Treatment Of Urothelial Cancer Research Articles

Enfortumab vedotin in the treatment of urothelial cancers and beyond.

Enfortumab vedotin (EV) is the first antibody-drug conjugate approved for locally advanced or metastatic urothelial cancers (la/mUCs), a disease group historically associated with limited prognosis and therapeutic options. EV consists of monomethyl auristatin E, a microtubule-disrupting agentlinked to an antibody targeting Nectin-4. In clinical trials, EV demonstrated high response rates and superior survival in the third-line setting for la/mUC compared with chemotherapy. Peripheral neuropathy and rash were among the most common serious adverse events. EV is currently approved in multiple countries for the treatment of la/mUC in the later-line setting. Ongoing trials seek to expand the indication for EV and to study therapeutic combinations with other agents.

Novel immunotherapy in the management of advanced urothelial cancer - review of the literature

Bladder neoplasms, with the most common urothelial carcinoma, are responsible for approximately 200,000 deaths annually, which is 2.1% of the total cancer deaths in 2018. Recent decades have brought a steadily growing share of this cancer in the statistics. The 5-year survival rate is 77.1% for the United States and it varies depending on the stage of the diagnosed neoplasm, from 96% for cancer in situ to only 5% for the disseminated form with distant metastases. The treatment of urothelial cancer can be divided depending on the stage and advancement. Three main categories of bladder cancer can be distinguished: non-muscle invasive bladder cancer, treated by surgical approaches, and muscle-invasive bladder cancer, treated with chemotherapeutics, lastly advanced bladder cancer with distant metastases, treated with intensive chemotherapy in the MVAC scheme (methotrexate, vinblastine, doxorubicin, and cisplatin). Recently introduced checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma by increasing patient life expectancy, progression-free survival, and durability of clinical response. This review of the literature will discuss the use of immunotherapy in the treatment of advanced bladder cancer.

Vδ2 T cells are associated with favorable clinical outcomes in patients with bladder cancer and their tumor reactivity can be boosted by BCG and zoledronate treatments

Background Bladder cancer is an important public health concern due to its prevalence, high risk of recurrence and associated cost of management. Although BCG instillation for urothelial cancer treatment is...

Gender and Advanced Urothelial Cancer: Outcome, Efficacy and Toxicity following Chemotherapy.

Background and Objectives: The incidence of urothelial cancer in males is higher than in females; however, females have a higher risk of recurrence and progression. The aim of our study was to report the effect of gender on the oncological outcome in advanced urothelial cancer. Materials and Methods: In our retrospective study, all patients had undergone primary surgical treatment for urothelial cancer and were affected by stage IV disease at the time of chemotherapy. Response to therapy and toxicity were evaluated. Subgroups were analyzed for tumour presentation, first- and second-line treatment response, progression-free survival (PFS) and overall survival (OS). Results. Seventy-five patients, 18 (24%) females and 57 (76%) males, were considered. Investigation into the distribution of individual characteristics according to gender revealed a significant difference only for smoking, with a prevalence of smokers in women (p = 0.029). At the end of follow-up, OS was higher in females (27.5% vs. 17.4%; p = 0.047). Smoking did not significantly influence OS (p = 0.055), while univariate Cox regression analysis confirmed that males had a higher risk of death (HR = 2.28, 95% CI 0.99–129 5.25), with borderline statistical significance (p = 0.053). Men showed higher PFS than women both after first-line (p = 0.051) and second-line chemotherapy (p = 0.018), with a lower risk of progression (HR = 0.29, 95% CI 0.10–0.86; p = 0.026). No differences were found between genders with regard to toxicity. Conclusions. In our series, PFS rates following first- and second-line therapies for advanced urothelial carcinoma confirmed that females have a greater risk of progression than males.

