Relevance of Detection of Mechanisms of Resistance to ALK Inhibitors in ALK-Rearranged NSCLC in Routine Practice

Philippe Jamme (1) , Clotilde Descarpentries (2) , Radj Gervais (3) , Eric Dansin (4) , Marie Wislez (5) , Valerie Grégoire (2) , Nicolas Richard (6, 7) , Simon Baldacci (1) , Nathalie Rabbe (5) , Maeva Kyheng (8) , Zoulika Kherrouche (1) , Fabienne Escande (2) , Marie Copin (1) , Alexis Cortot (9)

1 M3T - Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161
2 Pôle de Biologie Pathologie Génétique [CHU Lille]
3 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]
4 UNICANCER/Lille - Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille]
5 CHU Tenon [AP-HP]
6 Service de Génétique [CHU Caen]
7 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires
8 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
9 SIRIC-ONCOLille - Site de Recherche Intégrée en Cancérologie

BackgroundAnaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown efficacy in the treatment of ALK-rearranged non–small-cell lung cancer (NSCLC), but the disease eventually progresses in all patients. In many cases, resistance to ALK TKIs arises through ALK mutations. Although clinical and biological data suggest variations in TKI efficacy according to the mechanism of resistance, ALK mutations are still rarely investigated in routine practice.Materials and MethodsWe performed a retrospective multicentric study with an aim to determine the frequency and clinical relevance of ALK alterations detected using targeted next-generation sequencing in patients with advanced ALK-rearranged NSCLC after progression during an ALK TKI treatment. Data on clinical, pathological, and molecular characteristics and patient outcomes were collected.ResultsWe identified 23 patients with advanced ALK-rearranged NSCLC who, between January 2012 and May 2017, had undergone at least 1 repeat biopsy at progression during an ALK TKI treatment. A resistance mechanism was identified in 9 of the 23 patients (39%). The anomalies involved included 9 ALK mutations in 8 patients and one ALK amplification. The ALK mutation rate was 15% after failure of a first ALK TKI and 33% after failure of 2 ALK TKI treatments. Five of 7 patients who received a different ALK TKI after detection of an ALK mutation achieved an objective response. All of the patients who received a TKI presumed to act on the detected ALK mutant achieved disease control.ConclusionTargeted next-generation sequencing is suitable for detecting ALK resistance mutations in ALK-rearranged NSCLC patients in routine practice. It might help select the best treatment at the time of disease progression during treatment with an ALK TKI.

Mots clés: Anaplastic lymphoma kinase; Lung neoplasm; Mutation; Real-world evidence; Resistance

Domaines: Cancer

Philippe Jamme, Clotilde Descarpentries, Radj Gervais, Eric Dansin, Marie Wislez, et al.. Relevance of Detection of Mechanisms of Resistance to ALK Inhibitors in ALK-Rearranged NSCLC in Routine Practice. Clinical Lung Cancer, 2019, 20 (4), pp.297-304.e1. ⟨10.1016/j.cllc.2019.02.013⟩. ⟨hal-02267645⟩