title: Crizotinib primary resistance overcome by ceritinib in a patient with ALK-rearranged non-small cell lung cancer.
abstract: We report on the case of a patient affected by advanced non-small cell lung cancer (NSCLC) harboring an anaplastic lymphoma kinase (ALK) gene rearrangement who did not respond to crizotinib but subsequently benefited from treatment with ceritinib (LDK378). Although second-generation ALK inhibitors have shown activity in patients pretreated with crizotinib who experienced secondary resistance, this is the first report to date describing their efficacy in a case of primary resistance. Of note, none of the previously described molecular mechanisms explaining resistance to crizotinib was detected on either the initial or post-crizotinib biopsies. We hypothesize that crizotinib was powerless in controlling disease progression due to its inadequate inhibition of ALK signaling. Although we lack any molecular evidence elucidating the primary crizotinib resistance, we believe that ceritinib treatment led to tumor regression thanks to its superior biological potency.
authors.affiliation: Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif - France.|Medical Oncology Unit, University Hospital, Parma - Italy.|INSERM, U981, Gustave Roussy Cancer Campus, Villejuif - France.|Department of Medicine, University Paris-Sud, Kremlin Bicetre/Chatenay-Malabry - France.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facchinetti
authors.affiliation: Department of Radiology, Gustave Roussy Cancer Campus, Villejuif - France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Caramella
authors.affiliation: Department of Medical Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif - France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auger
authors.affiliation: Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif - France.
authors.forename: David
authors.initials: D
authors.lastname: Planchard
authors.affiliation: Department of Medical Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif - France.
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.affiliation: Department of Medicine, University Paris-Sud, Kremlin Bicetre/Chatenay-Malabry - France.|Department of Medical Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif - France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif - France.
authors.forename: Jordi
authors.initials: J
authors.lastname: Remon
authors.affiliation: Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif - France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.affiliation: INSERM, U981, Gustave Roussy Cancer Campus, Villejuif - France.|Department of Medicine, University Paris-Sud, Kremlin Bicetre/Chatenay-Malabry - France.|Department of Medical Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif - France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: INSERM, U981, Gustave Roussy Cancer Campus, Villejuif - France.|Department of Medicine, University Paris-Sud, Kremlin Bicetre/Chatenay-Malabry - France.
authors.forename: Luc
authors.initials: L
authors.lastname: Friboulet
authors.affiliation: Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif - France.|Department of Medicine, University Paris-Sud, Kremlin Bicetre/Chatenay-Malabry - France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D000077547:Crizotinib; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D057915:Drug Substitution; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D014178:Translocation, Genetic; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib