erdafitinib and Carcinoma--Transitional-Cell

FGFR inhibitors represent a new and promising therapeutic approach to urothelial cancer (UC). Erdafitinib (Balversa

Topics: Carcinoma, Transitional Cell; Humans; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Urinary Bladder Neoplasms

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

Comprehensive genomic profiling has an emerging role in cancer therapeutics. As treatment options remain needed for advanced cancers, patients are relying increasingly more on tumor genomic alterations as possible targets for cancer treatment. Frequent tumor fibroblast growth factor receptor (FGFR) alterations are seen in many cancers, and include genetic amplifications, mutations, rearrangements and fusions. FGFR inhibitors target these receptor alterations and show promise as a drug class. Currently 2 medications are currently FDA approved: erdafitinib and pemigatinib. Through the FDA accelerated approval process, erdafitinib is indicated to treat metastatic urothelial carcinoma with FGFR2 and FGFR3 alterations, whereas pemigatinib is indicated to treat unresectable cholangiocarcinoma with FGFR2 alterations. Despite growing knowledge about such advanced cancers, treatment is usually palliative. With multiple FGFR inhibitors in the pipeline, further FDA approvals are possible, and it is likely their role in therapy will extend to other cancer types. This review outlines erdafitinib, pemigatinib, their role in cancer, as well as outlining the possible future use of other FGFR inhibitors in urothelial carcinoma, cholangiocarcinoma, and other malignancies.

Topics: Bile Duct Neoplasms; Carcinoma, Transitional Cell; Cholangiocarcinoma; Clinical Trials as Topic; Humans; Morpholines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrroles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3

Urothelial carcinoma has become the ninth most common malignancy in the world. Since the 1980s, diverse studies and treatment methods came out with their possible effects along with certain limitations. Initially, platinum chemotherapy was considered as first-line treatment of the disease. Although it was proved to be effective initially, the most number of cases reported the reoccurrence of the disease. Furthermore, aberrant ligand- dependent and constitutive ligand-independent fibroblast growth factor receptor (FGFR) signaling has been reported in a large number of solid tumors, including urothelial carcinoma that became the basis for FGFR inhibition for the treatment of the disease. Erdafitinib is a pan-FGFR inhibitor that was recently approved in the USA for the treatment of locally advanced or metastatic FGFR3 or FGFR2 urothelial carcinoma. The drug is also being investigated as a treatment for other cancers, including cholangiocarcinoma, liver cancer, non-small cell lung cancer, prostate cancer, lymphoma cancer and oesophageal cancer. This article summarizes the various treatments that evolved for bladder cancer till now, a brief description of the biology of FGFR inhibition, clinical pharmacology, and various clinical trials of erdafitinib.

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Pyrazoles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 3; Urinary Bladder Neoplasms

Intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG immunotherapy prevents disease recurrence and progression to muscle-invasive disease following TURBT. Although most patients initially respond well to intravesical BCG, considerable concern has been raised for patients with BCG failure who are refractory or recur in 6 months after their last BCG, which implies 'BCG-unresponsiveness'. Based on current clinical guidelines, early radical cystectomy (RC) is recommended to treat BCG-unresponsive NMIBC. However, due to the high risk of morbidity and mortality of RC and patients' desire to preserve their own bladder, there is a critical unmet need for alternative conservative treatments as bladder-sparing strategies in BCG-unresponsive patients. Trials for effective bladder-sparing treatments are ongoing, and several novel agents have been recently tested in the NMIBC setting. The goal of this review is to introduce and summarize recently reported novel and emerging drugs and ongoing clinical trials for BCG-unresponsive NMIBC.

