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Table S1. Frequencies of gene locus amplifications across tumor types; Table S2. Effect of FGFR inhibitors on growth of RK3E expressing FGFR2 and FGFR3 fusion constructs and RT-4 bladder cancer cell line; Figure S1. Chemical structure of JNJ-42756493; Figure S2. Western Blot confirming the overexpression of HA-tagged FGFR2 fusion genes

Supplementary Figure S1. Mean concentration-time erdafitinib profiles after a single dose (cycle 1 day 1 [C1D1]) and at steady-state (cycle 2 day 1 [C2D1]) after daily dosing (Panel A) or intermittent dosing (Panel B). 9 mg QD Part 1 at Cycle 2 Day 1 (C2D1) was not reported as n=1.

Purpose:Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor.Patients and Methods:Patients age ≥18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating FGFR genomic alterations. In patients with such alterations, two selected doses/schedules identified during part 1 dose-escalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published (Tabernero JCO 2015;33:3401-8)] were tested.Results:The study included 187 patients. The most common treatment-related adverse events were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%), generally grade 1/2 severity. All cases of hyperphosphatemia were grade 1/2 except for 1 grade 3 event. Skin, nail, and eye changes were observed in 43%, 33%, and 28% of patients, respectively (mostly grade 1/2 and reversible after temporary dosing interruption). Urothelial carcinoma and cholangiocarcinoma were most responsive to erdafitinib, with objective response rates (ORR) of 46.2% (12/26) and 27.3% (3/11), respectively, in response-evaluable patients with FGFR mutations or fusions. All patients with urothelial carcinoma and cholangiocarcinoma who responded to erdafitinib carried FGFR mutations or fusions. Median response duration was 5.6 months for urothelial carcinoma and 11.4 months for cholangiocarcinoma. ORRs in other tumor types were Conclusions:Erdafitinib shows tolerability and preliminary clinical activity in advanced solid tumors with genomic changes in the FGFR pathway, at two different dosing schedules and with particularly encouraging responses in urothelial carcinoma and cholangiocarcinoma.

Purpose: Tumor-derived circulating cell–free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome.Experimental Design: Patients with BRAF V600 mutation–positive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a PCR-based assay. BRAF mutation status in cfDNA from patient plasma collected at baseline, 732 of 836 (88%) enrolled patients in total, was determined.Results: BRAF mutations were detectable in cfDNA in 76% and 81% of patients with BRAF V600E/V600K–positive tumors, respectively. Patients negative for BRAF mutations in cfDNA had longer progression-free survival (PFS) and overall survival in each of the four studies, compared with patients with detectable cfDNA BRAF mutations. The presence of BRAF-mutant cfDNA was an independent prognostic factor for PFS after multivariate adjustment for baseline factors in three of four studies. Patients negative for BRAF mutation–positive cfDNA in plasma had higher response rates to dabrafenib and trametinib.Conclusions: BRAF mutations in cfDNA are detectable in >75% of late-stage melanoma patients with BRAF mutation–positive tumors. The lack of circulating, BRAF mutation–positive cfDNA is clinically significant for metastatic melanoma patients, and may be a prognostic marker for better disease outcome. Clin Cancer Res; 22(3); 567–74. ©2015 AACR.

Supplementary Figure S1. Distribution of BRAF V600E cfDNA mutation fraction across study samples; Supplementary Figure S2. cfDNA-ND patients exhibited higher response rates to dabrafenib and trametinib compared with cfDNA V600E/K patients; Supplementary Table S1. Baseline clinical characteristics; Supplementary Table S2. Correlation between cfDNA mutation fraction, baseline tumor burden (SLD), and LDH; Supplementary Table S3. Association between cfDNA mutation fraction, with baseline covariates; Supplementary Table S4. Association between cfDNA mutation status, with baseline covariates; Supplementary Table S5. cfDNA-ND patients exhibited higher response rates to dabrafenib and trametinib compared with cfDNA V600E/K patients; Supplementary Table S6. cfDNA mutation fraction independently predicts PFS and OS in patients with baseline tumor V600E mutations

Supplementary Figure S1. Distribution of BRAF V600E cfDNA mutation fraction across study samples; Supplementary Figure S2. cfDNA-ND patients exhibited higher response rates to dabrafenib and trametinib compared with cfDNA V600E/K patients; Supplementary Table S1. Baseline clinical characteristics; Supplementary Table S2. Correlation between cfDNA mutation fraction, baseline tumor burden (SLD), and LDH; Supplementary Table S3. Association between cfDNA mutation fraction, with baseline covariates; Supplementary Table S4. Association between cfDNA mutation status, with baseline covariates; Supplementary Table S5. cfDNA-ND patients exhibited higher response rates to dabrafenib and trametinib compared with cfDNA V600E/K patients; Supplementary Table S6. cfDNA mutation fraction independently predicts PFS and OS in patients with baseline tumor V600E mutations

Supplementary Table S1. Arithmetic Mean {plus minus} SD Plasma Erdafitinib Pharmacokinetic Parameters after the First Erdafitinib Administration (Cycle 1 Day 1) or at Steady-State (Cycle 2 Day 1) in Patients Assigned to the Continuous Daily Dosing or the Intermittent (7 Days on/7 Days off) Dosing Regimen (Part 1 and Part 2 of the Study)

