Unresectable Urothelial Carcinoma Research Articles

Pemigatinib for metastatic or surgically unresectable urothelial carcinoma with FGF/FGFR genomic alterations: final results from FIGHT-201

Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714). Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 260 patients were enrolled and treated (A-CD, n= 101; A-ID, n= 103; B, n= 44; unconfirmed FGF/FGFR status, n= 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR [95% confidence interval (CI)] in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n= 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n= 3; V553M, n= 1; N540K/S, n= 2; M528I, n= 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each). Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements.

Safety and effectiveness of pembrolizumab monotherapy in Japanese patients with unresectable urothelial carcinoma: a nation-wide post-marketing surveillance

BackgroundThis study was conducted to identify factors associated with the safety and effectiveness of pembrolizumab in Japanese patients with unresectable urothelial carcinoma and to confirm the real-world safety and effectiveness of pembrolizumab in Japanese patients.MethodsThis multicenter, observational, post-marketing surveillance was conducted over a 1-year observation period starting at pembrolizumab initiation (200-mg pembrolizumab every 3 weeks); data were collected from case report forms (3 months and 1 year). Safety measures included treatment-related adverse events and adverse events of special interest (AEOSI). Effectiveness assessments included tumor response, objective response rate (ORR), and disease control rate (DCR).ResultsOverall, 1293 patients were evaluated for safety and 1136 for effectiveness. At 12 months, the treatment-related adverse event incidence was 53.8% (n = 696) and that of AEOSI was 25.0% (n = 323). The most frequent AEOSI of any grade were endocrinological disorder (10.4%, n = 134), interstitial lung disease (ILD) (7.2%, n = 93), and hepatic function disorder (4.9%, n = 64). Multivariate analysis demonstrated that the risk of developing ILD was almost seven times greater (odds ratio 6.60) in patients with a comorbidity of ILD, and approximately twice as high in patients aged ≥ 65 years (odds ratio 2.24) and with smoking history (odds ratio 1.79). The ORR was 26.1% and the DCR was 50.7%. The ORR was 46.4% in patients with a Bellmunt risk score of 0 and decreased as the Bellmunt risk score increased.ConclusionsThis post-marketing surveillance confirmed the safety and effectiveness of pembrolizumab in Japanese patients with unresectable urothelial carcinoma in the real-world setting.

The poor antitumor effect of pembrolizumab in advanced upper urothelial carcinoma with renal parenchymal invasion.

We investigated poor prognosticators in advanced or unresectable urothelial carcinoma, focusing on renal parenchymal invasion (RPI). This study included 48 bladder cancer (BC) and 67 upper tract urothelial carcinoma (UTUC) patients treated with pembrolizumab from December 2017 to September 2022 at Kobe University Hospital. Medical records were retrospectively reviewed for clinical characteristics, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Multivariate analyses were performed using the Cox proportional hazard regression model to identify parameters associated with either PFS or OS. Of 67 UTUC patients, 23 had RPI and 41 patients did not, while 3 cases could not be evaluated. Patients with RPI were predominantly elderly and had liver metastases. ORR for patients with RPI was 8.7%, while it was 19.5% for those without RPI. PFS was significantly shorter for patients with RPI compared with those without RPI. Patients with RPI had significantly shorter OS than those without RPI. On multivariate analysis, performance status (PS) ≥ 2, neutrophil-lymphocyte ratio (NLR) ≥ 3, C-reactive protein ≥0.3 mg/dL and RPI were independent prognostic factors for PFS. PS ≥ 2, NLR ≥ 3, visceral metastasis and RPI were independent prognostic factors for OS. UTUC patient OS was significantly shorter than BC patient OS, while no significant difference in PFS or OS was observed between BC patients and UTUC patients without RPI. RPI was a poor prognostic factor in advanced urothelial carcinoma treated with pembrolizumab, possibly resulting in a poorer prognosis for UTUC compared with BC.