Clinicopathological characterization, FGFR alteration prevalence, and outcomes of locally advanced or metastatic urothelial cancer in Latin America (LACOG 1518).

e16549 Background: Treatment of Urothelial Cancer (UC) is rapidly evolving with innovative biomarker-based approaches. Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are frequent in UC and are an emerging focus for targeted therapy. However, real-world data on FGFR prevalence, as well as clinicopathological characteristics and outcomes of patients (pts) with advanced UC in Latin America is lacking. Methods: LACOG 1518 is a multicenter multinational study that retrospectively included pts diagnosed with metastatic or relapsed UC between Jan-2016 and Dec-2019. Clinicopathological characteristics, outcomes and treatment patterns were retrieved from medical records. Archival tumor samples were analyzed for FGFR alterations by NGS. Results: Two hundred thirteen pts were included across 24 centers in 4 Latin American countries. Median age was 68 years (range, 31-90), most pts (75%) had PS 0-1, and 83 (39%) pts had clinical stage IV at diagnosis. Bladder was the primary site of disease in 190 (89%) pts, 92 (43.2%) pts had histological variants of UC - 46 (21.6%) pts with adenocarcinoma differentiation and 16 (7.5%) with squamous-cell differentiation. Patients with relapsed locoregional disease not candidates for curative therapy comprised 10.3% of the sample. Among pts with metastatic disease, visceral metastases were present in 99 (51%) pts. FGFR alterations eligible for treatment with FGFR inhibitors (FGFRi) were identified in 29 (14.8%) out of 196 pts tested and included 29 mutations (14 S249C, 7 Y373C, 5 R248C and 3 G370C) and 13 fusions (8 FGFR3-TACC3, 2 FGFR3-BAIAP2L1, 2 FGFR2-BICC1 and 1 FGFR2-CASP7). Other FGFR alterations were also present in 6 (3.1%) pts. Median overall survival since initial diagnosis and advanced disease were 31.6 months (95% CI, 25.5 – 37.6) and 15.2 months (95% CI, 12.4 – 17.9), respectively. Median time to treatment failure to the first treatment line was 3.9 months (95% CI, 3.0 – 4.4). Regarding treatment patterns, 175 (82.1%) pts received first line treatment: 127 (72.6%) combined chemotherapy, 29 (16.6%) immunotherapy alone, 15 (8.6%) single agent chemotherapy, and 4 (2.3%) chemo-immunotherapy. Gemcitabine-platinum combinations were the backbone of choice in 93.7% of pts receiving combined chemotherapy. Pembrolizumab and atezolizumab were the chosen first-line agents for 10.3% and 4% of the treated pts, respectively. Considering all treatment lines, 75 (35.2%) and 3 (1.4%) pts were exposed to immunotherapy and FGFRi in the course of their disease, respectively. Conclusions: The prevalence of FGFR alterations in advanced UC in Latin America is similar to those described in other regions. Our data suggest limited access to FGFR inhibitors for the treatment of advanced UC in Latin America.

Erdafitinib in locally advanced/metastatic urothelial carcinoma with certain FGFR genetic alterations.

FGFR inhibitors represent a new and promising therapeutic approach to urothelial cancer (UC). Erdafitinib (Balversa©) was the first FGFR inhibitor approved for the treatment of metastatic UC, showing proper pharmacological activity and a consistent safety profile in a population with limited or no therapeutic alternatives. While results from comparative phase II and III trials are needed to assess the efficacy of erdafitinib in different clinical settings, there are still questions unsolved regarding a typical class effect of FGFR inhibitors, hyperphosporemia. In this review, the authors focus on the state-of-art administration of erdatifinib in advanced UC, pointing out the more recent evidence, pitfalls and possible future research. Insight on the management of hyperphosporemia in patients undergoing treatment with FGFR inhibitors is also provided.

Update on systemic treatment of urothelial cancer: therapy in transition

The systemic treatment of locally advanced and metastatic urothelial carcinoma has been changing at a breathtaking pace for a few years. However, platinum-based chemotherapy continues to be the central component of perioperative therapies and first-line treatment in the metastatic stage. Immunotherapies with immune checkpoint inhibitors are now an integral part of therapy algorithms. New targeted forms of chemotherapy are about to be approved. Advances in understanding the molecular genetic analysis of tumour tissue will soon enable personalised therapy options. This article is intended to provide an overview of current systemic therapy options and the underlying database. New developments are identified by presenting ongoing phase III trials. After reading this article, the reader should feel informed about the current status of systemic therapy for urothelial carcinoma.

New Directions and Challenges in Targeted Therapies of Advanced Bladder Cancer: The Role of FGFR Inhibitors.

