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Takeshi Hirota, Shota Muraki, Ichiro Ieiri
The identification of anaplastic lymphoma kinase rearrangements in 2-5% of patients with non-small-cell lung cancer led to rapid advances in the clinical development of oral tyrosine kinase inhibitors. Anaplastic lymphoma kinase inhibitors are an effective treatment in preclinical models and patients with anaplastic lymphoma kinase-translocated cancers. Four anaplastic lymphoma kinase inhibitors (crizotinib, ceritinib, alectinib, and brigatinib) have recently been approved. Post-marketing studies provided additional pharmacokinetic information on their pharmacokinetic parameters...
June 19, 2018: Clinical Pharmacokinetics
V Subbiah, V Velcheti, B B Tuch, K Ebata, N L Busaidy, M E Cabanillas, L J Wirth, S Stock, S Smith, V Lauriault, S Corsi-Travali, D Henry, M Burkard, R Hamor, K Bouhana, S Winski, R D Wallace, D Hartley, S Rhodes, M Reddy, B J Brandhuber, S Andrews, S M Rothenberg, A Drilon
Purpose: Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed inhibit diverse RET fusions, activating mutations and acquired resistance mutations. Patients and Methods: Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models...
April 18, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
B Melosky
Background: The treatment paradigm for metastatic nonsquamous non-small-cell lung cancer (nsclc) continues to change. Algorithms published only 6 months ago are outdated today and are dramatically different from those published a few years ago. New driver mutations continue to be identified, and the development of therapies to inhibit oncogenic addiction is ongoing. Patient survival is improving as treatments become more personalized and effective. Methods: This review looks at the outcomes of recent trials and discusses treatment options for patients with metastatic nsclc of nonsquamous histology...
June 2018: Current Oncology
Alexa B Schrock, Viola W Zhu, Wen-Son Hsieh, Russell Madison, Benjamin Creelan, Jeffrey Silberberg, Dan Costin, Anjali Bharne, Ioana Bonta, Thangavijayan Bosemani, Petros Nikolinakos, Jeffrey S Ross, Vincent A Miller, Siraj M Ali, Samuel J Klempner, Sai-Hong Ignatius Ou
INTRODUCTION: We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR TKIs. METHODS: EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (FFPE tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians...
June 5, 2018: Journal of Thoracic Oncology
Federica Franchino, Roberta Rudà, Riccardo Soffietti
Advances in chemotherapy and targeted therapies have improved survival in cancer patients with an increase of the incidence of newly diagnosed brain metastases (BMs). Intracranial metastases are symptomatic in 60-70% of patients. Magnetic resonance imaging (MRI) with gadolinium is more sensitive than computed tomography and advanced neuroimaging techniques have been increasingly used in the detection, treatment planning, and follow-up of BM. Apart from the morphological analysis, the most effective tool for characterizing BM is immunohistochemistry...
2018: Frontiers in Oncology
Hironori Ashinuma, Masato Shingyoji, Yuzo Hasegawa, Sana Yokoi, Yasushi Yoshida
The mechanisms underlying anaplastic lymphoma kinase (ALK) resistance have not been well investigated in clinical practice. We herein report the case of a lung cancer patient with carcinomatous meningitis who had an ALK I1171T resistance mutation revealed by direct DNA sequencing of the cerebrospinal fluid after treatment with cytotoxic chemotherapy, crizotinib, and alectinib. I1171T is considered to be sensitive to ceritinib. Although ceritinib was not effective initially, we chose ceritinib again after whole-brain radiotherapy and ventriculoperitoneal shunting...
June 6, 2018: Internal Medicine
Dimitrios C Ziogas, Anna Tsiara, Georgios Tsironis, Maria Lykka, Michalis Liontos, Aristotelis Bamias, Meletios-Athanasios Dimopoulos
Targeting genomic alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, have radically changed the treatment of patients with non-small cell lung cancer (NSCLC). In the case of ALK-rearranged gene, subsequent rapid development of effective genotype-directed therapies with ALK tyrosine kinase inhibitors (TKIs) triggered major advances in the personalized molecularly based approach of NSCLC. Crizotinib was the first-in-class ALK TKI with proven superiority over standard platinum-based chemotherapy for the 1st-line therapy of ALK-rearranged NSCLC patients...