156P The association between response to enfortumab vedotin therapy and primary tumor location in Japanese urothelial carcinoma patients

Enfortumab vedotin (EV) was approved for patients with unresectable urothelial carcinoma who progressed after anti-cancer therapy on September 2021 in Japan based upon findings in the phase III EV-301 trial (NCT03474107). In the study upper tract urothelial carcinoma (UTUC) patients accounted for approximately 30% and the upper limit of hazard ratio of EV for progression-free survival was greater than 1. Therefore, we reviewed the association between response to EV therapy and primary tumor location in Japanese urothelial carcinoma patients using our real-world data.

A prospective exploratory clinical study of penpulimab plus anlotinib as first-line treatment for locally advanced or metastatic urothelial carcinoma.

4567 Background: A high unmet need remains for first-line cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (la/mUC).Immune checkpoint inhibitors have been implemented in the management of cisplatin-ineligible la/mUC. Penpulimab is a programmed death 1 (PD-1) inhibitor which had approved by the Chinese National Medical Products Administration (NMPA) on August 2021. Anlotinib is a novel oral multi-target tyrosine kinase inhibitor and primary targeted to VEGFR, FGFR, PDGFR and c-Kit. The current prospective single-arm phase Ⅱ clinical trial (ChiCTR1900028022) aimed to assess the efficacy and safety of penpulimab plus anlotinib as first-line therapy for la/mUC. Methods: Patients (pts) who had no prior systemic therapy and at least one measurable lesion according to RECIST v1.1 with histologically or cytologically confirmed locally advanced unresectable or metastatic urothelial carcinoma (including unresectable or metastatic urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis), 18-75 years, ECOG 0-2, were considered eligible for enrollment. Patients received 200 mg penpulimab intravenously on day 1 plus anlotinib, 8 mg oral daily for days 1-14 of a 21-day cycle until confirmed disease progression, intolerable toxicity, physician/patient decision to withdraw, or completion of 24 months of treatment. The primary endpoint was objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and safety. Results: As of Dec. 2021, 10 pts were enrolled, 9 pts had the best overall response assessments which inferred the ORR of 66.7%（95% CI, 29.9-92.5）and the DCR of 88.9% (PR in 6 pts and SD in 2 pts; 95% CI, 51.8-99.7). The median PFS was 8.2 months（(95% CI, 8.0-8.4). Any grades of adverse events (AEs) were observed in 90% (9/10) of pts, containing hyperthyroidism (33%), Creatinine increased (33%),haematuria (22%), anaemia (22%), hypertension (11%), fatigue (11%). High grade AEs of grade Ⅳ liver dysfunction were observed in one patient (11%). Conclusions: An effective treatment strategy for cisplatin-ineligible patients and for patients unable to receive chemotherapy is an important unmet clinical need. Penpulimab in combination with anlotinib in pts with la/mUC showed encouraging efficacy and satisfactory safety. Clinical trial information: ChiCTR1900028022.

Effects of Proton Pump Inhibitors on Survival Outcomes in Patients with Metastatic or Unresectable Urothelial Carcinoma Treated with Pembrolizumab.

The gut microbiome influences tumor response to immune checkpoint inhibitors (ICIs). The proton pump inhibitors (PPI) significantly impair diversity of the gut microbiota and can affect the efficacy of ICIs. Therefore, the present study aimed to evaluate the influence of PPI on survival in patients with metastatic or unresectable urothelial carcinoma receiving pembrolizumab. We conducted a retrospective cohort study of patients with metastatic or unresectable urothelial carcinoma receiving pembrolizumab. The use of PPI was defined as any administration for ≥30 d within 60 d prior and/or 30 d after treatment initiation. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and Cox proportional hazards regression analysis was performed to investigate prognostic factors based on patient characteristics. Seventy-nine patients were included in the analysis, and 34 patients (43.0%) received PPI. There were no significant differences in OS and PFS between PPI users and nonusers (median OS: 8.2 months vs. 11.2 months, hazard ratio (HR): 1.36, 95% confidence interval (CI): 0.75-2.42, p = 0.296; median PFS: 3.5 months vs. 5.1 months, HR: 1.63, 95% CI: 0.95-2.80, p = 0.069). In the multivariable analysis, PPI use was not associated with OS (HR 0.80, 95% CI 0.40-1.56, p = 0.526) or PFS (HR 1.44, 95% CI 0.79-2.60, p = 0.233). In conclusion, the estimated effect size of PPI use on survival in Japanese patients with metastatic or unresectable urothelial carcinoma treated with pembrolizumab was not reproducible.

