Entrectinib expands the range of treatment options for advanced NTRK+ solid tumours and ROS1+ NSCLC, and may be of particular value in patients with existing CNS metastases and those who are at risk of developing CNS metastases. READ ARTICLE
Drugs DOI:10.6084/m9.figshare.14150207
Authors: James E Frampton
Targeted therapies lead to acquired resistance through multiple mechanisms. The selective pressure of newer, more potent TKIs results in new resistance mechanisms. Article gives overview of strategies for overcoming resistance to TKIs targeting the common oncogenic gene fusions in NSCLC. READ ARTICLE
Translational Lung Cancer Research DOI: 10.21037/tlcr-2019-cnsclc-06
Authors: Alessandro Russo, Andrés F. Cardona, Christian Caglevic, Paolo Manca, Alejandro Ruiz-Patiño, Oscar Arrieta, Christian Rolfo
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NTRK1/3, ALK, and ROS1 translocations have been reported in a minor subset of papillary thyroid carcinomas (PTCs). We aimed to elucidate the prevalence and clinicopathological characteristics of these gene rearrangements and the utility of immunohistochemistry (IHC) in PTC and anaplastic thyroid carcinoma (ATC). We screened nonradiation-exposed cases of 307 PTCs and 16 ATCs by IHC for pan-Trk, ALK, and ROS1, followed by fluorescence in situ hybridization (FISH). In the PTC group, IHC for pan-Trk, ALK, and ROS1 was positive in 18 cases (5.9%), 1 case (0.3%), and 12 cases (3.9%), respectively. Among the pan-Trk IHC–positive cases (n = 18), 2 cases (11.1%; 0.7% of all PTCs) had NTRK1 or NTRK3 gene rearrangement with conventional PTC histology. The ALK IHC–positive case (n = 1) was the follicular variant of PTC with consistent ALK gene rearrangement. ROS1 gene rearrangement was not detectable in the ROS1 IHC–positive PTCs (0/12) by FISH. Most (approximately 70%) of the pan-Trk or ROS1 IHC–..... READ ARTICLE
Human Pathology DOI:10.1016/j.humpath.2020.09.004
Authors: Yui Nozaki, Hidetaka Yamamoto, Takeshi Iwasaki, Masanobu Sato, Rina Jiromaru, Takahiro Hongo, Ryuji Yasumatsu, Yoshinao Oda
Lung cancer is the leading cause of cancer death worldwide. In the past decade EGFR, ALK and ROS1 TKIs lead to an unprecedented survival improvement of oncogene-addicted NSCLC patients, with better toxicity profile compared to chemotherapy. In recent years the implementation of high-throughput sequencing platforms led to the identification of uncommon molecular alterations in oncogenic drivers, such as BRAF, MET, RET, HER2 and NTRK. Moreover, newly developed drugs have been found to be active against hard to target drivers, such as KRAS. Specific TKIs targeting these genomic alterations are currently in clinical development and showed impressive activity and survival improvement, leading to FDA-accelerated approval for some of them. However, virtually all patients develop resistance to TKIs by on-target or off-target mechanisms. Here we review the clinicopathological features, the emerging targeted therapies and mechanisms of resistance and strategies to overcome them of KRAS, BRAF, MET, RET, HER2 and NTRK-addicted advanced NSCLCs. READ ARTICLE
Critical Reviews in Oncology/Hematology DOI: 10.1016/j.critrevonc.2020.103119
Authors: Giuseppe Lamberti, Elisa Andrini, Monia Sisi, Alessandro RizzoaClaudia Parisi, Alessandro Di Federico, Francesco Gelsomino and Andrea Ardizzoni
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Five to ten percent of lung adenocarcinoma harbor chromosomal rearrangements affecting the ALK, ROS1, NTRK and RET genes. These rearrangements are associated with the production of fusion transcripts that lead to the synthesis of chimeric proteins with constitutive kinase activity. These abnormal proteins induce an oncogenic dependency that may be targeted by tyrosine kinase inhibitors. In this review, we will summarize the clinical and molecular epidemiology of chromosomal rearrangements affecting ALK, ROS1, NTRK and RET genes. We will describe the mechanisms of resistance to tyrosine kinase inhibitors that have been reported. We will present the molecular techniques that can be used to detect these rearrangements and the strategies set-up by the molecular oncology laboratories to diagnose these genetic alterations. READ ARTICLE
Bulletin du Cancer DOI:10.1016/j.bulcan.2020.05.008
Authors: Audrey Mansuet-Lupo, Simon Garinet, Diane Damotte, Marco Alifano, Hélène Blons, Marie Wislez, Karen Leroy
Objectives: Gene rearrangements involving NTRK1, NTRK2, NTRK3, ROS1 and ALK have been identified in many types of cancer, including non-small cell lung cancer (NSCLC). Data in malignant pleural mesothelioma (MPM), lung neuroendocrine tumors (NETs) and small-cell lung cancer (SCLC) are lacking. Given the activity of NTRK, ROS-1 and ALK inhibitors in tumors harboring gene fusions, we sought to explore such rearrangements in these less common tumors in addition to NSCLC. Conclusions: To our knowledge, we report for the first time NTRK and ALK rearrangements in a small subset of MPM. An ALK rearrangement was also detected in lung intermediate-grade NET (or atypical carcinoid). Our data suggest that IHC could be a useful screening test in such patients to ensure that all therapeutic strategies including targeted therapy are utilized. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.05.019
Authors: Jose Luis Leal, Geoffrey Peters, Marcin Szaumkessel, Trishe Leong, Khashayar Asadi, Gareth Rivalland, Hongdo Do, Clare Senko, Paul L.Mitchell, Chai Zi Quing, Alexander Dobrovic, Bibhusal Thapa, Thomas John
KEY POINTS:
Most epidermal growth factor receptor (EGFR)-mutated NSCLC (exon 19 del and L858R) should be
initially treated with osimertinib.
Anaplastic lymphoma kinase (ALK) fusion-positive NSCLC should be initially treated with alectinib,
brigatinib, or ceritinib; however, tolerability issues limit the use of ceritinib.
ROS1 fusion-positive NSCLC should be initially treated with entrectinib over crizotinib given central
nervous system activity.
BRAF V600E-mutated NSCLC should be initially treated with dabrafenib plus trametinib.
Neurotrophic tropomyosin receptor kinase fusion-positive NSCLC should be initially treated with
entrectinib or larotrectinib.
Patients with HER2 or EGFR exon 20 insertions, RET fusions, NRG1 fusions, MET amplification and
exon 14 skipping mutations, and KRAS G12C mutations should be initially treated with standard-ofcare chemoimmunotherapy; however, there are targeted therapies under investigation showing
promise. READ ARTICLE
Clinics in Chest Medicine DOI:10.1016/j.ccm.2020.02.003
Authors: Nicholas P. Giustini, Ah-Reum Jeong, James Buturla, Lyudmila Bazhenova