Topics: Adjuvants, Immunologic; Administration, Intravesical; Antineoplastic Agents; BCG Vaccine; Carcinoma, Transitional Cell; Clinical Trials as Topic; Genes, Viral; Genetic Therapy; Humans; Hyperthermia; Immune Checkpoint Inhibitors; Immunoconjugates; Organ Sparing Treatments; Photochemotherapy; Pyrazoles; Quinoxalines; Retreatment; Treatment Failure; 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

To provide an overview of fibroblast growth factor receptor (FGFR) gene alterations and the pharmacology, clinical effectiveness, dosage and administration, cost, and place in therapy of erdafitinib in bladder cancer.. Erdafitinib (Balversa, Janssen Pharmaceuticals) is a novel pan-FGFR inhibitor recently approved for the treatment of patients with advanced urothelial cancer with specific FGFR genetic alterations who have received at least one prior platinum-containing regimen. Erdafitinib binding to the FGFR2 and FGFR3 receptors inhibits FGF activity, resulting in cell death. Erdafitinib is available in tablet form, and the current recommended daily dosing is 8 mg, with dose escalation to 9 mg after 14 to 21 days of therapy if tolerated. A phase 2 clinical trial demonstrated that patients who received erdafitinib experienced on average 5.5 months of progression-free survival (95% confidence interval [CI], 4.2-6.0 months). In addition, 40% (95% CI, 31-50%) of patients responded to erdafitinib therapy. Patients receiving erdafitinib therapy should be monitored specifically for elevations in serum phosphate levels and changes in vision. Other adverse effects include anemia, thrombocytopenia, and electrolyte abnormalities.. Erdafitinib is the first small-molecule FGFR inhibitor approved for use in advanced bladder cancer.

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Humans; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3; Urinary Bladder Neoplasms

Topics: Carcinoma, Transitional Cell; Humans; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Treatment Outcome; Urologic Neoplasms; Urothelium

The recent approval of erdafitinib and the emergence of other potent and selective fibroblast growth factor receptor (FGFR) inhibitors (FGFRi's) are shifting the treatment paradigm for patients with advanced urothelial carcinoma (UC) harboring FGFR3 alterations. Whether such therapies can, and should, be combined with immune checkpoint inhibitors (ICI's) is an area of major research interest. Areas covered: Herein, we review the FGFR signaling pathway and impact of altered FGFR signaling on UC tumorigenesis, the clinical development of FGFRi's, the rationale for FGFRi-ICI combinations, current trials, and future directions. Expert opinion: FGFR3 altered UCs are not less responsive to ICI's compared with FGFR3 wild-type (WT) tumors. However, FGFR3 altered tumors may exhibit distinct immunobiology compared with WT tumors that could potentially be exploited therapeutically. Given these considerations along with the clinical non-cross resistance of these therapeutic classes, clinical investigation of regimens combining FGFR3i and ICI is warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Drug Development; Humans; Immune Checkpoint Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction; Urinary Bladder Neoplasms

Fibroblast growth factor receptor (FGFR) signalling, especially induced by FGFR3, is a crucial factor in the pathogenesis of urothelial carcinoma and was therefore extensively studied over the last decades. In this review, we summarize the most relevant findings of the past two years.. Recent studies support the concept that FGFR3 mediates a pathway of urothelial carcinogenesis associated with low malignant potential. FGFR3 may represent a highly accurate biomarker for diagnosis and prediction of recurrence, progression or therapy response. The pan FGFR-inhibitor erdafitinib was recently approved for urothelial carcinoma, whereas several other FGFR-targeted drugs are currently undergoing clinical trials.. Numerous recent studies focus on the role of FGFR3 in different urothelial carcinoma subtypes and its potential clinical application as noninvasive biomarker, as well as therapeutic target.