April 2018: Annals of Translational Medicine
Makoto Nishio, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Tomohiro Tanaka, Hiroshi Kuriki, Ali Zeaiter, Tomohide Tamura
OBJECTIVES: We determined the central nervous system (CNS) efficacy of alectinib by calculating time to CNS progression and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and death in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) enrolled in the J-ALEX phase III study. MATERIALS AND METHODS: Japanese patients aged ≥20 years with ALK-positive NSCLC who were ALK inhibitor-naïve and chemotherapy-naïve, or who had received one previous chemotherapy regimen, were enrolled...
July 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Junko Watanabe, Shinsaku Togo, Issei Sumiyoshi, Yukiko Namba, Kentaro Suina, Takafumi Mizuno, Kotaro Kadoya, Hiroaki Motomura, Moe Iwai, Tetsutaro Nagaoka, Shinichi Sasaki, Takuo Hayashi, Toshimasa Uekusa, Kanae Abe, Yasuo Urata, Fuminori Sakurai, Hiroyuki Mizuguchi, Shunsuke Kato, Kazuhisa Takahashi
Anti-anaplastic lymphoma kinase (ALK)-targeted therapy dramatically improves therapeutic responses in patients with ALK-rearranged lung adenocarcinoma (Ad-LC). A few cases of squamous cell lung carcinoma (Sq-LC) with ALK rearrangement have been reported; however, the clinicopathological features and clinical outcomes following treatment with ALK inhibitors are unknown. We addressed this in the present study by retrospectively comparing the clinical characteristics of five patients with ALK-rearranged Sq-LC with those of patients with ALK-rearranged Ad-LC and by evaluating representative cases of ALK inhibitor responders and non-responders...
May 8, 2018: Oncotarget
Solange Peters, Stefan Zimmermann
A decade after the discovery of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (EML4-ALK) rearrangements in non-small cell lung cancer (NSCLC), several inhibitors have gained regulatory approval, and their sequential use has deferred platinum-based chemotherapy to later lines of therapy. Nevertheless, although most ALK-driven tumors dramatically respond to ALK TKIs , all patients ultimately develop drug-resistant disease. Analysis of post-progression biopsy samples has provided invaluable insight into the mechanisms of resistance, now informing on subsequent therapeutic strategies...
May 28, 2018: Current Treatment Options in Oncology
Grainne M O'Kane, Natasha B Leighl
Central nervous system (CNS) metastases most commonly arise from lung cancer, with the majority of patients affected during their disease course. The prognosis for patients with untreated brain metastases is poor, with surgical resection and/or radiotherapy as classic therapeutic options. However, the value of systemic therapy in the management of CNS metastases from lung cancer is growing. Novel targeted agents for the treatment of non-small cell lung cancer (NSCLC) have demonstrated activity in treating patients with CNS involvement, and are potential alternatives to radiation and surgery...
May 24, 2018: CNS Drugs
Yosuke Makuuchi, Hidetoshi Hayashi, Koji Haratani, Junko Tanizaki, Kaoru Tanaka, Masayuki Takeda, Kazuko Sakai, Shigeki Shimizu, Akihiko Ito, Kazuto Nishio, Kazuhiko Nakagawa
The second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) alectinib and ceritinib are standard treatment options for patients with non-small cell lung cancer (NSCLC) positive for ALK fusion genes. However, almost all patients eventually develop resistance to these drugs. We here report a case of ALK -rearranged NSCLC that developed resistance to alectinib but remained sensitive to ceritinib. The L1196M mutation within the ALK fusion gene was detected after failure of consecutive treatment with crizotinib and alectinib, but no other mechanism underlying acquired resistance to ALK-TKIs was found to be operative...