Association of oncological response between the first-line chemotherapy and subsequent immune checkpoint inhibitors therapy in patients with unresectable or metastatic urothelial carcinoma.

Association of oncological response between the first-line chemotherapy and subsequent immune checkpoint inhibitors therapy in patients with unresectable or metastatic urothelial carcinoma.

Camrelizumab plus famitinib for advanced renal cell carcinoma or unresectable urothelial carcinoma: Updated results from a phase II trial.

4550 Background: Considering the synergistic/additive effect of PD-1 blockade and angiogenesis inhibition, we conducted an open-label, multi-center phase II study of camrelizumab (an anti-PD-1 antibody) plus famitinib (a TKI against VEGFR-2, PDGFR, c-kit, and FGFR) in pts with heavily treated advanced renal cell carcinoma (RCC) and unresectable urothelial carcinoma (UC). Methods: Based on an adaptive two-stage design, 22 pts were enrolled in the RCC and UC cohort, respectively, at stage 1; if there were ≥7 responders of the 22 pts, enrollment would be extend to 33 at stage 2. Pts received famitinib 20 mg orally QD plus camrelizumab 200 mg IV Q3W. Primary endpoint was ORR per RECIST v1.1. Preliminary data at stage 1 were reported at ASCO 2020 annual meeting (#5085). More than 7 pts in each cohort had CR/PR during stage 1; enrollment of stage 2 had been completed, and the data are firstly reported here. Results: 74 pts (38 advanced RCC and 36 unresectable UC) were enrolled from Jan 23, 2019 to Dec 14, 2020. In RCC cohort, 65.8% of pts had received ≥1 prior VEGFR inhibitors. In UC cohort, all pts had progressed on or relapsed after a platinum-containing chemotherapy. As of Jan 10, 2021, median time from enrollment to data cutoff was 18.8 mos (range, 8.5-22.7) for RCC cohort and 7.0 mos (range, 0.9-23.6) for UC cohort. In RCC cohort, ORR was 63.2% (95% CI, 46.0-78.2; 24 PRs), DCR was 89.5% (95% CI, 75.9-95.8), median DOR was not reached (range 2-19+ mos), mPFS was not reached, and 12-mo OS rate was 88.0%. Most pts (92.1%) had reduction in target lesions, and median reduction was 47% from baseline. ORR was 84.6% (95% CI, 57.8-97.3; 11/13) for untreated RCC pts and 52.0% (95% CI, 31.3-72.2; 13/25) for pre-treated pts; DCR was 100% (95% CI, 77.2-100.0) and 84.0% (95% CI, 65.3-93.6), mPFS was not reached and 13.4 mos (95% CI: 4.1-21.0), respectively. In UC cohort, of the 33 pts with post-baseline efficacy evaluation, ORR was 33.3% (95% CI, 19.8-50.4; 1 CR, 10 PRs), DCR was 60.6% (95% CI, 43.7-75.3), median DOR was not reached (range 1.0+-16.7+ mos), mPFS was 6.4 mos (95% CI, 2.1-11.8), and mOS was not reached. ORR trended to be higher for bladder cancer (43.8%, 7/16) than upper tract urothelial carcinoma (25.0%, 4/16). Treatment-related AEs (TRAEs) occurred in 97.3% of 74 pts. Grade 3 or 4 TRAEs occurred in 63.5% of pts, mainly hypertension (23.4%), decreased platelet count (21.3%), proteinuria (17.0%), anemia (14.9%), and palmar-plantar erythrodysesthesia syndrome (14.9%). 1 pt died of TRAE (multiple organ dysfunction syndrome). Conclusions: Camrelizumab plus famitinib showed potent anti-tumor activity in pts with advanced RCC and UC with no new safety concerns. Additionally, promising ORR and durable DOR were observed in pts with heavily-treated RCC. These results support further investigation in these settings. Clinical trial information: NCT03827837.