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Humans; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 3; Receptors, Fibroblast Growth Factor; Treatment Outcome; Urinary Bladder Neoplasms; Urologic Neoplasms

Erdafitinib is the first orally administered pan-fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the Food and Drug Administration (FDA).. Specifically binding to FGFR family (FGFR-1 to FGFR-4), erdafitinib leads to reduced cell signaling and cellular apoptosis. Coupled with the ability to bind to vascular endothelial growth factor 2 (VEGFR-2), KIT, Fms-related tyrosine kinase 4 (FLT4), platelet-derived growth factor receptor α and β (PDGFR-α and PDGFR-β), RET and colony-stimulating factor 1 receptor (CSF-1 R), erdafitinib has further reported antitumor features causing cell killing.. In this review, we provide a comprehensive overview of erdafitinib chemical structure, pharmacologic properties, and current knowledge of clinical efficacy in the treatment of locally advanced or metastatic urothelial carcinoma. This treatment, recently approved in the U.S., is available for adult patients harboring FGFR2/FGFR3 genetic alterations who progressed within 12 months of an adjuvant or neoadjuvant chemotherapy regimen including platinum or progressed during or after prior a chemotherapy regimen including platinum.

Topics: Administration, Oral; Adult; Antineoplastic Agents; Apoptosis; Carcinoma, Transitional Cell; Disease Progression; Humans; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Urinary Bladder Neoplasms

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

FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours.. The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976.. Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6-23·9), an objective response was observed in 64 (30% [95% CI 24-36]) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 [12%]), palmar-plantar erythrodysaesthesia syndrome (12 [6%]), and hyperphosphataemia (11 [5%]). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths.. RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours.. Janssen Research & Development.

Topics: Adolescent; Carcinoma, Transitional Cell; Disease Progression; Female; Humans; Male; Protein Kinase Inhibitors; Pyrazoles; Urinary Bladder Neoplasms

Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible. We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible. A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients).. Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Docetaxel; Humans; Immune Checkpoint Inhibitors; Receptors, Fibroblast Growth Factor; Urinary Bladder Neoplasms

Exposure-response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib.. Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety endpoints were adverse events typical for FGFR inhibitors.. Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 [95% CI 0.46-0.72] per mg/dL of PO4; p = 0.01), PFS (hazard ratio 0.80 [0.67-0.94] per mg/dL of PO4; p = 0.01), and ORR (odds ratio 1.38 [1.02-1.86] per mg/dL of PO4; p = 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4.. The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib's therapeutic benefit/risk ratio.. NCT02365597.

Topics: Aged; Carcinoma, Transitional Cell; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Receptors, Fibroblast Growth Factor; Survival Rate; 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

Topics: Carcinoma, Transitional Cell; Drug-Related Side Effects and Adverse Reactions; Humans; Mutation; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3; Urologic Neoplasms; Urothelium

Erdafitinib is a novel fibroblast growth factor receptor (FGFR) inhibitor that has shown great therapeutic promise for solid tumor patients with FGFR3 alterations, especially in urothelial carcinoma. However, the mechanisms of resistance to FGFR inhibitors remain poorly understood. In this study, we found Erdafitinib could kill cells by inducing incomplete autophagy and increasing intracellular reactive oxygen species levels. We have established an Erdafitinib-resistant cell line, RT-112-RS. whole transcriptome RNA sequencing (RNA-Seq) and Cytospace analysis performed on Erdafitinib-resistant RT-112-RS cells and parental RT-112 cells introduced P4HA2 as a linchpin to Erdafitinib resistance. The gain and loss of function study provided evidence for P4HA2 conferring such resistance in RT-112 cells. Furthermore, P4HA2 could stabilize the HIF-1α protein which then activated downstream target genes to reduce reactive oxygen species levels in bladder cancer. In turn, HIF-1α could directly bind to P4HA2 promoter, indicating a positive loop between P4HA2 and HIF-1α in bladder cancer. These results suggest a substantial role of P4HA2 in mediating acquired resistance to Erdafitinib and provide a potential target for bladder cancer treatment.

