.Abstract IMPORTANCE: 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. OBJECTIVE: 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. EVIDENCE REVIEW: 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. FINDING: 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. CONCLUSIONS AND RELEVANCE: 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.

Precision medicine in ALK rearranged NSCLC: A rapidly evolving scenario

Addeo Alfredo;Tabbò Fabrizio;Buffoni Lucio;Novello Silvia
Last
2018

Abstract

.Abstract IMPORTANCE: 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. OBJECTIVE: 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. EVIDENCE REVIEW: 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. FINDING: 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. CONCLUSIONS AND RELEVANCE: 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.
122
150
156
http://www.sciencedirect.com/science/article/pii/S1040842817304857?_rdoc=1&_fmt=high&_origin=gateway&_docanchor=&md5=b8429449ccfc9c30159a5f9aeaa92ffb
ALK rearrangment; Precision medicine; Target therapy
Addeo, Alfredo; Tabbò, Fabrizio; Robinson, Tim; Buffoni, Lucio; Novello, Silvia
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S1040842817304857-main.pdf

Accesso aperto con embargo fino al 30/12/2018

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 679.89 kB
Formato Adobe PDF
679.89 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1656373
Citazioni
  • ???jsp.display-item.citation.pmc??? 19
  • Scopus 35
  • ???jsp.display-item.citation.isi??? 30
social impact