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
Read MoreAs far as we are aware, this present clinical case is the first to report an acquired exon14 MET mutation
mediated resistance to alectinib in a patient with ALK rearrangement NSCLC. We had chosen to treat
our patient at the time of progression under alectinib with crizotinib with a short time efficacy, three and a
half months. READ ARTICLE
JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100082
Authors: Catherine Daniel, Celine Callens, Samia Melaabi, Ivan Bieche, Nicolas Girard,
MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy. Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET. READ ARTICLE
Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-19-3906
Authors: Ibiayi Dagogo-Jack, Satoshi Yoda, Jochen K. Lennerz, Adam Langenbucher, Jessica J. Lin, Marguerite M. Rooney, Kylie Prutisto-Chang, Audris Oh, Nathaniel A. Adams, Beow Y. Yeap, Emily Chin, Andrew Do, Hetal D. Marble, Sara E. Stevens, Subba R. Digumarthy, Ashish Saxena, Rebecca J. Nagy, Cyril H. Benes, Christopher G. Azzoli, Michael S. Lawrence, Justin F. Gainor, Alice T. Shaw, Aaron N. Hata
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More recently, alectinib has superseded crizotinib, an ALK/ROS1/MET inhibitor, as a first-line therapy due to its superiority in phase III trials. Although patients enjoy durable responses to alectinib, they eventually develop resistance. Here we describe four cases of primary resistance to alectinib in which the patients show little to no response to alectinib when administered as first or second-line therapy. In order to investigate primary resistance to alectinib, tissue was obtained during re-biopsy and subjected to routine clinical genetic analyses including gene fusion detection and genetic mutation analysis using the Archer FusionPlex and VariantPlex assays, respectively. Concurrently, at the time of biopsy, additional fresh tissue was procured for cell line derivation. The primary cell line was then used to assess ALK and other inhibitors’ potency by cell viability assays. Targeted analysis of signaling pathways was performed in the cell lines via western blot analysis and prox..... READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1160
Authors: A. Le, L. Tyler, K. Davies, K. Kondo, J. Pacheco, D. Merrick, D. Aisner, D.R. Camidge, R. Doebele
Introduction: Chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene are detected in approximately 5% of non–small-cell lung cancers (NSCLCs) and function as oncogenic driver genes.1 First- and second-generation ALK-tyrosine kinase inhibitors (TKIs) were developed and showed clinical response for ALK-rearranged NSCLC.2, 3, 4 However, resistance to those ALK-TKIs almost develops, resulting in clinical relapse.5, 6 Lorlatinib is a third-generation ALK-TKI and has demonstrated significant antitumor activity against ALK-rearranged NSCLC with previous ALK-TKI resistance.7, 8 Although lorlatinib response was observed, relapse on lorlatinib ultimately developed.9, 10, 11 Mechanisms of lorlatinib resistance were reported,9, 10, 11 but remained unknown. Moreover, post-lorlatinib treatment has not been determined. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2019.06.021
Authors: Jun Sakakibara-Konishi, Hidenori Kitai, Yasuyuki Ikezawa, Yutaka Hatanaka, Takaaki Sasaki, Ryohei Yoshida, Shinichi Chiba, Shingo Matsumoto, Koichi Goto, Hidenori Mizugaki, Naofumi Shinagawa
Introduction: The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. Conclusions: High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.07.017
Authors: Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kazuya Nishii, Takehiro Matsubara, Hiroe Kayatani, Hisao Higo, Kiichiro Ninomiya, Akiko Sato, Hiromi Watanabe, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Minoru Takata, Yoshinobu Maeda, Katsuyuki Kiura