Topics: Carcinoma, Transitional Cell; Cell Line, Tumor; Humans; Pyrazoles; Reactive Oxygen Species; Receptor, Fibroblast Growth Factor, Type 3; Urinary Bladder Neoplasms

Topics: Antibodies, Monoclonal; Carcinoma, Transitional Cell; Humans; Urinary Bladder Neoplasms; Urologic Neoplasms

A Hispanic man, aged 42 years, was diagnosed with stage IV metastatic urothelial bladder cancer (MUBC) with nonregional lymphadenopathies and lung, bone, and skin involvement. He received first-line treatment with gemcitabine and cisplatin for 6 cycles, achieving a partial response (PR). Next, he received immunotherapy maintenance with avelumab for 4 months until disease progression. A next-generation sequencing test of paraffin-embedded tumor tissue identified a fibroblast growth factor receptor 3 (FGFR3) S249C missense mutation.

Topics: Carcinoma, Transitional Cell; Cisplatin; Humans; Male; Pyrazoles; Urinary Bladder Neoplasms

Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer. We characterized the genetic landscape of FGFR-altered urothelial carcinoma and real-world clinical outcomes with erdafitinib, including on-treatment genomic evolution.. Prospectively collected clinical data were integrated with institutional genomic data to define the landscape of FGFR2/3-altered urothelial carcinoma. To identify mechanisms of erdafitinib resistance, a subset of patients underwent prospective cell-free (cf) DNA assessment.. FGFR3 alterations predictive of erdafitinib sensitivity were identified in 39% (199/504) of patients with non-muscle invasive, 14% (75/526) with muscle-invasive, 43% (81/187) with localized upper tract, and 26% (59/228) with metastatic specimens. One patient had a potentially sensitizing FGFR2 fusion. Among 27 FGFR3-altered cases with a primary tumor and metachronous metastasis, 7 paired specimens (26%) displayed discordant FGFR3 status. Erdafitinib achieved a response rate of 40% but median progression-free and overall survival of only 2.8 and 6.6 months, respectively (n = 32). Dose reductions (38%, 12/32) and interruptions (50%, 16/32) were common. Putative resistance mutations detected in cfDNA involved TP53 (n = 5), AKT1 (n = 1), and second-site FGFR3 mutations (n = 2).. FGFR3 mutations are common in urothelial carcinoma, whereas FGFR2 alterations are rare. Discordance of FGFR3 mutational status between primary and metastatic tumors occurs frequently and raises concern over sequencing archival primary tumors to guide patient selection for erdafitinib therapy. Erdafitinib responses were typically brief and dosing was limited by toxicity. FGFR3, AKT1, and TP53 mutations detected in cfDNA represent putative mechanisms of acquired erdafitinib resistance.

Topics: Carcinoma, Transitional Cell; Cell-Free Nucleic Acids; Genomics; Humans; Receptor, Fibroblast Growth Factor, Type 3; Treatment Outcome; Urinary Bladder Neoplasms

Erdafitinib is the first fibroblast growth factor receptor inhibitor approved by the U.S. Food and Drug Administration in April 2019 for the treatment of locally advanced and unresectable or metastatic urothelial carcinoma. Central serous chorioretinopathy is a common ocular adverse effect requiring frequent monitoring with ophthalmic examination.. This study aimed to increase awareness of erdafitinib-induced central serous chorioretinopathy, highlight erdafitinib dose management guidelines, and emphasize the importance of collaborating with oncologists to prevent adverse visual consequences.. An 80-year-old patient with an advanced urothelial cancer with fibroblast growth factor receptor mutations developed central serous chorioretinopathy when he was treated with daily 8 mg of erdafitinib. The erdafitinib-induced central serous chorioretinopathy resolved completely after the discontinuation of erdafitinib. He was then treated with daily 6 mg of erdafitinib and again developed central serous chorioretinopathy, which resolved completely upon discontinuation of the medication. The patient then decided to stop treatment with erdafitinib.. Erdafitinib, a potent tyrosine kinase receptor inhibitor of fibroblast growth factor receptors 1 to 4, demonstrates antitumor activity in advanced urothelial carcinoma with fibroblast growth factor receptor mutations with a response rate of approximately 40%. However, central serous chorioretinopathy develops in 25% of patients treated with a daily 8-mg dose of erdafitinib. Although most mild to moderate erdafitinib-induced central serous chorioretinopathies resolve with dose interruption or reduction, occasionally discontinuation of the medication is necessary. Therefore, careful coordination with oncologists is important to assess the impact of erdafitinib on vision, quality of life, and survival prognosis.

