title: A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma.
abstract: Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. The majority of ACCs express the oncogenic transcription factor MYB (also c-myb), often in the context of a MYB gene rearrangement. This phase II trial of the tyrosine kinase inhibitor (TKI) axitinib (Pfizer) tested the hypothesis that targeting pathways activated by MYB can be therapeutically effective for ACC.
  
  
  
  This is a minimax two-stage, phase II trial that enrolled patients with incurable ACC of any primary site. Progressive or symptomatic disease was required. Patients were treated with axitinib 5 mg oral twice daily; dose escalation was allowed. The primary end point was best overall response (BOR). An exploratory analysis correlating biomarkers to drug benefit was conducted, including next-generation sequencing (NGS) in 11 patients.
  
  
  
  Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses. Twenty-five (75.8%) patients had stable disease, 10 of whom had disease stability for >6 months. The median progression-free survival (PFS) was 5.7 months (range 0.92-21.8 months). Grade 3 axitinib-related toxicities included hypertension, oral pain and fatigue. A trend toward superior PFS was noted with the MYB/NFIB rearrangement, although this was not statistically significant. NGS revealed three tumors with 4q12 amplification, producing increased copies of axitinib-targeted genes PDGFR/KDR/KIT. Two 4q12 amplified patients achieved stable disease for >6 months, including one with significant tumor reduction and the longest PFS on study (21.8 months).
  
  
  
  Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy.
authors: Department of Medicine Department of Medicine hoa@mskcc.org.
authors: A L
authors: AL
authors: Ho
authors: Department of Medicine.
authors: L
authors: L
authors: Dunn
authors: Department of Medicine Department of Medicine.
authors: E J
authors: EJ
authors: Sherman
authors: Department of Medicine Department of Medicine.
authors: M G
authors: MG
authors: Fury
authors: Department of Medicine Department of Medicine.
authors: S S
authors: SS
authors: Baxi
authors: Department of Pathology.
authors: R
authors: R
authors: Chandramohan
authors: Department of Pathology.
authors: S
authors: S
authors: Dogan
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, USA.
authors: L G T
authors: LG
authors: Morris
authors: Department of Medicine.
authors: G D
authors: GD
authors: Cullen
authors: Department of Radiology Department of Radiology, Weill Cornell Medical College, New York City.
authors: S
authors: S
authors: Haque
authors: Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, USA.
authors: C S
authors: CS
authors: Sima
authors: Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, USA.
authors: A
authors: A
authors: Ni
authors: Department of Pathology.
authors: C R
authors: CR
authors: Antonescu
authors: Department of Pathology.
authors: N
authors: N
authors: Katabi
authors: Department of Medicine Department of Medicine.
authors: D G
authors: DG
authors: Pfister
mesh_terms: D000328:Adult; D000368:Aged; D000077784:Axitinib; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D051839:NFI Transcription Factors / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics*
chemical_list: D007093:Imidazoles; D007191:Indazoles; D051839:NFI Transcription Factors; C110754:NFIB protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D020598:Proto-Oncogene Proteins c-myb; D000077784:Axitinib
keywords: MYB; adenoid cystic carcinoma; axitinib