Metastatic adenoid cystic carcinoma (ACC) is a rare, incurable malignancy of the salivary glands with no reliable treatment. Over 90% of ACC carry a t(6;9) translocation that leads to MYB overexpression and upregulation of the fibroblast growth factor 2 (FGF2) ligand. Dovitinib (DOV) is a receptor TKI with multiple targets including FGFR and VEGFR. In preclinical studies, DOV showed a suppressive effect in ACC xenografts. We hypothesized that DOV would have beneficial clinical effects.
Patients (pts) with incurable ACC were recruited if they had progressed within 12 months prior to study entry (> 10% change, new lesion(s), or worsening clinical status). The primary outcome was clinical benefit rate (CBR), a composite endpoint of CR, PR, or SD of > six months. Sample size of 20 evaluable pts was based on a CBR of 75%, estimated from natural history and previous studies. Archival tissue was obtained for MYB-NFIB gene translocation by FISH analysis and FGFR and phospho-FGFR expression. Pts received DOV 500mg orally 5 days on/2 days off on a 28-day cycle with response assessed every 12 weeks.
21 pts (11 female) with a mean age of 55.9 years (range 38.1, 81.5) were enrolled. Best response was SD in 15 pts. CBR was 7/21 (33.3%). Five of 18 pts with measurable disease (27.8%) had some regression. PFS at 12 months was 37.6%, and 1-year OS was 61.6%. Most patients tolerated DOV reasonably well but six pts discontinued because of toxicity and five required dose reductions. The most frequent attributable AEs were diarrhea (91%), nausea (67%), fatigue (71%), rash (38%), anorexia, and vomiting (33% each). Six of 15 pts (40%) had wild type MYB by FISH. Wild type (WT) status was not prognostic for OS (p = 0.38) or PFS (p = 0.18). MYB IHC was not prognostic for either OS (p = 0.086) or PFS (p = 0.74), but pFGFR IHC score was significantly prognostic for OS (HR = 1.35, 95% CI = 1.01-1.80, p = 0.040), but not PFS (p = 0.11).
DOV toxicity was generally manageable with predominantly gastrointestinal adverse events. However, objective responses were not observed and the primary endpoint of clinical benefit was not met. Although tumor pFGFR IHC score appeared prognostic, no pharmacodynamic predictors of clinical activity from DOV were identified.
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All authors have declared no conflicts of interest.