Topics: Aged, 80 and over; Carcinoma, Transitional Cell; Central Serous Chorioretinopathy; Female; Humans; Male; Protein Kinase Inhibitors; Pyrazoles; Quality of Life; Quinoxalines; Receptors, Fibroblast Growth Factor; United States; Urinary Bladder Neoplasms

Topics: Carcinoma, Transitional Cell; Humans; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Urinary Bladder Neoplasms

Erdafitinib is the first treatment targeting susceptible fibroblast growth factor receptor (FGFR) genetic alterations in patients with locally advanced or metastatic urothelial carcinoma. A simple and precise spectrofluorimetric method was developed for its determination depending on fluorescence enhancement using Kolliphor RH 40 micellar medium at pH 10. The fluorescence intensity was measured at 495 nm after excitation at 410 nm. Different experimental parameters affecting the fluorescence intensity, including type of organized medium, diluting solvent, buffer type and pH were studied during optimization phase. Validation according to ICH Q2(R1) guidance was fully fulfilled. The method was linear over the range of 50 - 800 ng/mL. The lower limit of detection (LOD) and lower limit of quantitation (LOQ) were 14.36 and 43.50 ng/mL, respectively. The relative standard deviation values of intraday and interday precisions were less than 1.93 %. The proposed method was successfully applied to laboratory-prepared tablets. Furthermore, the high sensitivity of the method allowed its application on spiked human plasma samples with a high percent of recovery. The greenness of the method was investigated as an Eco-friendly alternative for erdafitinib determination with minimal organic solvent consumption.

Topics: Carcinoma, Transitional Cell; Humans; Micelles; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Solvents; Spectrometry, Fluorescence; Urinary Bladder Neoplasms

Metastatic urothelial cancer is a lethal disease. Although recent advances in immunotherapies and targeted therapy against fibroblast growth factor receptor (FGFR)2/3 mutation (erdafitinib) have improved patient survival, there is still a critical need for novel therapeutic strategies for patients who do not benefit from these treatments. Evasion of apoptosis through amplifying anti-apoptotic Bcl-2 family proteins (Mcl-1, Bcl-xL, Bcl-2) is one mechanism responsible for treatment resistance in urothelial cancers, suggesting that targeting anti-apoptotic proteins may be a possible therapeutic strategy for urothelial cancers. Here, we showed that erdafitinib increased Mcl-1 degradation mainly through previously unknown mechanisms and synergized with a BH3 mimetic drug targeting Bcl-xL/Bcl-2 to induce apoptosis in FGFR wild-type urothelial cancer cells. Strikingly, clinical sequencing data showed amplification of MCL1 or BCL2L1 (encoding Bcl-xL) in subsets of FGFR mutation-negative bladder cancer tissues. In conclusion, these findings suggest that exploiting apoptosis pathways may be a promising treatment strategy for patients with FGFR wild-type metastatic urothelial cancer with Mcl-1 or Bcl-xL overexpression.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Carcinoma, Transitional Cell; Cell Line, Tumor; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Quinoxalines; Receptors, Fibroblast Growth Factor

