Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas.

The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes. In an unselected population of non-small cell lung carcinomas (NSCLCs), RET fusions are present in 1% to 2% of cases. This incidence increases substantially, however, in never-smokers with lung adenocarcinomas that lack other known driver oncogenes. Although preclinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors, clinical data on response are lacking. We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase II trial for patients with RET fusion-positive NSCLCs (NCT01639508). Confirmed partial responses were observed in 2 patients, including one harboring a novel TRIM33-RET fusion. A third patient with a KIF5B-RET fusion has had prolonged stable disease approaching 8 months (31 weeks). All three patients remain progression-free on treatment.

[1]  Yuki Togashi,et al.  RET, ROS1 and ALK fusions in lung cancer , 2012, Nature Medicine.

[2]  M. Pierotti,et al.  RET and NTRK1 proto‐oncogenes in human diseases , 2003, Journal of cellular physiology.

[3]  Laura A. Sullivan,et al.  Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung Cancer , 2007, Cell.

[4]  A. Tsao,et al.  ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers , 2012 .

[5]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.

[6]  Edward S. Kim,et al.  Epidermal Growth Factor Receptor Inhibition in Lung Cancer , 2013 .

[7]  Derek Y. Chiang,et al.  EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer , 2008, Clinical Cancer Research.

[8]  P. Chambon,et al.  TIF1gamma, a novel member of the transcriptional intermediary factor 1 family. , 1999, Oncogene.

[9]  Jeffrey W. Clark,et al.  Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. , 2010, The New England journal of medicine.

[10]  Edward S. Kim,et al.  Epidermal growth factor receptor inhibition in lung cancer: status 2012. , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[11]  M. Ladanyi,et al.  Prevalence, Clinicopathologic Associations, and Molecular Spectrum of ERBB2 (HER2) Tyrosine Kinase Mutations in Lung Adenocarcinomas , 2012, Clinical Cancer Research.

[12]  Doron Lipson,et al.  Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies , 2012, Nature Medicine.

[13]  Yasushi Totoki,et al.  KIF5B-RET fusions in lung adenocarcinoma , 2012, Nature Medicine.

[14]  Jeffrey W. Clark,et al.  ROS1 rearrangements define a unique molecular class of lung cancers. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Tatsuo Ito,et al.  Identification of KIF5B-RET and GOPC-ROS1 Fusions in Lung Adenocarcinomas through a Comprehensive mRNA-Based Screen for Tyrosine Kinase Fusions , 2012, Clinical Cancer Research.

[16]  M. Stratton,et al.  The cancer genome , 2009, Nature.

[17]  Young Lim Choi,et al.  EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. , 2010, The New England journal of medicine.

[18]  Jan Osinga,et al.  The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells. , 2011, Journal of Clinical Endocrinology and Metabolism.

[19]  A. Bounacer,et al.  High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation , 1997, Oncogene.

[20]  C. Couture,et al.  Immunohistochemistry is a Reliable Screening Tool for Identification of ALK Rearrangement in Non–Small-Cell Lung Carcinoma and is Antibody Dependent , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[21]  Seungbok Lee,et al.  A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. , 2012, Genome research.

[22]  H. Aburatani,et al.  Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer , 2007, Nature.

[23]  H. Ji,et al.  RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  H. Rabes,et al.  The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas , 1999, Oncogene.

[25]  P. Chambon,et al.  TIF1γ, a novel member of the transcriptional intermediary factor 1 family , 1999, Oncogene.

[26]  Y. Ishikawa,et al.  EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset , 2009, Modern Pathology.

[27]  F. Cappuzzo,et al.  Identifying and Targeting ROS1 Gene Fusions in Non–Small Cell Lung Cancer , 2012, Clinical Cancer Research.

[28]  L. Mariani,et al.  RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.