Alfredo Addeo1, Fabrizio Tabbò2, Tim Robinson3, Lucio Buffoni2, Silvia Novello2. 1. Oncology Department, University Hospital Geneva, Rue Gabrielle-Perret-Gentil 4, Geneva, CH, Switzerland. Electronic address: alfredo.addeo76@gmail.com. 2. Oncology Department, San Luigi Hospital University of Turin, Orbassano, Turin, Italy. 3. Oncology Department, Bristol University Hospital Trust, Horfield Road, Bristol, UK.
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.
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+ NSCLCpatients 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 NSCLCpatients, 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+ NSCLCpatients 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+ NSCLCpatients 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+ NSCLCpatients who develop resistance mutations that are still targetable by a different ALK inhibitor.
Authors: Emilio Francesco Giunta; Alessio Signori; Howard Jack West; Giulio Metro; Alex Friedlaender; Kaushal Parikh; Giuseppe Luigi Banna; Alfredo Addeo Journal: Front Oncol Date: 2022-06-14 Impact factor: 5.738
Authors: Jesús García-Foncillas; Jesús Argente; Luis Bujanda; Victoria Cardona; Bonaventura Casanova; Ana Fernández-Montes; José A Horcajadas; Andrés Iñiguez; Alberto Ortiz; José L Pablos; María Vanessa Pérez Gómez Journal: Mol Diagn Ther Date: 2021-07-30 Impact factor: 4.074