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Background: Receptor tyrosine kinases (RTKs) play key roles in tumorigenesis. The multi-RTK inhibitor dovitinib has demonstrated promising antitumor activity in multiple cancers., Patients and Methods: In this phase 2, open-label, single-arm study, patients with advanced malignancies with RTK-pathway genetic aberrations whose disease progressed on/following standard treatment received dovitinib (500 mg/day; 5-days-on/2-days-off). The primary endpoint was clinical benefit rate (CBR; complete response, partial response [PR], or stable disease [SD] for ≥ 16 weeks)., Results: Of 80 patients enrolled, common tumors included gastrointestinal stromal tumors (GIST; 20.0%), colorectal cancer (CRC; 18.8%), and ovarian cancer (10.0%). Patients were heavily pretreated (median prior lines = 4; 67.5% had ≥ 3 prior lines). Genetic aberrations included cKIT (28.8%), FGFR3 (15.0%), and RET (15.0%). The CBR was 13.8%; one PR (GIST) and 10 SD (adenoid cystic [ n = 3]; ovarian [ n = 3]; GIST [ n = 2]; CRC [ n = 1]; gastroesophageal junction [ n = 1]). The most common treatment-related adverse events were fatigue, diarrhea, nausea, and vomiting., Conclusions: In this heterogeneous patient population, the safety profile was acceptable for dovitinib therapy. A subset of patients with RTK pathway-activated tumors experienced clinical benefit. However, the primary endpoint was not met, suggesting further refinement of predictive biomarkers is required., Competing Interests: CONFLICTS OF INTEREST M.H. Taylor reports receiving honoraria for Advisory Boards from ArQule, Array Biopharma, Bayer, Blueprint Medicines, Loxo Oncology, Novartis and honoraria for Advisory Boards and Speakers fees from Bristol-Myers Squibb and Eisai, outside the submitted work. A.S. Alva reports grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Esanik, Genentech, Ionis, Janssen, Merck, Progenics, and Prometheus; and personal fees from Merck and AstraZeneca for Advisory Boards, outside the submitted work. T. Larson has nothing to disclose. S. Szpakowski reports employment by, and stock ownership of Novartis. D. Purkayastha, A. Amin, and L. Karpiak report employment by Novartis. S.A. Piha-Paul reports clinical trial research support from AbbVie, Aminex Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol-Myers Squib, Cerulean Pharma, Chugai Pharmaceutical, Curis, Five Prime Therapeutics, Genmab A/S, GlaxoSmithKline, Helix BioPharma, Incyte, Jacobio Pharmaceuticals, Medimmune, Medivation, Merck Sharp & Dohme, NewLink Genetics Corporation, Blue Link Pharmaceuticals, Novartis, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Taiho Oncology, Tesaro, TransThera Bio, and Xuan Zhu Biopharma, outside the submitted work.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease occurring in 1 in 35,000 births and leads to an increased risk of a phenotypically diverse array of tumor types including, but not limited to, clear cell renal cell carcinoma (ccRCC) and hemangioblastomas (HBs). Previous studies of patients with VHL disease treated with the tyrosine kinase inhibitor (TKI) sunitinib did not show clinical response in HBs. Interestingly, VHL-related HBs displayed increased fibroblast growth factor receptor 3 (FGFR3) protein expression when compared to VHL-related ccRCCs. Therefore, in this pilot study, we assessed the safety and efficacy profile of TKI 258 (dovitinib), a multi-tyrosine kinase inhibitor of VEGF receptor and fibroblast growth factor (FGF), in patients with VHL disease who had measureable HBs. The trial was stopped after six patients enrolled after the toxicity stopping rule was triggered. With regards to safety, 6/6 subjects had at least one adverse event (AE). Best response in 6/6 subjects was stable disease (SD) in HBs. While the negative safety and efficacy results of this pilot study do not favor the use of dovitinib for the treatment of asymptomatic HBs in VHL disease patients, further investigation into alternative scheduling and other FGFR inhibitors for the treatment of HBs in VHL disease patients is warranted given the promising pre-clinical and molecular data., Competing Interests: CONFLICTS OF INTEREST None.

Fibroblast Growth Factor Receptor (FGFR) signaling is a complex pathway which controls several processes, including cell proliferation, survival, migration, and metabolism. FGFR1 signaling is frequently deregulated via amplification/over-expression in NSCLC of squamous histotype (SQCLC), however its inhibition has not been successfully translated in clinical setting. We determined whether targeting downstream signaling implicated in FGFR1 effects on glucose metabolism potentiates the anti-tumor activity of FGFR1 inhibition in SQCLC. In FGFR1 amplified/over-expressing SQCLC cell lines, FGF2-mediated stimulation of FGFR1 under serum-deprivation activated both MAPK and AKT/mTOR pathways and increased glucose uptake, glycolysis, and lactate production, through AKT/mTOR-dependent HIF-1α accumulation and up-regulation of GLUT-1 glucose transporter. These effects were hindered by PD173074 and NVP-BGJ398, selective FGFR inhibitors, as well as by dovitinib, a multi-kinase inhibitor. Glucose metabolism was hampered by the FGFR inhibitors also under hypoxic conditions, with consequent inhibition of cell proliferation and viability. In presence of serum, glucose metabolism was impaired only in cell models in which FGFR1 inhibition was associated with AKT/mTOR down-regulation. When the activation of the AKT/mTOR pathway persisted despite FGFR1 down-regulation, the efficacy of NVP-BGJ398 could be significantly improved by the combination with NVP-BEZ235 or other inhibitors of this signaling cascade, both in vitro and in xenotransplanted nude mice. Collectively our results indicate that inhibition of FGFR1 signaling impacts on cancer cell growth also by affecting glucose energy metabolism. In addition, this study strongly suggests that the therapeutic efficacy of FGFR1 targeting molecules in SQCLC may be implemented by combined treatments tackling on glucose metabolism., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.