Simple SummaryThe aim of this study was to present and analyze the up-to-date literature describing the epidemiology, genetics, and histopathology of bladder cancer, as well as the latest methods of bladder cancer treatment. The treatment of urothelial cancer was divided depending on its stage and advancement. FGFR3 mutations and overexpression occur more frequently in bladder cancer than any other malignancy, occurring in nearly 80% of the tumors. Closer acknowledgement of targeted therapy will help physicians to navigate specific groups of patients for whom this treatment strategy can be beneficial. To that end, intense clinical research was conducted, bringing evidence for effectiveness and safety of FGFR inhibitors. Recent years of research have truly set a positive perspective for the better understanding of the complex issue of urothelial carcinoma pathology and management.Bladder neoplasms, including the most common urothelial carcinoma, have been an escalating problem for years, especially in highly developed countries. Recent decades have brought us a steadily growing share of this cancer in terms of both morbidity and mortality statistics. Bladder neoplasms are not only a therapeutic challenge but also an economical one due to the demanding, costly diagnostics and treatment. The treatment of urothelial cancer can be divided depending on the stage and advancement; thus, we can distinguish three main categories: non-muscle invasive bladder cancer, conventionally treated by surgical interventions; muscle invasive bladder cancer, conventionally treated with chemotherapeutics; and advanced bladder cancer with distant metastases, conventionally treated with the intensive chemotherapy in the MVAC scheme (methotrexate, vinblastine, doxorubicin, and cisplatin). Recent years have brought a breakthrough: immunotherapy and targeted therapy were discovered to be beneficial for patients disqualified from chemotherapy or patients who progressed despite treatment. This literature review summarizes the latest research into the use of targeted therapy in the treatment of advanced bladder cancer, its benefits, and its limitations.

Frontiers in Non-metastatic, Muscle-invasive Bladder Cancer

The treatment landscape of bladder cancer is rapidly changing, with the introduction of novel therapies such as immune checkpoint inhibitors (ICIs), targeted therapies and antibody–drug conjugates. While most of the initial developments were in the treatment of metastatic disease, several recent advances have been made in the treatment of non-metastatic muscle-invasive disease. ICIs have demonstrated a role in the adjuvant treatment of muscle-invasive bladder cancer and on-going studies are poised to better elucidate that role. Multiple studies are also investigating a role for ICIs as monotherapy or in combination with other treatments in the neoadjuvant treatment of urothelial cancer. There are also on-going studies exploring novel approaches to bladder preservation in patients with muscle-invasive bladder cancer.

Urothelial cancer: population-based analysis of the problem in Ukraine

The aim of this work was to conduct a population analysis on the basis of the National Cancer Registry with the primary goal: to determine the effectiveness of urothelial cancer treatment in Ukraine; and the secondary goal: to identify the main trends and approaches to therapy with an assessment of their impact on overall survival. Materials and methods. The design of the study was retrospective observational. The analysis was conducted based on the data of the National Cancer Registry from 2008 to 2020. A total of 12,698 patients with urothelial tumors of the upper urinary tract and bladder who underwent surgical treatment were analyzed. Statistical sampling was performed based on the creation of the most homogeneous groups of patients with bladder cancer (BC) and the upper urinary tract carcinoma (UUTc) who had the required number of notified parameters for further analysis. The primary objectives of the analysis were to determine: the average age of primary detection of the studied nosologies, level of detection depending on gender, frequency of diagnosis verification before surgery, extent of surgery, frequency of postoperative complications based on data on 30-day rehospitalization, the level of deviation of the principles for prophylactic medical patients’ examination from generally accepted recommendations. The secondary objective was to assess the cumulative survival of patients with urothelial tumors depending on the localization of the primary tumor and the type of surgery (organ-sparing or radical). Results. Organ-sparing treatment was more typical for BC, while radical treatment was performed in 15 % of patients with carcinomas. Organ-sparing treatment was more typical for UUTc (40%). It should be noted that in this nosology it is acceptable for invasive forms of urothelial cancer. The level of 30-day hospitalization was low in both pathologies, with a slightly greater advantage of UUTc. The level of complications is grade III according to the Clavien-Dindo classification, averaging 0.2 % for the entire pool of patients. For BC, the overall survival rates by stages were: I — 73%, II — 49 %, III — 18 % and IV — 11 % (chi-square=1,807.207; p= 0.000001). For UUTc, the levels of 5-year overall survival correspond to the literature data, but there is a significant negative tendency to decrease the latter after a 10-year period for all stages (chi-square = 146.298; p = 0.000003). In Ukraine, organ-sparing treatment for UUTc was not inferior to radical nephroureterectomy in the context of 5-year survival (51.3 vs. 51%; log-rank test). The obtained data testify in favor of the 15% advantage of the total survival of patients who underwent radical nephroureterectomy at the premises of the National Cancer Institute (high volume center), compared to other regions of Ukraine. Levels of 5- and 10-year survival in both nosologies were characterized by a statistically non-significant advantage of UUTc over BC of 7 %. Conclusions. Superficial and locally advanced tumors are the most complex ones in the treatment of urothelial cancer of the bladder and upper urinary tract in Ukraine. Superficial tumors require the most radical surgeries and subsequent effective local treatment. Locally advanced tumors require a comprehensive approach to treatment, adequate systemic therapy influences the final indicators of overall survival. In cases of surgical resectability and preservation of renal function, UUTc requires organ-sparing treatment; this approach aims to increase creatinine clearance in patients before systemic chemotherapy and to reduce the likelihood of progression of comorbidities and associated mortality.