Camrelizumab plus famitinib malate in patients with advanced renal cell cancer and unresectable urothelial carcinoma: A multicenter, open-label, single-arm, phase II trial.

5085 Background: Camrelizumab (SHR-1210) is a humanised anti-PD-1 antibody. Famitinib malate is a tyrosine kinase inhibitor (TKI) against VEGFR-2, PDGFR, c-kit, and FGFR. This is an ongoing, open label, multi-center Phase II study to assess the preliminary efficacy and safety of camrelizumab in combination with famitinib malate in patients (pts) with genitourinary cancers and gynecologic cancers. Here we just report genitourinary cancers results. Methods: Eligible pts were aged 18 or older, who had advanced clear-cell renal-cell carcinoma with their primary tumour resected or unresectable urothelial carcinoma, had an ECOG performance status of 0-1and measurable disease. Previous system treatments were allowed (excluding prior PD-1/PD-L1 inhibitors or famitinib treatment). Famitinib 20 mg was administered orally once daily with SHR-1210 200 mg given intravenously every 3 weeks. We assessed antitumour activity and safety in all pts who received at least one dose treatment. The primary end point was objective response rate (ORR) per RECIST v1.1. Results: From 23 Jan 2019 to 24 Jun2019, 35 pts were enrolled (25 with RCC, 10 with UC). Median previous treatment line was 1 (range, 1-4), and 50.0% of pts had received ≥2 prior therapies in RCC, all pts received one or more-line therapies in UC. At the data cut-off date (Dec 31, 2019), after at least 6 months follow-up, 22 (63%) pts were still receiving study treatment. The most common reason for discontinuing treatments was disease progression (n = 10). 16 pts achieved a confirmed response, all were partial response, with 8 additional > 24 weeks stable disease. the ORR was 52.0% (13/25, 95% CI 31.3% to 72.2%) in RCC and 30.0% (3/10) in UC, the disease control rate was 84.0% (21/25) in RCC and 70.0% in UC. 13/16 confirmed PR pts were still on treatment, the median duration of response is not reached. The most common grade 3-4 treatment-related AEs (TRAEs) were hypertension (17.1%), proteinuria (11.4%), platelet count decreased (8.6%), hand-foot syndrome (8.6%) and anemia (5.7%). Immune-related adverse events were observed in 7 pts (20%) of 35 pts, 1 pt (2.9%) with grade 3 enteritis. Conclusions: The camrelizumab with famitinib combination appeared to show encouraging activity in pts with heavy-treated RCC and UC, and the safety profile of the combination seemed to be manageable and consistent with that of each drug alone. This combination represented a novel potential treatment option for these settings and warranted further investigation. Clinical trial information: NCT03827837 .

Treating Japanese Patients With Pembrolizumab for Platinum-Refractory Advanced Urothelial Carcinoma in Real-World Clinical Practice.

