Phase II study of dovitinib in patients progressing on anti-vascular endothelial growth factor therapy

• Published in: Cancer treatment and research communications 2017, Vol.10, p.21-26
• Main Authors: Semrad, Thomas J., Kim, Edward J., Tanaka, Michael S., Sands, Jacob, Roberts, Chris, Burich, Rebekah A., Li, Yu, Gandara, David R., Lara, Primo, Mack, Philip C.
• Format: Article
• Language: English
• Subjects: Angiogenesis inhibitors; Dovitinib; Fibroblast growth factors; Vascular endothelial growth factors
• ISSN: 2468-2942; 2468-2942
• DOI: 10.1016/j.ctarc.2016.12.002

Prior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-vascular endothelial growth factor (VEGF) therapy. We tested dovitinib, an inhibitor of both FGF and VEGF receptors, in patients progressing on anti-VEGF treatment. Patients with measurable advanced colorectal or non-small cell lung cancer with progression despite anti-VEGF treatment within 56 days, good performance status and adequate organ function were eligible. A research tumor biopsy was followed by treatment with dovitinib 500mg on a 5-day on /2-day off schedule for 28-day cycles. The primary endpoint of tumor response was evaluated every 2 cycles. Secondary endpoints included toxicity and 8-week disease control rate. Intratumor mRNA expression of angiogenic mediators was analyzed using a next generation sequencing based expression array. Ten patients treated previously with bevacizumab or ziv-aflibercept enrolled. The study closed with termination of dovitinib development. No responses were observed in 7 evaluable patients. The best response was stable disease in 1 patient. Common toxicities included gastrointestinal, metabolic, and biochemical derangements. All patients experienced at least one grade ≥3 treatment-related adverse event, most commonly fatigue, elevated GGT, and lymphopenia. Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA. We found no evidence for the activity of dovitinib in patients who had recently progressed on anti-VEGF therapy and toxicities were significant. In tumors progressing despite anti-VEGF therapy, a multitude of pro-angiogenic mediators are expressed, including members of the FGF pathway.