Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSe phase II trial

被引：151

作者：

Moro-Sibilot, D. ^{[1
,2
]}

Cozic, N. ^{[3
,4
]}

Pero, M. ^{[5
]}

Mazieres, J. ^{[6
,7
]}

Otto, J. ^{[8
]}

Souquet, P. J. ^{[9
]}

Bahleda, R. ^{[10
]}

Wislez, M. ^{[11
,12
]}

Zalcman, G. ^{[13
,14
]}

Guibert, S. D. ^{[15
]}

Barlesi, F. ^{[16
,17
]}

Mennecier, B. ^{[18
]}

Monnet, I ^{[19
]}

Sabatier, R. ^{[20
,21
]}

Bota, S. ^{[22
]}

Dubos, C. ^{[23
]}

Verriele, V. ^{[24
]}

Haddad, V ^{[25
]}

Ferretti, G. ^{[26
]}

Cortot, A. ^{[27
,28
]}

De Fraipont, F. ^{[29
]}

Jimenez, M. ^{[30
]}

Hoog-Labouret, N. ^{[31
]}

Vassal, G. ^{[32
]}

机构：

[1] Grenoble Alpes Univ Hosp, Thorac Oncol Unit, CS10217, F-38043 Grenoble, France

[2] IFCT, Paris, France

[3] Paris Saclay Univ, Dept Biostat & Epidemiol, INSERM U1018, ESP, Gustave Roussy Canc Campus, Villejuif, France

[4] Paris Sud Univ, Villejuif, France

[5] Leon Berard Canc Ctr, Dept Med Oncol, Lyon, France

[6] Toulouse Univ Hosp, Pneumol Dept, Toulouse, France

[7] Paul Sabatier Univ, Toulouse, France

[8] Antoine Lacassagne Canc Ctr, Dept Med, Nice, France

[9] Hosp Civils Lyon, Lyon Sud Hosp Ctr, Dept Pneumol & Thorac Oncol, Pierre Benite, France

[10] Drug Dev Dept DITEP, Gustave Roussy Canc Campus, Villejuif, France

[11] Tenon Hosp, AP HP, Pneumol Dept, Paris, France

[12] Pierre & Marie Curie Univ, Paris, France

[13] Hop Xavier Bichat, AP HP, CIC INSERM 1425, Thorac Oncol Dept, Paris, France

[14] Paris Diderot Univ, Paris, France

[15] Pontchaillou, Hematol Dept, Rennes, France

[16] AP HM, Multidisciplinary Oncol & Therapeut Innovat Dept, Marseille, France

[17] Marseille Univ, INSERM, CNRS, CRCM, Marseille, France

[18] Strasbourg Univ Hosp, Pneumol Dept, Strasbourg, France

[19] CHIC Creteil, Pneumol Dept, Creteil, France

[20] Paoli Calmettes Inst, CRCM, CNRS UMR7258, Dept Med Oncol,Inserm 1068, Marseille, France

[21] Aix Marseille Univ, Marseille, France

[22] Rouen Univ Hosp, Charles Nicolle Hosp, Pneumol Dept, Rouen, France

[23] Francois Baclesse Canc Ctr, Pneumol Dept, Caen, France

[24] ICO, Paul Papin Canc Ctr, Anat & Pathol Cytol Dept, Angers, France

[25] Leon Berard Canc Ctr, Dept Tumour Biol, Lyon, France

[26] Grenoble Alpes Univ Hosp, Radiol & Med Imaging Dept, Grenoble, France

[27] Lille Univ Hosp, Dept Thorac Oncol, Lille, France

[28] Univ Lille, Lille, France

[29] Grenoble Alpes Univ Hosp, Mol Genet Unit Hereditary Dis & Oncol, Grenoble, France

[30] Res & Dev UNICANCER, Paris, France

[31] French Natl Canc Inst, Boulogne, France

[32] Clin Res Div, Gustave Roussy Canc Campus, Villejuif, France

来源：

ANNALS OF ONCOLOGY | 2019年 / 30卷 / 12期

关键词：

ROS1; fusion; c-MET amplification; c-MET-mutation; targeted therapy; crizotinib; lung cancer; LUNG; MUTATIONS; RATIONALE; INHIBITOR;

D O I：

10.1093/annonc/mdz407

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: In 2013, the French National Cancer Institute initiated the AcSe program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). Patients and methods: Advanced NSCLC patients with c-MET >= 6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. Results: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET >= 6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET >= 6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET >= 6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET- >= 6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported. Conclusions: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET >= 6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified.

引用

页码：1985 / 1991

页数：7

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