BackgroundSince December 2017, pembrolizumab has been approved in Japan as a second-line treatment for radical unresectable urothelial carcinoma (UC) that has become exacerbated after chemotherapy by the international randomized phase 3 trial, KEYNOTE-045. The aim of this study was to evaluate the oncological efficacy and safety of pembrolizumab after failure of platinum-based chemotherapy in Japanese patients with advanced UC in real-world clinical practice.MethodsA total of 34 patients who received pembrolizumab after the failure of platinum-based chemotherapy for advanced urothelial carcinoma at four institutions between January 2018 and August 2019 were retrospectively evaluated. In all patients, UC was histopathologically diagnosed, and disease progression after platinum-based chemotherapy was radiologically confirmed.ResultsThe median follow-up period was 7.7 months. The objective response rate, median progression-free survival, and median overall survival were 20.6%, 3.3 months, and 11.7 months, respectively. Regarding the toxicities associated with pembrolizumab, adverse events (AEs) of any grade occurred in 61.8%, and grade 3 AEs occurred in 23.5%; grade ≥ 4 AEs did not occur in any patients. Univariate analyses revealed that the Eastern Cooperative Oncology Group Performance Status, neutrophil/lymphocyte ratio, liver metastases, and time from previous chemotherapy were prognostic variables. Multivariate analyses revealed that liver metastases (positive: hazard ratio, 4.23; 95% confidence interval, 1.48 - 12.08; P < 0.01) and time from previous chemotherapy (≥ 3 months: hazard ratio, 5.06; 95% confidence interval, 1.43 - 17.91; P = 0.01) were independent prognostic factors.ConclusionsIn this real-world clinical study, these findings concerning the efficacy and safety of pembrolizumab for advanced UC in Japanese patients were comparable to those of the open-label, international, phase 3 trial KEYNOTE-045. Liver metastases and time from previous chemotherapy were independent prognostic factors in the present study.

Abstract 1262: Relationship between RAS, BRAF, PIK3CA and location of primary tumor in urothelial carcinoma

Abstract Purpose: In urothelial carcinoma (UC), somatic mutations in RAS, BRAF, and PIK3CA genes are suggested for prognostic markers as well as for therapeutic targets. Studies have reported that upper tract (renal pelvis and ureter) and bladder UC differ in factors including prognosis and genetic features. Methods: We investigated the difference in clinicopathological features and oncogenic mutations (RAS, BRAF, and PIK3CA) according to the location of primary disease. In a prospective biomarker study in patients with metastatic or unresectable UC, tumor DNA was analyzed for mutations in KRAS, NRAS, HRAS, BRAF, and PIK3CAusing Ampliseq v2 platform. We further stratified the frequency of the mutations by the location of primary tumor. Results: Among a total of 210 patients, those with upper tract UC and bladder UC were 90 and 120 patients, respectively. Missense mutations in KRAS, NRAS, HRAS, BRAF, and PIK3CA were present in 9 (4.3%), 1 (0.5%), 18 (8.6%), 4 (1.9%), and 32 (15.2%) patients, respectively. PIK3CA mutations were detected in 16 patients with upper tract UC (17.8%) and 16 patients with bladder UC (13.3%). Likewise, HRAS mutations were detected more frequently in upper tract UC (10/90, 11.1%) than bladder UC (8/120, 6.7%). In metastatic UC setting, PIK3CA or HRAS mutations were not associated with different overall survival. Conclusions: PIK3CA and HRAS mutations were more frequently observed in patients with upper tract UC compared to those with bladder UC. The different genetic features need to be studied by further studies. Note: This abstract was not presented at the meeting. Citation Format: Young Saing Kim, Sang-Cheol Lee, In Gyu Hwang, Su Jin Lee, Se Hoon Park. Relationship between RAS, BRAF, PIK3CA and location of primary tumor in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1262.

Abstract CT179: ATLAS: A Phase II, open-label study of rucaparib in patients with locally advanced or metastatic urothelial carcinoma

