FGFR Inhibitor in FGFR Dysregulated Cancer

Downstream signaling of fibroblast growth factor receptors 1-4 (FGFR 1-4) regulates cell proliferation, migration, differentiation and survival in healthy cells. Genetic alterations (amplifications, point-mutations and translocations) in FGFR1-4 genes cause altered signaling and oncogenic transformation. FGFR-alterations with sensitivity to kinase inhibition have been identified in a variety of tumors such as breast-, bladder- and endometrial-cancer, squamous cell lung and head and neck cancer, cholangiocarcinoma and glioblastoma. First-in-man/phase-I clinical trials with erdafitinib and BGJ398 - both selective FGFR inhibitors - enrolled patients with any genetic alterations in FGFR. The trials showed clinical responses with differences according to the type of FGFR alterations and histological subtypes. In the BGJ398 trial, the partial response rate was 11% (4/36) in patients with FGFR1 amplified squamous NSCLC (sqNSCLC) and 38% (3/8) in patients with FGFR3-mutant bladder cancer. No PR was observed in patients with FGFR1/2 amplified (n=25) and FGFR3 mutant (n=1) breast cancer. All patients with FGFR2-translocated (n=2) and FGFR2-mutated cholangiocarcinoma (n=1) showed reduced tumor burden of 20% and 10%, respectively. In the erdafitinib trial, 5 partial responses were seen in FGFR translocated tumors: 3/8 (37.5%) patients with urothelial carcinoma, 1/3 (33%) patients with glioblastoma and 1 patient with endometrial cancer reached PR. Summing up the results of the phase-I trials, the inhibition of FGFR downstream pathways in FGFR translocated and mutated solid tumors exerted clinical activity. Thus, focusing treatment with FGFR inhibitors on FGFR mutated and translocated solid tumors may increase response rates, progression free and overall survival in these tumors with otherwise adverse prognosis. In NSCLC patients without druggable alterations in genes as EGFR, ALK or ROS1 and without high PD-L1 (Programmed cell death 1 ligand 1) expression, prognosis remains adverse with a median survival time of about 18 months. Particularly in sqNSCLC, only few driver mutations have been identified yet. Of these, solely mutations of the KRAS gene (although observed at low frequency in sqNSCLC) were explored in large clinical studies targeting KRAS downstream signaling with no survival benefit comparing to chemotherapy. Immunotherapy with PD-1 antibodies such as nivolumab and pembrolizumab showed benefit in patients with high PD-L1 expression mainly. The frequency of somatic FGFR1-3 mutations in lung cancer is about 4% (Helsten et al., 2016). Translocations occur with a similar frequency of about 4% in lung cancer. Multiple of these FGFR alterations are shown to have oncogenic potential as demonstrated in multiple in vitro, in vivo and first-in-man studies. Preclinical models in NSCLC cell lines and xenografts showed oncogenic activity of FGFR2/3 mutations with consecutive sensitivity to FGFR inhibitors. Similarly, FGFR3-TACC translocation exerted kinase activation in sqNSCLC cell lines and other tumor types. Furthermore, patient derived FGFR3-fusion lung xenograft model showed responses to FGFR targeted treatment. In summary, on the basis of genetically and phenotypically validated cell-line panels, in vivo and particularly on the basis of clinical data, there is strong evidence for a clinical benefit from FGFR inhibition for patients with FGFR altered NSCLC. The primary objective of the trial is to analyze the efficacy of erdafitinib in NSCLC patients with FGFR genetic alterations. NSCLC patient number will be based on a statistical hypothesis aiming at increasing the response rate comparing to chemotherapy/immunotherapy after standard treatment.