title: Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial.
abstract: Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Imatinib followed by sunitinib and regorafenib is the standard sequence of treatment for advanced disease. Pazopanib is effective in soft tissue sarcomas but has never been assessed in advanced GIST in a randomised trial. We aimed to assess the efficacy and safety of pazopanib in patients with previously treated advanced GIST.
  
  
  
  In this randomised, open-label phase 2 study, we enrolled adults (aged ≥18 years) with advanced GIST resistant to imatinib and sunitinib from 12 comprehensive cancer centres or university hospitals in France and randomly assigned them 1:1 using an interactive web-based centralised platform to 800 mg oral pazopanib once daily in 4-week cycles plus best supportive care or best supportive care alone. Randomisation was stratified by the number of previous treatment regimens (2 vs ≥3); no-one was masked to treatment group allocation. Upon disease progression, patients in the best supportive care group were allowed to switch to pazopanib as compassionate treatment. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat. All randomised participants who received at least one dose of pazopanib were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01323400.
  
  
  
  Between April 12, 2011, and Dec 9, 2013, 81 patients were enrolled and randomly assigned to pazopanib plus best supportive care (n=40) or best supportive care alone (n=41). The median follow-up was 26·4 months (IQR 22·0-37·8) in the pazopanib plus best supportive care group and 28·9 months (22·0-35·2) in the best supportive care group. 4-month investigator-assessed progression-free survival was 45·2% (95% CI 29·1-60·0) in the pazopanib plus best supportive care group versus 17·6% (7·8-30·8) in the best supportive care group (hazard ratio [HR] 0·59, 95% CI 0·37-0·96; p=0·029). Median progression-free survival was 3·4 months (95% CI 2·4-5·6) with pazopanib plus best supportive care and 2·3 months (2·1-3·3) with best supportive care alone (HR 0·59 [0·37-0·96], p=0·03). 36 (88%) of the patients originally assigned to the best supportive care group switched to pazopanib following investigator-assessed disease progression; these patients had a median progression-free survival from pazopanib initiation of 3·5 months (95% CI 2·2-5·2). 55 (72%) of the 76 pazopanib-treated patients had pazopanib-related grade 3 or worse adverse events, the most common of which was hypertension (15 [38%] in the pazopanib plus best supportive care group and 13 [36%] in the best supportive care group). 20 (26%) patients had pazopanib-related serious adverse events (14 [35%] in the pazopanib plus best supportive care group and six [17%] in the best supportive care group), including pulmonary embolism in eight (9%) patients (five [13%] in the pazopanib plus best supportive care group and three [7%] in the best supportive care group). Three pazopanib-related deaths occurred (two pulmonary embolisms [one in each group] and one hepatic cytolysis [in the best supportive care group]). Three adverse event-related but not pazopanib-related deaths occurred in the best supportive care group after switch to pazopanib; these deaths were from hyperammonaemic encephalopathy, pneumopathy, and respiratory failure.
  
  
  
  Pazopanib plus best supportive care improves progression-free survival compared with best supportive care alone in patients with advanced GIST resistant to imatinib and sunitinib, with a toxicity profile similar to that reported for other sarcomas. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting for these patients.
  
  
  
  GlaxoSmithKline, French National Cancer Institute, EuroSARC (FP7-278742), Centre Léon Bérard.
authors.affiliation: Department of Cancer Medicine, Gustave Roussy, Villejuif, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Mir
authors.affiliation: Direction of Clinical Research and Innovation, Centre Léon Bérard, Lyon, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Cropet
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Toulmonde
authors.affiliation: Department of Cancer Medicine, Gustave Roussy, Villejuif, France.
authors.forename: Axel Le
authors.initials: AL
authors.lastname: Cesne
authors.affiliation: Pharmacology Department, Université de Bordeaux INSERM U657, Bordeaux, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Molimard
authors.affiliation: Department of Medical Oncology, Institut de Cancérologie de l'Ouest René Gauducheau, Saint Herblain, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bompas
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Cassier
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Department of Medical Oncology, Institut de Cancérologie de Lorraine-Alexis Vautrin, Nancy, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Rios
authors.affiliation: Department of Medical Oncology, Centre Oscar Lambret, Lille, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Adenis
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
authors.affiliation: Department of Medical Oncology, Centre Hospitalier Universitaire, Reims, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bouché
authors.affiliation: Pharmacology Department, Université de Bordeaux INSERM U657, Bordeaux, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Chauzit
authors.affiliation: Hôpital de la Timone, Marseille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Duffaud
authors.affiliation: Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Department of Medical Oncology, Centre George-François Leclerc, Dijon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Isambert
authors.affiliation: Direction of Clinical Research and Innovation, Centre Léon Bérard, Lyon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Gautier
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, Lyon, France. Electronic address: jean-yves.blay@lyon.unicancer.fr.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Direction of Clinical Research and Innovation, Centre Léon Bérard, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Pérol
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D005260:Female; D005602:France; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000009:adverse effects; D007191:Indazoles; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D007191:Indazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; C516667:pazopanib; D000068877:Imatinib Mesylate; D000077210:Sunitinib