Abstract Background: For patients with metastatic urothelial carcinoma (mUC) that has progressed on or after platinum-based chemotherapy (cisplatin or carboplatin) and/or immune checkpoint inhibitors, there are currently no standard treatments, emphasizing the urgent unmet need for additional treatment options. Based on analysis of The Cancer Genome Atlas bladder cancer dataset, ≈60% of muscle invasive bladder tumors have homologous recombination (HR) deficiency (HRD), as defined by high genomic loss of heterozygosity (LOH) or a deleterious mutation in a DNA repair pathway gene. Poly(ADP-ribose) polymerase (PARP) inhibitors such as rucaparib exert their antitumor activity through synthetic lethality in cancer cells with HRD. Tumors with HRD have been shown to be sensitive to PARP inhibitors in breast, ovarian, and prostate cancers, and PARP inhibitors are approved for the treatment of patients with breast or ovarian cancer. Although there are little data on their activity in mUC, we hypothesize that PARP inhibition may have antitumor activity in this tumor type. The ATLAS (NCT03397394) trial is evaluating the efficacy and safety of the PARP inhibitor rucaparib as monotherapy for patients with locally advanced (unresectable) urothelial carcinoma or mUC previously treated with 1-2 anticancer treatments for advanced/metastatic disease. Methods: Eligible patients must have received 1-2 prior treatments (eg, platinum-based chemotherapy, immune checkpoint inhibitor, and/or clinical trial agent) and have radiographic progression, measurable disease (RECIST version 1.1), and adequate organ function. Tumor HRD is not required as rucaparib may potentially benefit patients with HR-proficient or HR-deficient tumors; however, fresh tumor or recently obtained archival tissue is mandatory for central HRD profiling. Prior PARP inhibitor treatment is an exclusion criterion. All patients will receive rucaparib monotherapy (600 mg BID) until disease progression or other reason for discontinuation. The primary endpoint is confirmed objective response rate (investigator assessed per RECIST version 1.1) in the intent-to-treat and HRD-positive (signature based on tumor genomic LOH) populations. Secondary endpoints include response duration, progression-free survival, overall survival, safety, and pharmacokinetics. Exploratory endpoints include evaluating plasma and tumor samples for biomarkers associated with response and resistance to rucaparib. The study has &amp;gt;90% power to reject the null hypothesis (P=0.10) at a one-sided 5% significance level if the true response rate for rucaparib is 20%. ATLAS is currently enrolling at ≈65 sites in 6 countries (France, Germany, Italy, Spain, United Kingdom, and United States), with a target enrollment of 200 patients. Citation Format: Petros Grivas, Min Yuen Teo, Nicholas Vogelzang, Ajjai Alva, Yousef Zakharia, Nabil Adra, Alexandra Drakaki, Arif Hussain, Rafael Morales-Barrera, Andrea Necchi, Alejo Rodriguez-Vida, Susan Feyerabend, Sumati Gupta, Debra H. Josephs, Yohann Loriot, Sandy Srinivas, Kenton Wride, Daleen Thomas, Rachel Dusek, Andrew D. Simmons, Dale Nepert, Simon Chowdhury. ATLAS: A Phase II, open-label study of rucaparib in patients with locally advanced or metastatic urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT179.

Fibroblast Growth Factor Receptors (FGFRs): Structures and Small Molecule Inhibitors.

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell membrane that play crucial roles in both developmental and adult cells. Dysregulation of FGFRs has been implicated in a wide variety of cancers, such as urothelial carcinoma, hepatocellular carcinoma, ovarian cancer and lung adenocarcinoma. Due to their functional importance, FGFRs have been considered as promising drug targets for the therapy of various cancers. Multiple small molecule inhibitors targeting this family of kinases have been developed, and some of them are in clinical trials. Furthermore, the pan-FGFR inhibitor erdafitinib (JNJ-42756493) has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic or unresectable urothelial carcinoma (mUC). This review summarizes the structure of FGFR, especially its kinase domain, and the development of small molecule FGFR inhibitors.

