title: First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.
abstract: The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients.
  
  
  
  This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m2or carboplatin AUC 5-6 plus pemetrexed 500 mg/m2] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1-2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099.
  
  
  
  Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6-27·2) in the ceritinib group and 8·1 months (5·8-11·1) in the chemotherapy group (hazard ratio 0·55 [95% CI 0·42-0·73]; p<0·00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotransferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group.
  
  
  
  First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC.
  
  
  
  Novartis Pharmaceuticals Corporation.
authors.affiliation: University Paris-Sud, Orsay, France; Institut Gustave Roussy, Villejuif, France. Electronic address: Jean-Charles.Soria@gustaveroussy.fr.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: National Cancer Centre Singapore and Genome Institute of Singapore, Singapore.
authors.forename: Daniel S W
authors.initials: DSW
authors.lastname: Tan
authors.affiliation: Azienda Ospedale Perugia, Perugia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Chiari
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.affiliation: University Hospital Virgen del RocioDoce de Octubre, Universidad Complutense & CNIO, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: University Hospital Cologne, Cologne, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Songklanagarind Hospital, Songkla, Thailand.
authors.forename: Sarayut L
authors.initials: SL
authors.lastname: Geater
authors.affiliation: State Pavlov Medical University, St Petersburg, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Orlov
authors.affiliation: Az. Ospedaliera San Gerardo, Monza, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Cortinovis
authors.affiliation: National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: Respiratory Oncology Unit, Department of Respiratory and Critical Care Medicine, Otto-Wagner-Spital, Vienna, Austria.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Hochmair
authors.affiliation: CHU de LILLE, Lille, France.
authors.forename: Alexis B
authors.initials: AB
authors.lastname: Cortot
authors.affiliation: Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Tsai
authors.affiliation: Hôpital Albert Michallon, Grenoble, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Moro-Sibilot
authors.affiliation: University Hospital A Coruña, La Coruna, Spain.
authors.forename: Rosario G
authors.initials: RG
authors.lastname: Campelo
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Tracey
authors.initials: T
authors.lastname: McCulloch
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Paramita
authors.initials: P
authors.lastname: Sen
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Dugan
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Serafino
authors.initials: S
authors.lastname: Pantano
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Branle
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Cristian
authors.initials: C
authors.lastname: Massacesi
authors.affiliation: Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: de Castro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed / Q000008:administration & dosage / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D013450:Sulfones; D000068437:Pemetrexed; D016190:Carboplatin; C586847:ceritinib; D002945:Cisplatin