The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 'CREATE'. (May 2018)

• Record Type: Journal Article
• Authors: Schöffski, Patrick; Wozniak, Agnieszka; Leahy, Michael G.; Aamdal, Steinar; Rutkowski, Piotr; Bauer, Sebastian; Richter, Stephan; Grünwald, Viktor; Debiec-Rychter, Maria; Sciot, Raf; Geoerger, Birgit; Marréaud, Sandrine; Collette, Sandra; Nzokirantevye, Axelle; Strauss, Sandra J.
• Is Part Of: European journal of cancer. Volume 94(2018)
• Page Start: 156
• Page End: 167
• Publication Date: 2018-05
• Subjects: Alveolar rhabdomyosarcoma -- ARMS -- Metastasis -- FOXO1 -- ALK -- Crizotinib; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2018.02.011
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: Alveolar rhabdomyosarcomas (ARMSs) can harbour MET and anaplastic lymphoma kinase (ALK) alterations. We prospectively assessed crizotinib in patients with advanced/metastatic ARMS. Methods: Eligible patients with a central diagnosis of ARMS received oral crizotinib 250 mg twice daily. Patients were attributed to MET/ALK + or MET/ALK − subcohorts by assessing the presence or absence of the forkhead box O1 ( FOXO1 ; a marker of MET upregulation) and/or ALK gene rearrangement. The primary end-point was the objective response rate (ORR). Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS) and safety. Findings: Nineteen of 20 consenting patients had centrally confirmed ARMS. Molecular assessment revealed rearrangement of FOXO1 in 17 tumours and ALK in none. Thirteen eligible patients were treated, but only eight were evaluable for the primary end-point because of the observed aggressiveness of the disease. Among seven evaluable MET +/ ALK − patients, only one achieved a confirmed partial response (ORR: 14.3%; 95% confidence interval [CI]: 0.3–57.8) with a DOR of 52 d. Further MET +/ ALK − efficacy end-points were DCR: 14.3% (95% CI: 0.3–57.8), median PFS: 1.3 months (95% CI: 0.5–1.5) and median OS: 5.6 months (95% CI: 0.7–7.0). The remaining MET +/ ALK − and MET −/ ALK − patients had early progression as best response. Common treatment-related adverse events were fatigue (5/13 [38.5%]), nausea (4/13 [30.8%]), anorexia (4/13 [30.8%]), vomiting (2/13 [15.4%]) and constipation (2/13 [15.4%]). All 13 treated patients died early because of progressive disease. Interpretation: Crizotinib is well tolerated but lacks clinically meaningful activity as a single agent in patients with advanced metastatic ARMS. Assessing single agents in aggressive, chemotherapy-refractory ARMS is challenging, and future trials should explore established chemotherapy ± investigational compounds in earlier lines of treatment. Clinical Trial Number: EORTC 90101, ClinicalTrials.govNCT01524926 . Highlights: Chemotherapy-refractory ARMS is a clinically aggressive disease. ARMS is commonly associated with FOXO1 rearrangement, but a low incidence of ALK alterations. Crizotinib is well-tolerated in chemotherapy-refractory ARMS. However, crizotinib has limited single-agent activity in chemotherapy-refractory ARMS without ALK rearrangement. Future trials in this disease should test conventional chemotherapy +/− novel agent.