erdafitinib and palbociclib

Bladder cancer is one of the leading causes of death in Europe and the United States. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients with median overall survival of 15months and a 5-year survival rate of ⩽10%. Furthermore, unfit patients for cisplatin have no standard of care for first line therapy in advance disease Most second-line chemotherapeutic agents tested have been disappointing. Newer targeted drugs and immunotherapies are being studied in the metastatic setting, their usefulness in the neoadjuvant and adjuvant settings is also an intriguing area of ongoing research. Thus, new treatment strategies are clearly needed. The comprehensive evaluation of multiple molecular pathways characterized by The Cancer Genome Atlas project has shed light on potential therapeutic targets for bladder urothelial carcinomas. We have focused especially on emerging therapies in locally advanced and metastatic urothelial carcinoma with an emphasis on immune checkpoints inhibitors and FGFR targeted therapies, which have shown great promise in early clinical studies.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Transitional Cell; Humans; Ipilimumab; Nivolumab; Phenylurea Compounds; Piperazines; Pyrazoles; Pyridines; Pyrimidines; Quinolines; Quinoxalines; Receptors, Fibroblast Growth Factor; Urinary Bladder Neoplasms

Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.

Topics: Aminopyridines; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Circulating Tumor DNA; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Resistance, Neoplasm; Female; Fulvestrant; High-Throughput Nucleotide Sequencing; Humans; MCF-7 Cells; Mice; Mutation; Naphthalenes; Piperazines; Progression-Free Survival; Proportional Hazards Models; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridines; Quinolines; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 2; Receptors, Estrogen; Signal Transduction; Xenograft Model Antitumor Assays