Significant Antitumor Activity of E-3810, a Novel FGFR and VEGFR Inhibitor, in Patients With FGFR1 Amplified Breast Cancer

Background Amplification of the FGFR1 gene occurs in subsets of tumors, notably breast cancer (BC), where the altered FGF pathway may be clinically relevant. Methods E-3810 is a kinase inhibitor targeting FGFR1 and VEGFR1, 2, 3. Its safety and activity, at the daily oral dose of 20 or 15 mg on a continuous schedule, are being assessed in patients with solid tumors and FGFR1 amplification or potentially sensitive to antiangiogenic agents. The study is an open label non comparative extension of the first in man dose-escalation trial; the efficacy threshold, set for the FGFR1+ cohort only, requires 3/14 confirmed objective RECIST responses or non-progressive disease ≥ 6 cycles (one-stage Fleming design: H0 5%, H1 30%, power 80%). Results 46 patients with various tumor types (including 13 FGFR1+) were recruited. 8 patients (4/13 and 4/33 treated respectively at 20 and 15 mg; none in the FGFR1+ cohort) were withdrawn for toxicity including: G3 proteinuria (5), headache and vomiting (2), pancreatic enzymes increase (1), recovered in all cases. Hypertension G2-3, proteinuria G2, GI intolerance, asthenia and weight loss led to dose reduction in 20 patients; frequent TSH increase required supplementation. Tolerability was better in the FGFR1+ cohort, in line with a limited prior exposure to antiangiogenic treatments. Antitumor activity is shown in the table: Antiangiogenic Sensitive FGF-amplified (1) Evaluable PR SD PD Evaluable PR SD PD Breast cancer 1 1 9 4** 3 2 Other 23 3*** 13 7 2 1* 1 Total 24 3 14 7 11 4 4 3 (1) incl. the two BC patients with 11q amplification; * SD ≥ 24 weeks; ** 1 PET response (bone lesions); ***2 thyroid; 1 thymic carcinoma. 12 women with BC were recruited (9 HR + , 1 HER2 + /HR + , 2 TN); 8 were FGFR1 + , 2 more had 11q amplification (CGH). They were treated with a median of 5 prior chemotherapy lines; 9, 10 and 5 patients also received ≥ 1 endocrine, antiangiogenic and experimental therapies, respectively. There were 4 PRs sustained over 4-6 courses (3 FGFR1 and one FGF4 amplification), with 3 responders still on treatment. Conclusions E-3810 has shown significant activity in heavily pretreated BC, with durable responses in patients with altered FGF pathway. Further studies are planned in this population. Disclosure R. Cereda: Currently an employee and stock holder at EOS SpA. M.G. Camboni: Currently an employee and stock holder at EOS SpA. All other authors have declared no conflicts of interest.