Precision medicine in ALK rearranged NSCLC: A rapidly evolving scenario

• Published in: Critical reviews in oncology/hematology Vol. 122; pp. 150 - 156
• Main Authors: Addeo, Alfredo, Tabbò, Fabrizio, Robinson, Tim, Buffoni, Lucio, Novello, Silvia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-02-2018
• Subjects: ALK rearrangment; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Drug Resistance, Neoplasm; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Precision medicine; Precision Medicine - methods; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Target therapy; Precision medicine; Target therapy; ALK rearrangment
• ISSN: 1040-8428; 1879-0461
• DOI: 10.1016/j.critrevonc.2017.12.015

The identification of anaplastic lymphoma kinase (ALK) rearrangements in 2-5% of non-small cell lung cancer (NSCLC) patients led to the rapid clinical development of its oral tyrosine kinase inhibitor (TKI). Crizotinib was the first ALK inhibitor approved and utilised in the treatment of ALK+ NSCLC patients in the second line setting first and subsequently in the first line one. Since then many other ALK inhibitors have been developed (ceritinib, alectinib, brigatinib, lorlatinib,etc) and the treatment paradigm of these patients has considerably drifted. The questions regarding their treatment at progression remains unanswered at the moment.
Our review clarifies what it is the state of the art in the treatment of ALK rearranged NSCLC patients, highlights the mechanisms of primary and secondary resistance mutations and suggests a treatment algorithm based on specific primary resistance or acquired mutations.
Studies that enrolled ALK+ NSCLC patients with locally advance or metastatic disease receiving treatment with ALK inhibitor, first or second line, were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library). Trials were excluded if they were phase 1, enrolled less than 10 patients.
Overall 1942 patients were included in our review. It confirms the role and the efficacy in first line of Alectinib but it highlights also that all the ALK inhibitors could play a crucial role during the patients’ journey. Identifying the different mutations and utilising the most active ALK inhibitor depending on the “up-to-date” driven mutation is the way forward in the management of those patients.
the review shows the rapid drifting in the management of ALK+ NSCLC patients and the importance of fully understanding and acknowledging the role of the resistance mutation, primary or acquired. We strongly advocate a comprehensive genomic approach in the management of ALK+ NSCLC patients who develop resistance mutations that are still targetable by a different ALK inhibitor.