654

作者：

Paik, Paul K. ^{[1
]}

Felip, Enriqueta ^{[2
]}

Veillon, Remi ^{[4
]}

Sakai, Hiroshi ^{[7
,8
]}

Cortot, Alexis B. ^{[5
]}

Garassino, Marina C. ^{[10
]}

Mazieres, Julien ^{[6
]}

Viteri, Santiago ^{[3
]}

Senellart, Helene ^{[7
]}

Van Meerbeeck, Jan ^{[13
]}

Raskin, Jo ^{[13
]}

Reinmuth, Niels ^{[14
]}

Conte, Pierfranco ^{[11
,12
]}

Kowalski, Dariusz ^{[21
]}

Cho, Byoung Chul ^{[22
]}

Patel, Jyoti D. ^{[26
]}

Horn, Leora ^{[27
]}

Griesinger, Frank ^{[15
]}

Han, Ji-Youn ^{[23
]}

Kim, Young-Chul ^{[24
,25
]}

Chang, Gee-Chen ^{[28
,33
]}

Tsai, Chen-Liang ^{[29
]}

Yang, James C. -H. ^{[30
]}

Chen, Yuh-Min ^{[31
,32
]}

Smit, Egbert F. ^{[34
]}

van der Wekken, Anthonie J. ^{[35
,36
]}

Kato, Terufumi ^{[9
]}

Juraeva, Dilafruz ^{[16
]}

Stroh, Christopher ^{[17
]}

Bruns, Rolf ^{[18
]}

Straub, Josef ^{[19
]}

Johne, Andreas ^{[20
]}

Scheele, Juergen ^{[20
]}

Heymach, John V. ^{[37
]}

Le, Xiuning ^{[37
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, 530 E 74th St, New York, NY 10065 USA

[2] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol, Dept Oncol, Barcelona, Spain

[3] Dexeus Univ Hosp, Dr Rosell Oncol Inst, Quironsalud Grp, Barcelona, Spain

[4] Ctr Hosp Univ CHU Bordeaux, Serv Malad Resp, Bordeaux, France

[5] Univ Lille, Thorac Oncol Dept, Inst Pasteur Lille, CHU Lille,CNRS,INSERM,UMR9020,UMR S 1277 Canther, Lille, France

[6] Univ Paul Sabatier, Inst Univ Canc Toulouse, CHU Toulouse, Toulouse, France

[7] Inst Cancerol Ouest Rene Gauducheau Ctr, St Herblain, France

[8] Saitama Canc Ctr, Saitama, Japan

[9] Kanagawa Canc Ctr, Dept Thorac Oncol, Yokohama, Kanagawa, Japan

[10] Fdn IRCCS Ist Nazl Tumori, Dept Med Oncol, Milan, Italy

[11] Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy

[12] IRCCS, Ist Oncol Veneto, Oncol Med 2, Padua, Italy

[13] Univ Hosp, Edegem, Belgium

[14] Asklepios Lung Clin, Munich, Germany

[15] Univ Med Oldenburg, Pius Hosp Oldenburg, Oldenburg, Germany

[16] Merck, Dept Bioinformat, Translat Med, Darmstadt, Germany

[17] Merck, Translat Innovat Platform, Oncol, Darmstadt, Germany

[18] Merck, Dept Biostat, Darmstadt, Germany

[19] Merck, Dept Clin Biomarkers & Compan Diagnost, Translat Med, Darmstadt, Germany

[20] Merck, Global Clin Dev, Darmstadt, Germany

[21] Maria Sklodowska Curie Natl Res Inst Oncol, Dept Lung Canc & Thorac Oncol, Warsaw, Poland

[22] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul, South Korea

[23] Natl Canc Ctr, Ctr Lung Canc, Goyang, South Korea

[24] Chonnam Natl Univ, Sch Med, Hwasun, South Korea

[25] Hwasun Hosp, Hwasun, South Korea

[26] Northwestern Univ, Lurie Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA

[27] Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN USA

[28] Natl Yang Ming Univ, Sch Med, Fac Med, Taipei, Taiwan

[29] Natl Def Med Ctr, Triserv Gen Hosp, Dept Internal Med, Div Chest Med, Taipei, Taiwan

[30] Natl Taiwan Univ Hosp, Taipei, Taiwan

[31] Taipei Vet Gen Hosp, Dept Chest Med, Taipei, Taiwan

[32] Natl Yang Ming Univ, Sch Med, Taipei, Taiwan

[33] Taichung Vet Gen Hosp, Dept Internal Med, Div Chest Med, Taichung, Taiwan

[34] Netherlands Canc Inst, Dept Thorac Oncol, Amsterdam, Netherlands

[35] Univ Groningen, Dept Pulmonol, Groningen, Netherlands

[36] Univ Med Ctr Groningen, Groningen, Netherlands

[37] Univ Texas Houston, MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2020年 / 383卷 / 10期

关键词：

INHIBITOR TEPOTINIB; ACQUIRED-RESISTANCE; CRIZOTINIB; AMPLIFICATION; CARCINOMA; NSCLC;

D O I：

10.1056/NEJMoa2004407

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driverMEToccurs 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 confirmedMETexon 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 aMETexon 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 confirmedMETexon 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.

引用

页码：931 / 943

页数：13

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