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      Alectinib in the treatment of ALK-positive non-small cell lung cancer: an update on its properties, efficacy, safety and place in therapy

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          Abstract

          Anaplastic lymphoma kinase (ALK) rearrangement is identified in 3–7% of advanced non-small cell lung cancer (NSCLC) cases, and ALK tyrosine kinase inhibitors (TKIs) have revolutionized the management of this subset of NSCLC patients. ALK–TKIs have been proven highly effective in ALK-rearranged advanced NSCLC patients, but after initial responses and benefit, a subsequent progression inevitably occurs. Understanding acquired-resistance mechanisms and defining an appropriate algorithm is becoming even more essential, particularly considering the availability of extremely efficacious next-generation ALK inhibitors. The aim of this review is the analysis of current data about ALK inhibition as a therapeutic strategy in ALK-rearranged NSCLC management, with a focus on a specific ALK–TKI, alectinib. Alectinib is a highly selective inhibitor of ALK and showed systemic and central nervous system (CNS) efficacy in the treatment of this particular population. The change of first-line approach, and consequently of further lines of therapy, in ALK-rearranged NSCLC patients is still a matter of debate. A summary of evidence from randomized trials evaluating alectinib will be presented in order to discuss the available clinical evidence, safety and place in therapy.

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          Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

          Klarisa Rikova, Ailan Guo, Qingfu Zeng … (2008)
          Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.
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            Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

            Alice Shaw, Beow Yeap, Mari Mino-Kenudson … (2009)
            The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
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              First-line ceritinib versus platinum-based chemotherapy in advanced ALK -rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study

              Maximillian Hochmair, Fabrice Branle, Serafino Pantano … (2017)
              The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients.
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                Author and article information

                Contributors
                Tiziana Vavalà:
                ORCID: https://orcid.org/0000-0003-2367-0608
                Silvia Novello
                Journal
                Journal ID (nlm-ta): Ther Adv Med Oncol
                Journal ID (iso-abbrev): Ther Adv Med Oncol
                Journal ID (publisher-id): TAM
                Journal ID (hwp): sptam
                Title: Therapeutic Advances in Medical Oncology
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 1758-8340
                ISSN (Electronic): 1758-8359
                Publication date (Electronic): 03 August 2018
                Publication date Collection: 2018
                Volume: 10
                Electronic Location Identifier: 1758835918789364
                Affiliations
                [1-1758835918789364]SC of Oncology at ASL CN1, Ospedale Civile di Saluzzo, Cuneo, Italy
                [2-1758835918789364]Department of Oncology, University of Torino, AOU S. Luigi Gonzaga, Regione Gonzole 10, Orbassano (TO), Turin, Orbassano 10043, Italy
                Author notes
                Author information
                https://orcid.org/0000-0003-2367-0608
                Article
                Publisher ID: 10.1177_1758835918789364
                DOI: 10.1177/1758835918789364
                PMC ID: 6077883
                PubMed ID: 30090122
                SO-VID: 969b1531-2447-4d66-81a2-f621cdaa6862
                Copyright © © The Author(s), 2018
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 11 March 2018
                Date accepted : 19 June 2018
                Categories
                Subject: Review
                Custom metadata
                cover-date January-December 2018

                Keywords: alectinib,alectinib clinical trials,alk,alk inhibitors,alk-rearranged nsclc,alk–tki,alk–tyrosine kinase inhibitors,eml4–alk,non-small cell lung cancer,nsclc
                Data availability:
                Keywords: alectinib, alectinib clinical trials, alk, alk inhibitors, alk-rearranged nsclc, alk–tki, alk–tyrosine kinase inhibitors, eml4–alk, non-small cell lung cancer, nsclc

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