title: Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial.
abstract: BACKGROUND
  Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline.
  
  
  METHODS
  In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov, NCT01900743.
  
  
  RESULTS
  From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9-2·3) with regorafenib versus 1·7 months (0·9-1·8) with placebo (HR 0·89 [95% CI 0·48-1·64] p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5-5·0) with regorafenib versus 1·8 (1·0-2·8) months with placebo (HR 0·46 [95% CI 0·46-0·80] p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4-11·6) with regorafenib versus 1·0 (0·8-1·4) with placebo (HR 0·10 [95% CI 0·03-0·35] p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0-7·8) with regorafenib versus 1·0 (0·9-1·9) with placebo (HR 0·46 [95% CI 0·25-0·81] p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 [19%] events in the 89 patients in the regorafenib group vs two [2%] events in the 92 patients in the placebo group), hand and foot skin reaction (14 [15%] vs no events) and asthenia (12 [13%] vs six [6%]). One treatment-related death occurred in the regorafenib group due to liver failure.
  
  
  CONCLUSIONS
  Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib.
  
  
  BACKGROUND
  Bayer HealthCare.
authors.affiliation: Medical Oncology Department, Gustave Roussy, Villejuif, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Mir
authors.affiliation: Medical University Vienna, General Hospital, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brodowicz
authors.affiliation: Medical Oncology Department, Institut Bergonié, Bordeaux, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
authors.affiliation: Biostatisitics and Methodology Unit, Centre Oscar Lambret, Lille, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wallet
authors.affiliation: Medical Oncology Department, Centre Léon Bérard, Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Medical Oncology Department, Institut Paoli-Calmette, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Medical Oncology Department, Institut Universitaire de Cancérologie de Toulouse, Oncopôle, Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
authors.affiliation: Medical Oncology Department, Institut Curie, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Piperno-Neumann
authors.affiliation: Medical Oncology Department, René Gauducheau, Saint-Herblain, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bompas
authors.affiliation: Medical Oncology Department, CH La Timone, Marseille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Salas
authors.affiliation: Medical Oncology Department, Centre Eugène Marquis, Rennes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Perrin
authors.affiliation: Medical Oncology Department, Centre François Baclesse, Caen, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Delcambre
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Liegl-Atzwanger
authors.affiliation: Medical Oncology Department, Institut Bergonié, Bordeaux, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Toulmonde
authors.affiliation: Medical Oncology Department, Gustave Roussy, Villejuif, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dumont
authors.affiliation: Medical Oncology Department, Centre Léon Bérard, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Clinical Resarch Unit, Centre Oscar Lambret and Methodology and Clinical Research Platform of SIRIC OncoLille, Lille, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Clisant
authors.affiliation: Radiology Department, Centre Oscar Lambret, Lille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Taieb
authors.affiliation: Medical Oncology Department, Centre Henri Becquerel, Rouen France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Guillemet
authors.affiliation: Medical Oncology Department, Centre Alexis Vautrin, Nancy, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Rios
authors.affiliation: Medical Oncology Department, Institut de Cancérologie de la Loire Lucien Neuwirth, St Priest En Jarez, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Collard
authors.affiliation: Medical Oncology Department, Centre René Huguenin, Saint-Cloud, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bozec
authors.affiliation: Medical Oncology Department, Institut de Cancérologie de Montpellier; Montpellier, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Cupissol
authors.affiliation: Medical Oncology Department, Centre Antoine Lacassagne, Nice, France.
authors.forename: Esma
authors.initials: E
authors.lastname: Saada-Bouzid
authors.affiliation: Medical Oncology Department, Hopital Saint-Louis, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lemaignan
authors.affiliation: Medical Oncology Department, Universitätsklinik für Innere Medizin I, Innsbruck, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eisterer
authors.affiliation: Medical Oncology Department, Centre GF Leclerq, Dijon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Isambert
authors.affiliation: Medical Oncology Department, Hopital Saint-Jacques, Besançon, France; Medical Oncology department, Centre Oscar Lambret, Lille, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Chaigneau
authors.affiliation: Medical Oncology Department, Gustave Roussy, Villejuif, France.
authors.forename: Axel Le
authors.initials: AL
authors.lastname: Cesne
authors.affiliation: Methodology and Clinical Research Platform of SIRIC OncoLille, Lille, France. Electronic address: n-penel@o-lambret.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Penel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib