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Treating ALK-positive lung cancer--early successes and future challenges.

ABSTRACT: Rearrangements of the anaplastic lymphoma kinase (ALK) gene occur infrequently in non-small-cell lung cancer (NSCLC), but provide an important paradigm for oncogene-directed therapy in this disease. Crizotinib, an orally bioavailable inhibitor of ALK, provides significant benefit for patients with ALK-positive (ALK+) NSCLC in association with characteristic, mostly mild, toxic effects, and this drug has been approved by the FDA for clinical use in this molecularly defined subgroup of lung cancer. Many new ALK inhibitors are being developed and understanding the challenges of determining and addressing the adverse effects that are likely to be ALK specific, while maximizing the time of benefit on targeted agents, and understanding the mechanisms that underlie drug resistance will be critical in the future for informing the optimal therapy of ALK+ NSCLC.

SUBMITTER: Camidge DR

PROVIDER: S-EPMC4142046 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Treating ALK-positive lung cancer--early successes and future challenges.

Camidge D Ross DR Doebele Robert C RC

Nature reviews. Clinical oncology 20120403 5

Rearrangements of the anaplastic lymphoma kinase (ALK) gene occur infrequently in non-small-cell lung cancer (NSCLC), but provide an important paradigm for oncogene-directed therapy in this disease. Crizotinib, an orally bioavailable inhibitor of ALK, provides significant benefit for patients with ALK-positive (ALK+) NSCLC in association with characteristic, mostly mild, toxic effects, and this drug has been approved by the FDA for clinical use in this molecularly defined subgroup of lung cancer ...[more]

PMID: 22473102

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Treating ALK-positive non-small cell lung cancer.

Project description: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. However, the acquired resistance to crizotinib and its diminished efficacy to the central nervous system (CNS) relapse led to the development of several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib. To date, four ALK TKIs, crizotinib, ceritinib, alectinib and brigatinib have received approval from the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) and even more agents are currently under investigation for the treatment of ALK-rearranged NSCLC. However, the optimal frontline approach and the exact sequence of ALK inhibitors are still under consideration. Recently announced results of phase III trials recognized higher efficacy of alectinib compared to crizotinib in first-line setting, even in patients with CNS involvement. In this review, we will discuss the current knowledge regarding the biology of the ALK-positive NSCLC, the available therapeutic inhibitors and we will focus on the raised issues from their use in clinical practise.

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Current opportunities and challenges in ALK-positive lung cancer.

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Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer.

Project description:The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be more potent than crizotinib or effective on crizotinib-resistant patients, have been developed. Although these ALK-TKIs show an excellent response initially, most patients eventually acquire resistance. Therefore, careful consideration of the resistance mechanisms might lead to superior therapeutic strategies. Here, we summarize the history of ALK-TKIs and their underlying resistance mechanisms in both the preclinical and clinical settings. In addition, we discuss potential future treatment strategies in ALK-TKI-naïve and -resistant patients with lung cancer harboring the EML4-ALK fusion gene.

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Atherosclerosis: Successes, Surprises, and Future Challenges.

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Treating patients with ALK-positive non-small cell lung cancer: latest evidence and management strategy.

Project description:Rearrangements in anaplastic lymphoma kinase (ALK) gene and echinoderm microtubule-associated protein-like 4 (EML4) gene were first described in a small portion of patients with non-small cell lung cancer (NSCLC) in 2007. Fluorescence in situ hybridization is used as the diagnostic test for detecting an EML4-ALK rearrangement. Crizotinib, an ALK inhibitor, is effective in treating advanced ALK-positive NSCLC, and the US Food and Drug Administration approved it for treating ALK-positive NSCLC in 2011. Several mechanisms of acquired resistance to crizotinib have recently been reported. Second-generation ALK inhibitors were designed to overcome these resistance mechanisms. Two of them, ceritinib and alectinib, were approved in 2014 for advanced ALK-positive NSCLC in the US and Japan, respectively. Heat shock protein 90 (Hsp90) inhibitors also showed activity against ALK-positive NSCLC. Here we review the recent development of crizotinib, ceritinib, alectinib and other second-generation ALK inhibitors as well as Hsp90 inhibitors. We also discuss management strategies for advanced ALK-positive NSCLC.

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Clinical outcomes of patients with resected, early-stage ALK-positive lung cancer.

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Early-stage anaplastic lymphoma kinase (<i>ALK</i>)-positive lung cancer: a narrative review.

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| S-EPMC9989809 | biostudies-literature

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