Clinical outcomes of anti-programmed death‑(ligand) 1 (anti-PD-[L]1) therapy in patients with locally advanced or metastatic urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (To analyze the outcomes of patients with mUC and anyIn this noninterventional, retrospective, multicenter study, clinical practice data were collected fromInvestigator‑determined overall response rate (ORR), disease control rate (DCR), and overall survival (OS) were assessed in multivariate and unadjusted analyses.Ninety-four patients (66% men; median age, 63 yr) with mUC and knownSome evidence of lower response rates and shortened OS following anti-PD-(L)1 therapy was observed inPatients with metastatic urothelial carcinoma and prespecified fibroblast growth factor receptor alterations (

TPS10058 Background: FGFR gene alterations have been observed in pediatric patients with cancers and represent potentially targetable genomic variants. Gliomas (high- and low-grade) and soft tissue sarcomas are among the pediatric solid tumors that may harbor FGFR alterations. Erdafitinib is a selective pan-FGFR inhibitor approved in patients with locally advanced or metastatic urothelial carcinoma with susceptible FGFR2/3 alterations. RAGNAR (NCT04083976) is an ongoing single-arm, open-label, phase 2 histology-agnostic study investigating the efficacy and safety of erdafitinib in patients with advanced solid tumors exhibiting FGFR alterations after failure of standard systemic therapies. Here we describe the pediatric study cohort. Methods: The pediatric cohort (n = 26, planned) includes patients (≥ 6- < 18 y) with advanced solid tumors (measurable disease per RECIST v.1.1 or RANO [brain tumors]) with FGFR mutations, gene fusions, or internal tandem duplication (patients with FGFR amplification are not eligible) identified via local test reports or central molecular testing. Eligible patients will have received ≥ 1 lines of prior systemic therapy, have exhausted or be unable to tolerate standard-of-care therapies, and have documented disease progression and measurable disease. In addition, up to 6 patients in this cohort will be allowed to be treatment naive. Children and adolescents will be treated with oral erdafitinib, allowing pharmacodynamically guided uptitration based on serum phosphate levels to maximize efficacy. Treatment will continue until progressive disease. The primary end point is overall response rate (ORR) assessed by an independent review committee. Secondary efficacy end points include ORR assessed by the investigator, duration of response, disease control rate, clinical benefit rate, progression-free survival, and overall survival. Other secondary end points are pharmacokinetic exposure parameters, incidence/severity of adverse events, and change from baseline in patient-reported health status. End-of-treatment visit will occur 30 days after the last dose of erdafitinib. A follow-up phase will continue until death, withdrawal of consent, loss to follow-up, or end of study. As of January 2022, 3 patients have been enrolled. Clinical trial information: NCT04083976.

Background 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. Methods 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. Findings 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. Interpretation 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.

Limited data are available on the prognostic and predictive value of fibroblast growth factor receptor alterations (FGFRa) relative to clinical outcomes in patients with non-muscle-invasive bladder cancer (NMIBC).To determine whether FGFRa may be clinically useful in stratifying for treatment response in a real-world cohort of patients with pT1 NMIBC treated and untreated with bacillus Calmette-Guérin (BCG) instillation therapy.A pooled dataset of matched clinical and genomic data (1992-2015) for pT1 NMIBC patients was assessed by the Bladder Cancer Research Initiative for Drug Targets in Germany consortium.Key efficacy outcomes were recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS), which were estimated by Kaplan-Meier analysis, with hazard ratios calculated using a multivariate Cox proportional-hazard model.In this retrospective study of 263 patients with high-grade NMIBC, at a median follow-up of 63 mo, 32% showed recurrence and 15% progressed to muscle-invasive bladder cancer. FGFRa were found in 43% of patients, including 39% mutations and 5.7% fusions. FGFRa were associated with lower rates of concomitant carcinoma in situ. Among patients with or without FGFRa, there was no significant difference in PFS, RFS, and DSS in those who were BCG treated or BCG naive, or in the overall population. Limitations include the retrospective design from a single-center setting.In patients with high-risk NMIBC, FGFRa were frequently observed. Patients with FGFRa who often exhibit recurrence/relapse after BCG treatment have a high unmet need.Our retrospective study suggests that fibroblast growth factor receptor alterations (FGFRa) occur frequently in non-muscle-invasive bladder cancer (NMIBC). Outcomes were similar with or without FGFRa in patients with NMIBC, both overall and for standard bacillus Calmette-Guérin (BCG) treatment.

