A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma

Abstract

Purpose: Genetic and preclinical studies have implicated FGFR signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor of FGFR activity, may be active in ACC.Experimental Design: In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500 mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate and change in tumor growth rate. Progression-free survival, overall survival, metabolic response, biomarker, and quality of life were secondary endpoints.Results: Of 34 evaluable patients, 2 (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on treatment (P < 0.001). Toxicity was moderate; 63% of patients developed grade 3-4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on ¹⁸FDG-PET scans was seen in 3 of 15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with overexpression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib.Conclusions: Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably with those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine whether FGFR signaling is a valid therapeutic target in ACC. Clin Cancer Res; 23(15); 4138-45. ©2017 AACR.

Figure 1

Response to treatment. Maximum percentage change from baseline in target lesions. SD4 indicates stable disease at 4 month assessment. SD2 indicates stable disease at 2 month assessment. TF indicates a patient with stable disease who died while on study. uPR indicates the unconfirmed partial response. PR indicates the confirmed partial response.

Figure 2

Change point analysis plot. This figure demonstrates the assessment of tumor growth kinetics based on pre-study and on-study measurements of the sum of the longest diameters of target lesions. The measurements at month zero are the on-study scans. Up to 3 pre-study scans were evaluated up to 9 months prior to study enrollment. The tumor diameter sums are shown for 34 patients. The thick blue line is the summary change point analysis line as modeled using piecewise linear models of tumor growth allowing for one inflection point for the pre and post treatment periods. The component of the summary line for the slope of tumor growth rate pretreatment was 1.95. The slope of that blue summary line post treatment was 0.63 (p<0.001). Repeated measures model results: [Table: see text]

Figure 3

Patient survival data. (A) Progression-free survival. (B) Overall survival.

Figure 3

Patient survival data. (A) Progression-free survival. (B) Overall survival.