title: Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: a randomized controlled open-label trial.
abstract: BACKGROUND
  Masitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance.
  
  
  METHODS
  Prospective, multicenter, randomized, open-label trial. Patients with inoperable, advanced imatinib-resistant GIST were randomized (1 : 1) to receive masitinib (12 mg/kg/day) or sunitinib (50 mg/day 4-weeks-on/2-weeks-off) until progression, intolerance, or refusal. Primary efficacy analysis was noncomparative, testing whether masitinib attained a median progression-free survival (PFS) (blind centrally reviewed RECIST) threshold of >3 months according to the lower bound of the 90% unilateral confidence interval (CI). Secondary analyses on overall survival (OS) and PFS were comparative with results presented according to a two-sided 95% CI.
  
  
  RESULTS
  Forty-four patients were randomized to receive masitinib (n = 23) or sunitinib (n = 21). Median follow-up was 14 months. Patients receiving masitinib experienced less toxicity than those receiving sunitinib, with significantly lower occurrence of severe adverse events (52% versus 91%, respectively, P = 0.008). Median PFS (central RECIST) for the noncomparative primary analysis in the masitinib treatment arm was 3.71 months (90% CI 3.65). Secondary analyses showed that median OS was significantly longer for patients receiving masitinib followed by post-progression addition of sunitinib when compared against patients treated directly with sunitinib in second-line [hazard ratio (HR) = 0.27, 95% CI 0.09-0.85, P = 0.016]. This improvement was sustainable as evidenced by 26-month follow-up OS data (HR = 0.40, 95% CI 0.16-0.96, P = 0.033); an additional 12.4 months survival advantage being reported for the masitinib treatment arm. Risk of progression while under treatment with masitinib was in the same range as for sunitinib (HR = 1.1, 95% CI 0.6-2.2, P = 0.833).
  
  
  CONCLUSIONS
  Primary efficacy analysis ensured the masitinib treatment arm could satisfy a prespecified PFS threshold. Secondary efficacy analysis showed that masitinib followed by the standard of care generated a statistically significant survival benefit over standard of care. Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit-risk ratio. Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted.
authors.affiliation: Department of Gastrointestinal Oncology, Centre Oscar Lambret, Lille.
authors.forename: A
authors.initials: A
authors.lastname: Adenis
authors.affiliation: Department of Medicine, Centre Léon Bérard (CLB), Lyon.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Department of Medicine, Institut Bergonié, Bordeaux.
authors.forename: B
authors.initials: B
authors.lastname: Bui-Nguyen
authors.affiliation: Department of Gastroenterology and Digestive Oncology, CHU Hôpital Robert Debré, Reims.
authors.forename: O
authors.initials: O
authors.lastname: Bouché
authors.affiliation: Department of Medical Oncology, Institut Paoli-Calmettes, Marseille.
authors.forename: F
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Department of Oncology, Centre Georges François Leclerc, Dijon.
authors.forename: N
authors.initials: N
authors.lastname: Isambert
authors.affiliation: Department of Medical Oncology, Centre René Gauducheau, Saint Herblain.
authors.forename: E
authors.initials: E
authors.lastname: Bompas
authors.affiliation: Department of Medical Oncology, Hôpital Jean Minjoz, Besançon.
authors.forename: L
authors.initials: L
authors.lastname: Chaigneau
authors.affiliation: Department of Medicine, Institut Gustave Roussy (IGR), Villejuif, France.
authors.forename: J
authors.initials: J
authors.lastname: Domont
authors.affiliation: Department of Medicine, Centre Léon Bérard (CLB), Lyon.
authors.forename: I
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Department of Medicine, Institut Gustave Roussy (IGR), Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Blésius
authors.affiliation: Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St Louis, St Louis, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Van Tine
authors.affiliation: Oncology Centre, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: V R
authors.initials: VR
authors.lastname: Bulusu
authors.affiliation: CRCM (Signaling, Hematopoiesis and Mechanism of Oncogenesis), INSERM U1068, Marseille; Institut Paoli-Calmettes, Aix-Marseille Université, Marseille; CNRS UMR7258, Marseille; AB Science, Paris.
authors.forename: P
authors.initials: P
authors.lastname: Dubreuil
authors.affiliation: AB Science, Paris.
authors.forename: C D
authors.initials: CD
authors.lastname: Mansfield
authors.affiliation: AB Science, Paris.
authors.forename: Y
authors.initials: Y
authors.lastname: Acin
authors.affiliation: AB Science, Paris.
authors.forename: A
authors.initials: A
authors.lastname: Moussy
authors.affiliation: AB Science, Paris; Department of Hematology, Hôpital Necker, Paris; Department of Hematology, CNRS UMR 8147, Université Paris V René Descartes, Paris; Institut Imagine, Université Sorbonne Paris Cité, Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Hermine
authors.affiliation: Department of Medicine, Institut Gustave Roussy (IGR), Villejuif, France. Electronic address: axel.lecesne@gustaveroussy.fr.
authors.forename: A
authors.initials: A
authors.lastname: Le Cesne
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000401:mortality*; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D010880:Piperidines; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D011725:Pyridines; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use; D000077210:Sunitinib; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D013844:Thiazoles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C526575:masitinib; D000077210:Sunitinib
keywords: GIST; imatinib-resistant GIST; phase II study; tyrosine kinase inhibitor