Erdafitinib is an approved tyrosine kinase inhibitor that inhibits fibroblast growth factor receptor. It has been described as one of the potent anti-tumor drugs especially for the treatment of urothelial carcinoma. In this study, we have investigated the binding dynamics of erdafitinib with human serum albumin (HSA) using multiple spectroscopic techniques. The outcome of the results suggests the occurrence of static quenching during the interaction of HSA with erdafitinib which leads to the formation of non-fluorescent HSA-erdafitinib ground state complex. Formation of HSA-erdafitinib complex was also confirmed from the findings of absorption spectral analysis. The changes in microenvironment around hydrophobic domains (especially tryptophan and tyrosine) were deciphered from fluorescence spectroscopy which was further confirmed by synchronous spectral analysis. In order to gain insight into the binding site of erdafitinib in HSA, molecular docking combined with competitive displacement assay was performed. The modified form of Stern Volmer equation was used to estimate various binding parameters including number of binding sites. The findings are indicative of a single binding site (

Topics: Binding Sites; Carcinoma, Transitional Cell; Circular Dichroism; Humans; Molecular Docking Simulation; Protein Binding; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Serum Albumin, Human; Spectrometry, Fluorescence; Thermodynamics; Tumor Microenvironment; Urinary Bladder Neoplasms

Topics: Carcinoma, Transitional Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Gene Fusion; Humans; Molecular Targeted Therapy; Morpholines; Mutation; Phenylurea Compounds; Piperazines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrroles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3; Thiophenes; Urinary Bladder Neoplasms

Topics: Carcinoma, Transitional Cell; Humans; Pyrazoles; Quinoxalines; Urologic Neoplasms

Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor received accelerated approval from the US Food and Drug Administration (FDA) for locally advanced or metastatic urothelial carcinoma (mUC) in adult patients with specific FGFR3/2 genetic alterations who progressed during or after ≥1 line of prior platinum-containing chemotherapy (PCC), including within 12 months of neoadjuvant or adjuvant PCC. Concordance between the clinical trial assay (CTA) used in a phase 2 study and QIAGEN's therascreen® FGFR kit (a two-step, multiplex, real-time, RT-PCR assay), the FDA-approved companion diagnostic (CDx) with erdafitinib, was evaluated in this bridging study. Study samples included 100 CTA-confirmed FGFR-positive samples from 100 erdafitinib-treated mUC patients, plus 200 CTA-confirmed FGFR-negative samples from the phase 2 study. The primary objective was met if the lower bound of 95% CI of objective response rate (ORR) in CDx-confirmed patients with FGFR alterations was >25%. Demographics were similar between the bridging study and CTA-screened patients. In total, 292 of 300 samples (97.3%) with valid CDx results showed high analytical concordance versus CTA (percent agreement [95% CI]: positive percent agreement, 87.2 [79.0; 92.5]; negative percent agreement, 97.0 [93.5; 98.6]; overall percent agreement, 93.8 [90.5; 96.1]). Investigator-assessed ORR in the 81 CDx-identified, erdafitinib-treated patients who tested positive for both assays was 45.7% (95% CI: 35.3%; 56.5%) versus 40.4% (95% CI: 30.7%; 50.1%) for CTA and met the criteria for primary objective. High ORR and clinical concordance to CTA suggest that QIAGEN's CDx can reliably select mUC patients who would potentially benefit from erdafitinib treatment.

Topics: Aged; Carcinoma, Transitional Cell; Female; Humans; Male; Middle Aged; Pyrazoles; Quinoxalines; Real-Time Polymerase Chain Reaction; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3; Urologic Neoplasms

Erdafitinib (Balversa™, Janssen Pharmaceutical Companies) is a pan-fibroblast growth factor receptor (FGFR) inhibitor that was recently approved in the USA for the treatment of locally advanced or metastatic FGFR3 or FGFR2 urothelial carcinoma. The drug is also being investigated as a treatment for other cancers including cholangiocarcinoma, liver cancer, non-small cell lung cancer, prostate cancer, lymphoma and oesophageal cancer. This article summarizes the milestones in the development of erdafitinib leading to this first approval for the treatment of urothelial carcinoma.

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Drug Approval; Humans; Protein Kinase Inhibitors; Pyrazoles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3; Treatment Outcome; United States; United States Food and Drug Administration; Urologic Neoplasms