Overall survival, costs, and healthcare resource use by line of therapy in Medicare patients with newly diagnosed metastatic urothelial carcinoma

Aims: Medicare patients with metastatic or surgically unresectable urothelial carcinoma (mUC) often receive platinum-based chemotherapy as first line of therapy (LOT), but invariably progress, requiring additional LOTs and healthcare resource use (HCRU). To better understand the evolving mUC treatment landscape, the economic burden of chemotherapy-based mUC treatments among US Medicare patients was estimated.Methods: Newly diagnosed Medicare patients with mUC were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were followed from diagnosis to death, disenrollment, or end of study to characterize LOTs (first [LOT1], second [LOT2], and third or greater [LOT3+]). Kaplan-Meier methods were used to estimate overall survival (OS) by LOT. HCRU and mean costs were reported over the follow-up period, LOT duration, and maximum LOT received.Results: Among 1,873 eligible patients with mUC (median age = 77 years; median follow-up = 7.5 months), 1,035 (55%) received no chemotherapy. Among chemotherapy-treated patients, 61% had LOT1 only, 25% had LOT1 and LOT2 only, and 14% had LOT3+. Median OS was 8.1 months, range was 4.3 (untreated) to 29.8 (LOT3+) months. HCRU frequency increased with additional LOTs. Mean cumulative per-patient cost was $82,912 for all patients, increasing with additional LOTs (untreated = $57,207; LOT1 = $99,213; LOT2 = $125,190; LOT3+ = $163,884). Mean per patient per month cost was $18,827 for all patients, decreasing with increasing number of LOTs received (untreated = $27,211; LOT1 = $9,601; LOT2 = $7,325; LOT3+ = $6,017).Limitations: Potential for treatment misclassification when using the algorithm defining LOTs and non-generalizability of results to younger patients.Conclusions: Over 50% of Medicare patients with mUC received no chemotherapy. Among chemotherapy-treated patients, most received only one LOT. Additional LOTs led to higher mean costs and HCRU, but as patients were followed longer, monthly costs decreased. As treatments evolve to include immuno-oncology agents, these findings provide a clinically relevant economic benchmark for mUC treatment across different traditional LOTs.

900P - Interim results of fight-201, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with metastatic or surgically unresectable urothelial carcinoma (UC) harboring fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations (GA)

900P - Interim results of fight-201, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with metastatic or surgically unresectable urothelial carcinoma (UC) harboring fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations (GA)

920TiP - Erdafitinib compared with vinflunine or docetaxel or pembrolizumab in patients (pts) with metastatic or surgically unresectable (M/UR) urothelial carcinoma (UC) and selected fgfr gene alterations (FGFRalt): The phase III THOR study

920TiP - Erdafitinib compared with vinflunine or docetaxel or pembrolizumab in patients (pts) with metastatic or surgically unresectable (M/UR) urothelial carcinoma (UC) and selected fgfr gene alterations (FGFRalt): The phase III THOR study

First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt).

4503Background: ERDA is an FGFR inhibitor with activity in pts with mUC and FGFRalt. FGFRalt occur in 10-20% of mUC and are enriched in immunologically “cold” luminal 1 UC. Two independent published reports showed a 5% investigator-reported response rate to prior immune checkpoint inhibitors (ICI) among pts with select FGFRalt, suggesting a need for new treatment options in this population. Here we report efficacy and safety of ERDA in the global open-label phase 2 study BLC2001 (NCT02365597). Methods: Pts had measurable mUC with prespecified FGFRalt, ECOG 0-2, and progression during/following ≥ 1 line of prior chemo or ≤ 12 mos of [neo]adjuvant chemo, or were cisplatin ineligible, chemo naive. Prior ICI treatment was allowed. The optimal schedule of ERDA determined in the initial part of the study was 8 mg/d continuous ERDA in 28-d cycles with uptitration to 9 mg/d if protocol-defined target serum phosphate level was not reached and if no significant treatment-related adverse events (TRAEs) occurred. Pri...

Erdafitinib (ERDA; JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRa): Phase 2 continuous versus intermittent dosing.