May 1, 2018: Oncotarget
Han Wang, Yao Wang, Wentao Guo, Bin Du, Xiaobing Huang, Riping Wu, Baoyu Yang, Xiaoyan Lin, Yilan Wu
Background: Mutated anaplastic lymphoma kinase (ALK) drives the development of advanced non-small cell lung cancer (NSCLC). Most reported small-molecule inhibitors targeting the ALK domain do not display good inhibition of the G1202R solvent front mutation. The solvent front mutation was assumed to hinder drug binding. However, a different fact could be uncovered by the simulations reported in this study through a structural analog of alectinib (JH-VIII-157-02), which demonstrated potent effects against the G1202R mutation...
2018: Drug Design, Development and Therapy
Karen L Reckamp
Molecular testing is recommended for initial diagnosis in patients with non-small cell lung cancer (NSCLC), according to the updated NCCN Guidelines, because targeted therapies are available that can improve patient outcomes. Targeted therapies are currently approved for EGFR mutations, ALK and ROS1 gene rearrangements, and BRAF mutations, with the list of emerging "actionable" targets growing. The 2018 NCCN Guidelines for NSCLC incorporate new therapies, including the EGFR tyrosine kinase inhibitor osimertinib and the ALK inhibitor alectinib, as first-line preferences...
May 2018: Journal of the National Comprehensive Cancer Network: JNCCN
Rubens Barros Costa, Ricardo L B Costa, Sarah M Talamantes, Jason B Kaplan, Manali A Bhave, Alfred Rademaker, Corinne Miller, Benedito A Carneiro, Devalingam Mahalingam, Young Kwang Chae
Introduction: Anaplastic lymphoma kinase ( ALK ) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update. Materials and Methods: A systematic literature search was performed in July 2017. Studies evaluating US FDA approved doses of one of the following ALK inhibitors: Crizotinib, Ceritinib, Alectinib or Brigatinib as monotherapy were included...
April 24, 2018: Oncotarget
Peter N Morcos, Eveline Nueesch, Felix Jaminion, Elena Guerini, Joy C Hsu, Walter Bordogna, Bogdana Balas, Francois Mercier
PURPOSE: Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3-39.0) for alectinib 600 mg twice daily (BID). We investigated exposure-response relationships from final pooled phase II OS and safety data to assess alectinib dose selection...
May 10, 2018: Cancer Chemotherapy and Pharmacology
Ray Sagawa, Takehiko Ohba, Eisaku Ito, Susumu Isogai
Anaplastic lymphoma kinase (ALK) rearrangement is usually observed in patients with adenocarcinoma. Herein, we report a case of squamous cell carcinoma (SCC) with ALK rearrangement treated with alectinib. The patient was a 73-year-old woman without a smoking history. She consulted us with nonproductive cough and loss of appetite. Computed tomography scan revealed a mass in the left lower lobe of the lung. According to the pathological examinations, we diagnosed the tumor as SCC. Because the patient had never smoked, we searched for driver mutations and found that the tumor harbored ALK rearrangement...
2018: Case Reports in Oncological Medicine
Kojiro Nagai, Hiroyuki Ono, Motokazu Matsuura, Michael Hann, Sayo Ueda, Sakiya Yoshimoto, Masanori Tamaki, Taichi Murakami, Hideharu Abe, Hisashi Ishikura, Toshio Doi
Alectinib is a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor and is generally effective and tolerated in patients who have demonstrated disease progression or adverse effects while on the first generation inhibitor, crizotinib. ALK inhibitors can cause a reversible chronic increase of serum creatinine concentration; however, they rarely induce progressive renal insufficiency. We herein report a case of a 68-year-old woman diagnosed with ALK-positive advanced non-small cell lung cancer and who received ALK inhibitors...
April 2018: Oxford Medical Case Reports
Elizabeth Gourd
No abstract text is available yet for this article.
April 19, 2018: Lancet Oncology
S Novello, J Mazières, I-J Oh, J de Castro, M R Migliorino, Å Helland, R Dziadziuszko, F Griesinger, A Kotb, A Zeaiter, A Cardona, B Balas, H K Johannsdottir, A Das-Gupta, J Wolf
Background: This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib. Patients and methods: ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib...
April 14, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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