title: Clinical impact of sequential treatment with ALK-TKIs in patients with advanced ALK-positive non-small cell lung cancer: Results of a multicenter analysis.
abstract: OBJECTIVE
  Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) is sensitive to treatment with an ALK-tyrosine kinase inhibitor (-TKI). However, the benefit of sequential treatment with a 2nd ALK-TKI in patients who fail a 1st ALK-TKI has been poorly addressed.
  
  
  METHODS
  We collected the data of 69 advanced ALK-positive NSCLCs who were treated with one or more ALK-TKIs at three Italian institutions. The clinical outcome of treatment with an ALK-TKI and the patterns of treatment upon failing a 1st ALK-TKI were recorded.
  
  
  RESULTS
  Objective response rate (ORR) and median progression-free survival (PFS) on a 1st ALK-TKI (mostly crizotinib) were 60.9% and 12 months, respectively. Of the 50 patients who progressed on a 1st ALK-TKI, 22 were further treated with a 2nd ALK-TKI (either ceritinib or alectinib), for whom an ORR of 86.4% and median PFS of 7 months, respectively, were reported. Conversely, 13 patients underwent rapid clinical/radiographic disease progression leading to death shortly after discontinuation of the 1st ALK-TKI, 7 patients were managed with a 1st ALK-TKI beyond progression, and 8 patients transitioned to other systemic treatments (mostly chemotherapy). Post-progression survival (PPS) significantly favored the 22 patients who were sequentially treated with a 2nd ALK-TKI over those who transitioned to other systemic treatments (P=0.03), but not versus those who were treated with a 1st ALK-TKI beyond progression (P=0.89).
  
  
  CONCLUSIONS
  Sequential treatment with a 2nd ALK-TKI is effective in patients who fail a 1st ALK-TKI. Continuous ALK-inhibition upon failing a 1st ALK-TKI may be associated with improved clinical outcome.
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Chiari
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy. Electronic address: giulio.metro@yahoo.com.
authors.forename: Giulio
authors.initials: G
authors.lastname: Metro
authors.affiliation: Medical Oncology, University of Rome 'La Sapienza', Sant'Andrea Hospital, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Iacono
authors.affiliation: Department of Experimental Medicine, Section of Anatomic Pathology and Histology, School of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Bellezza
authors.affiliation: Department of Diagnostic Imaging, School of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rebonato
authors.affiliation: Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dubini
authors.affiliation: Biostatistics, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bennati
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Paglialunga
authors.affiliation: Medical Oncology, Istituto Scientifico per la Cura e lo Studio dei Tumori (IRST) IRCCS, Meldola, FC, Italy.
authors.forename: Marco Angelo
authors.initials: MA
authors.lastname: Burgio
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Baglivo
authors.affiliation: Medical Oncology, University of Rome 'La Sapienza', Sant'Andrea Hospital, Rome, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Giusti
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Minotti
authors.affiliation: Medical Oncology, Istituto Scientifico per la Cura e lo Studio dei Tumori (IRST) IRCCS, Meldola, FC, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Delmonte
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Crinò
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism*; D000077547:Crizotinib; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; ALK-TKI; Alectinib; Ceritinib; Crizotinib; Non-small cell lung cancer