erdafitinib and Neoplasm-Metastasis

Metastatic urothelial carcinoma (mUC) remains a fatal malignancy, despite the recent addition of immune check point inhibitors (ICIs), an FGFR inhibitor and an antibody-drug conjugate (ADC) to the therapeutic armamentarium. The survival rates are particularly dismal after first-line treatment failure, entailing an urgent need for more effective therapies. Advances in understanding biomarkers and identifying targetable molecules have broadened the pathways under investigation in mUC.. This review summarizes mUC salvage therapy options, including chemotherapy, ICI, and novel promising agents, including targeted therapies, ADCs, cytotoxic agents and vaccines. For the literature review, a PubMed search and relevant data presented at international conferences were used.. The approval of ICIs, FGFR inhibitor erdafitinib and ADC enfortumab vedotin in the salvage setting has transformed the mUC landscape. Yet there are additional promising agents currently under study. Toxicities are observed with ADCs and FGFR inhibitors, but appear manageable in most patients. The molecular heterogeneity and complex tumor biology are challenging barriers for progress in the therapy of mUC. Advances in molecular profiling, defining validated predictive markers, rational combinations of agents and therapeutically actionable targets will help develop personalized compounds with higher efficacy and less toxicity with hopes to improve outcomes for mUC.

Topics: Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoma, Transitional Cell; Humans; Immune Checkpoint Inhibitors; Molecular Targeted Therapy; Neoplasm Metastasis; Pyrazoles; Quinoxalines; Salvage Therapy; Survival Rate; Urinary Bladder Neoplasms

Topics: Animals; Carcinoma, Transitional Cell; Humans; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3; Urinary Bladder Neoplasms

Therapeutic options for metastatic bladder cancer (BC) have seen minimal evolution over the past 30 years, with platinum-based chemotherapy remaining the mainstay of standard of care for metastatic BC. Recently, five immune checkpoint inhibitors (ICIs) have been approved by the FDA as second-line therapy, and two ICIs are approved as first-line treatment in selected patients. Molecular alterations of muscle-invasive bladder cancer (MIBC) have been reported by The Cancer Genome Atlas. About 15% of patients with MIBC have molecular alterations in the fibroblast growth factor (FGF) axis. Several ongoing trials are testing novel FGF receptor (FGFR) inhibitors in patients with FGFR genomic aberrations. Recently, erdafitinib, a pan-FGFR inhibitor, was approved by the FDA in patients with metastatic BC who have progressed on platinum-based chemotherapy. We reviewed the literature over the last decade and provide a summary of current knowledge of FGF signaling, and the prognosis associated with FGFR mutations in BC. We cover the role of FGFR inhibition with non-selective and selective tyrosine kinase inhibitors as well as novel agents in metastatic BC. Efficacy and safety data including insights from mechanism-based toxicity are reported for selected populations of metastatic BC with FGFR aberrations. Current strategies to managing resistance to anti-FGFR agents is addressed, and the importance of developing reliable biomarkers as the therapeutic landscape moves towards an individualized therapeutic approach.

Topics: Antineoplastic Agents; Humans; Neoplasm Metastasis; Pyrazoles; Quinoxalines; Randomized Controlled Trials as Topic; Receptors, Fibroblast Growth Factor; Urinary Bladder Neoplasms

Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study.. The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0-2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597.. Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7-26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30-49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3-4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3-4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths.. With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations.. Janssen Research & Development.

Topics: Aged; Carcinoma, Transitional Cell; Central Serous Chorioretinopathy; ErbB Receptors; Follow-Up Studies; Humans; Middle Aged; Mutation; Neoplasm Metastasis; Pyrazoles; Quinoxalines; Urinary Bladder Neoplasms

Alterations in the gene encoding fibroblast growth factor receptor (. In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified. A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths.. The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Humans; Kaplan-Meier Estimate; Middle Aged; Mutation; Neoplasm Metastasis; Progression-Free Survival; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Quinoxalines; Receptors, Fibroblast Growth Factor; Treatment Outcome; Urologic Neoplasms; Urothelium