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

Abstract

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.

Figure 1.

Axitinib efficacy in incurable adenoid cystic carcinoma patients. (A) Summary of efficacy data. (B) Waterfall plot of maximum tumor reduction. Hash denotes that RECIST progression was due to the appearance of a new site of disease. (C) Kaplan–Meier curve for progression-free survival (PFS).

Figure 2.

Adenoid cystic carcinoma (ACC) biomarkers/genomics and axitinib efficacy. (A) MYB immunohistochemistry and FISH for MYB and NFIB rearrangements. (B) Progression-free survival for the FISH detected MYB+/NFIB+ rearrangements and other FISH patterns (MYB+/NFIB−, MYB−/NFIB+, and MYB−/NFIB−). (C) Genetic alterations detected in ACC tumors from 11 enrolled study patients. Asterisk denotes the case that was profiled on the FoundationOne platform. (D) Significant response in a primary lung ACC tumor harboring both MYB/NFIB rearrangements and 4q12 amplification (14-fold amplification in PDGFRA/KDR/KIT).