A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma

Ann Oncol. 2016 Oct;27(10):1902-8. doi: 10.1093/annonc/mdw287. Epub 2016 Aug 26.


Background: 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.

Patients and methods: 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.

Results: 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).

Conclusions: 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.

Keywords: MYB; adenoid cystic carcinoma; axitinib.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Axitinib
  • Carcinoma, Adenoid Cystic / drug therapy*
  • Carcinoma, Adenoid Cystic / genetics
  • Carcinoma, Adenoid Cystic / pathology
  • Chromosomes, Human, Pair 4 / genetics
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Drug-Related Side Effects and Adverse Reactions
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Imidazoles / administration & dosage*
  • Imidazoles / adverse effects
  • Indazoles / administration & dosage*
  • Indazoles / adverse effects
  • Male
  • Middle Aged
  • NFI Transcription Factors / genetics*
  • Oncogene Proteins, Fusion / genetics
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Proto-Oncogene Proteins c-myb / genetics*


  • Imidazoles
  • Indazoles
  • NFI Transcription Factors
  • NFIB protein, human
  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myb
  • Axitinib