title: Spotlight on crizotinib in the first-line treatment of ALK-positive advanced non-small-cell lung cancer: patients selection and perspectives.
abstract: Around 4% of advanced non-small-cell lung cancers (NSCLCs) have anALKrearrangement at the time of diagnosis. This molecular feature is more frequent in young patients, with no/light smoking habit and with adenocarcinoma pathological subtype. Crizotinib is a tyrosine kinase inhibitor, targeting ALK, ROS1, RON, and MET. The preclinical efficacy results led to a fast-track clinical development. The US Food and Drug Administration (FDA) approval was achieved after the Phase I clinical trial in 2011 in ALK-rearranged advanced NSCLC progressing after a first-line treatment. In 2013, the randomized Phase III trial PROFILE-1007 confirmed the efficacy of crizotinib in ALK-rearranged NSCLC, compared to cytotoxic chemotherapy, in second-line setting or more. In 2014, the PROFILE-1014 trial showed the superiority of crizotinib in the first-line setting compared to the pemetrexed platinum doublet chemotherapy. The response rate was 74%, and the progression-free survival was 10.9 months with crizotinib. Based on these results, crizotinib received approval from the FDA and European Medicines Agency for first-line treatment of ALK-rearranged NSCLC. The various molecular mechanisms at the time of the progression (ALK mutations or amplification, ALK-independent mechanisms) encourage performing re-biopsy at the time of progression under crizotinib. The best treatment strategy at the progression (crizotinib continuation beyond progression, switch to second-generation tyrosine kinase inhibitors, or cytotoxic chemotherapy) depends on the phenotype of the progression, the molecular status, and the physical condition of the patient.
authors.affiliation: Respiratory Diseases and Thoracic Oncology Department, APHP-Ambroise Paré Hospital, Boulogne-Billancourt, France; EA4340 Laboratory, UVSQ, Paris-Saclay University, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Giroux-Leprieur
authors.affiliation: Respiratory Diseases Department, APHP - Tenon Hospital, Paris, France; Sorbonne University, GRC 04, UPMC Univ Paris 06, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Fallet
authors.affiliation: Respiratory Diseases Department, APHP - Tenon Hospital, Paris, France; Sorbonne University, GRC 04, UPMC Univ Paris 06, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.affiliation: Respiratory Diseases Department, APHP - Tenon Hospital, Paris, France; Sorbonne University, GRC 04, UPMC Univ Paris 06, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Wislez
keywords: ALK rearrangement; crizotinib; non-small-cell lung carcinoma