411 Background: Although immune checkpoint inhibitors (ICI) have improved outcomes in some pts with platinum-resistant mUC, many pts (eg, pts with TCGA luminal 1 tumors, many of whom are FGFRa) may not benefit. ERDA, a pan-FGFR (1-4) inhibitor, demonstrated promising phase 1 activity: 11 partial responses among 24 FGFRa mUC pts. We report efficacy and safety of ERDA in the ongoing global open-label phase 2 study BLC2001 (NCT02365597). Methods: Pts had measurable mUC with specific FGFR2/ FGFR3 mutations or translocations per central lab Janssen assay, ECOG 0-2, and were chemorefractory (progressed during/following ≥ 1 line of prior systemic chemo or ≤ 12 mos of [neo]adjuvant chemo). Cisplatin-ineligible, chemo-naïve pts, and prior ICI treatment were allowed. Pts were randomized 1:1 to 28-d cycles of oral 6 mg/d continuous dosing (6 C) or 10 mg/d intermittent 7 d on/7 d off dosing (10 I) ERDA; the dose was further uptitrated if no significant treatment-related adverse events (TRAEs) were observed. The primary end point was ORR. Results: 78 pts received 6 C and 33 pts received 10 I (10 I cohort stopped early) ERDA. 31 pts in 6 C arm were further uptitrated. Across arms, 50% had ≥ 2 prior lines of therapy; 93% were chemorefractory. Confirmed ORRs (RECIST 1.1) were 35% and 24%, and disease control rates (CR+PR+SD) were 74% and 73% in the 6 C and 10 I arms, respectively. Adverse events (AEs) were manageable, and there were no treatment-related deaths (Table). Treatment is ongoing in 10 pts. Conclusions: ERDA (6 C or 10 I) has promising efficacy and tolerability in pts with FGFRa mUC. Based on these results and ERDA pharmacometric modeling, dosing was optimized at 8 mg/d (continuous), and this cohort is ongoing. Phase 3 study is planned. Clinical trial information: NCT02365597. [Table: see text]

Pretreatment Neutrophil-Lymphocyte Ratio as a Predictor in Bladder Cancer and Metastatic or Unresectable Urothelial Carcinoma Patients: a Pooled Analysis of Comparative Studies

Background/Aims: Emerging studies have shown that the neutrophil-lymphocyte ratio (NLR) is a potential predictor in various tumors. Our study was conducted to assess the prognostic value of the pretreatment NLR in bladder cancer and metastatic or unresectable urothelial carcinoma (mUC or uUC) patients up to July 2017. The correlation between the pretreatment NLR and pathological characteristics was also evaluated in bladder cancer patients. Methods: The hazard ratio (HR) and odds ratio (OR) with the 95% confidence interval (CI) were extracted or calculated from the included studies for further pooled analysis. A total of 21 studies were included in a pooled analysis. Results: The pooled results indicated that a high pretreatment NLR was associated with reduced overall survival (OS) (HR=1.27, 95% CI=1.12-1.43), relapse-free survival (RFS) (HR=1.41, 95% CI=1.23-1.60), progression-free survival (PFS) (HR=1.75, 95% CI=1.36-2.15), disease-specific survival (DSS) and cancer-specific survival (CSS) (HR=1.27, 95% CI=1.19-1.35) in the bladder cancer patients. Additionally, an elevated pretreatment NLR suggested a worse OS rate in the mUC or uUC patients (HR=1.63, 95% CI=1.34-1.91). The pooled ORs and 95% CIs showed that a high pretreatment NLR could be a risk indicator for certain pathological features, such as lymphovascular invasion, a positive margin status and advanced tumor stage. Conclusions: our results showed that a high pretreatment NLR predicted poor prognosis in bladder cancer, mUC and uUC patients.

1131P - Medical costs and health care resource use (HCRU) in elderly us patients (pts) with newly diagnosed metastatic or surgically unresectable urothelial carcinoma (mUC) using surveillance, epidemiology, and end results (SEER) medicare data

1131P - Medical costs and health care resource use (HCRU) in elderly us patients (pts) with newly diagnosed metastatic or surgically unresectable urothelial carcinoma (mUC) using surveillance, epidemiology, and end results (SEER) medicare data