Purpose:Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor.Patients and Methods:Patients age ≥18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating FGFR genomic alterations. In patients with such alterations, two selected doses/schedules identified during part 1 dose-escalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published (Tabernero JCO 2015;33:3401-8)] were tested.Results:The study included 187 patients. The most common treatment-related adverse events were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%), generally grade 1/2 severity. All cases of hyperphosphatemia were grade 1/2 except for 1 grade 3 event. Skin, nail, and eye changes were observed in 43%, 33%, and 28% of patients, respectively (mostly grade 1/2 and reversible after temporary dosing interruption). Urothelial carcinoma and cholangiocarcinoma were most responsive to erdafitinib, with objective response rates (ORR) of 46.2% (12/26) and 27.3% (3/11), respectively, in response-evaluable patients with FGFR mutations or fusions. All patients with urothelial carcinoma and cholangiocarcinoma who responded to erdafitinib carried FGFR mutations or fusions. Median response duration was 5.6 months for urothelial carcinoma and 11.4 months for cholangiocarcinoma. ORRs in other tumor types were Conclusions:Erdafitinib shows tolerability and preliminary clinical activity in advanced solid tumors with genomic changes in the FGFR pathway, at two different dosing schedules and with particularly encouraging responses in urothelial carcinoma and cholangiocarcinoma.

Objective To examine the disease-specific survival(DSS) after checkpoint inhibitor(CPI) therapy based on FGFR alterations and FGFR mRNA expression levels in patients with metastatic urothelial cancer(mUCa) within a multi-center cohort. Methods Within a cohort of 72 patients with mUCa from five academic centers in Germany FGFR alterations, as well as FGFR1-4 mRNA expression levels in tumor samples from the primary tumor or metastatic sites. Spearman rank correlations, logistic regression, as well as Kaplan-Meier survival analyses and univariate Cox proportional hazards regression models were employed to examine the impact of different FGFR patterns on the DSS after CPI treatment. Results FGFR3 mutations or gene fusions (gene alterations) were detected in 16.9% of all samples. Patients with or without FGFR3 gene alterations did not show different oncological outcomes undergoing CPI treatment. Low expression of FGFR2 mRNA alone, as well as the combination of either low FGFR2mRNA expression and FGFR3 gene alteration or high FGFR3mRNA expression (P = 0.027), identified a subgroup of patients with unfavorable outcomes, comprising 40% of the total cohort. This trend was also observed in univariate Cox proportional hazards regression analysis(FGFR3 gene alteration: Hazard ratio(HR) 5.33, 95%Confidence interval(CI)1.76-15.0, P = 0.004; FGFR3mRNA expression:HR 3.04, 95%CI 1.40-7.13, P = 0.005). Conclusion Assessment of FGFR mRNA expression identified a high-risk subgroup of patients with mUCa. These patients showing overexpression of FGFR3 mRNA were found to have unfavorable DSS after CPI treatment. Using this approach may be suitable for identifying a patient population with poor response to CPI treatment, which may benefit from early FGFR inhibition.

4081 Background: FGFR alts (mutations and fusions) have been reported in multiple advanced solid tumors at varying frequencies. These alts may function as oncogenic drivers of disease independent of the underlying tumor type. RAGNAR is an ongoing phase 2, histology-agnostic trial investigating the efficacy and safety of erdafitinib, a selective pan-FGFRi, in patients (pts) with advanced solid tumors and FGFR alts. Little is known about the incidence, diversity or predominant FGFR alts across solid tumors in the clinical setting. Here, we provide an update on molecular screening and enrollment in the primary analysis population. Methods: Pts with advanced solid tumors were molecularly screened for eligible FGFR alts via central next generation sequencing (NGS) or review of local NGS reports. Underlying tumor type, FGFR alts, demographics and key disease characteristics were collected at baseline. Results: From Nov 2019 to Jan 2021, 5758 pts were molecularly screened (central or local) in 15 countries. 191 pts (3.3%) fulfilled primary analysis molecular eligibility criteria; 110 pts were enrolled. Among pts enrolled, 14 (12.7%) had central screening and 96 (87.3%) had local NGS reports. Eligible FGFR alts were identified in 19 tumor types, including rare cancers and ones (eg, pancreatic) with a very low prevalence of FGFR alts in genomic databases (Table). Median age was 57 y, and 19 pts (17.3%) were < 40 y. Gender distribution was even. Conclusions: Findings from molecular screening in the RAGNAR study indicate a wide range of FGFR-altered tumor types, including a notable number of cancers where eligible FGFR alts were considered exceedingly rare (eg, pancreatic). These results demonstrate the feasibility of conducting clinical trials on pts with rare genetic alts by adopting a histology-agnostic design and using both central testing and local NGS reports for molecular screening. This approach also helps investigate rare tumors, where histology-specific trials are challenging. Efficacy and safety results from the RAGNAR study will help define the benefit of erdafitinib in FGFR-altered advanced solid tumors. Clinical trial information: NCT04083976. [Table: see text]

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 prespecifiedA 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

Einleitung: Im Zeitalter der individualisierten onkologischen Therapie wurden FGFR3 Mutationen, FGFR2 und FGFR3 Genefusionen und darüber hinaus FGFR-mRNA-Expression als potentielle onkologische Targetstrukturen und ihre Assoziation zu anti-PD-1 und anti-PD-L1 (IO) Therapieergebnissen in einer Multicenter-Patientenkohorte[zum vollständigen Text gelangen Sie über die oben angegebene URL], 66. Kongress der Nordrhein-Westfälischen Gesellschaft für Urologie