Update on systemic treatment of upper tract urothelial carcinoma: a narrative review of the literature.

Urothelial cancer (UC) is most commonly found in the urinary bladder, but can also appear in the upper urinary tract, where it is associated with several disease-specific challenges affecting its diagnosis, clinical staging, surgical management, and systemic therapy. A significant number of patients experience extra-vesical disease recurrence despite radical nephroureterectomy (RNU), leading to inevitable demise. Over the last years, the therapeutic armamentarium of UC has expanded with several systemic treatment options entering clinical care and deliver the potential to support a more individualized treatment in the near future. Currently, novel targeted therapies are emerging, accompanied with extensive biomarker research, which leads to a better understanding of the disease and therefore, reshaping the treatment landscape continuously and decisively. Though, systemic treatment of UTUC comes along with certain challenges that are specific to the disease, e.g., loss of renal function after RNU, which might result in ineligibility for a cisplatin-based chemotherapy. In this narrative review, the current standard of systemic treatment of UC in the perioperative and metastatic treatment setting are reported, with focus on UTUC. In addition, molecular aspects of UTUC, as well as future directions and specific implications for treatment of patients diagnosed with UTUC are discussed.

MP19-07 PALLIATIVE CARE EXPERIENCES AND ATTITUDES AMONG PATIENT AND CAREGIVER PARTICIPANTS IN THE BLADDER CANCER ADVOCACY NETWORK PATIENT SURVEY NETWORK

You have accessJournal of UrologyHealth Services Research: Practice Patterns, Quality of Life and Shared Decision Making II (MP19)1 Sep 2021MP19-07 PALLIATIVE CARE EXPERIENCES AND ATTITUDES AMONG PATIENT AND CAREGIVER PARTICIPANTS IN THE BLADDER CANCER ADVOCACY NETWORK PATIENT SURVEY NETWORK Pauline Filippou, Lee A Hugar, Rishi R Sekar, Renata Louwers, Ann Pomper, Stephanie Chisolm, Angela B Smith, John L Gore, and Scott M Gilbert Pauline FilippouPauline Filippou More articles by this author , Lee A HugarLee A Hugar More articles by this author , Rishi R SekarRishi R Sekar More articles by this author , Renata LouwersRenata Louwers More articles by this author , Ann PomperAnn Pomper More articles by this author , Stephanie ChisolmStephanie Chisolm More articles by this author , Angela B SmithAngela B Smith More articles by this author , John L GoreJohn L Gore More articles by this author , and Scott M GilbertScott M Gilbert More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002004.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Palliative care (PC) is underutilized amongst patients with advanced urothelial cancer despite known benefits and guideline recommendations. Little is known regarding the barriers to access of PC by patients with urothelial cancer. We sought to describe patient and caregiver experiences associated with PC and its introduction to patients and caregivers by non-PC clinicians. METHODS: We surveyed patients with urothelial cancer and their caregivers through the BCAN Patient Survey Network to understand experiences and attitudes surrounding PC referral. Patients were also queried regarding demographic, socioeconomic, and clinical characteristics, with specific attention to geographic location of residence and stage of urothelial cancer. RESULTS: Of the 286 survey respondents, 258 patients (90%) self-identified as having urothelial cancer and 28 (10%) as current or former caregivers. Of the 72% of respondents living in the US, 94% lived in areas with grade A (excellent) or B (good) access to PC based on the 2019 Center to Advance Palliative Care report card. Caregivers were more likely to consider PC for themselves or a loved one compared with patients (mean 88.7 vs 67.4 on a 0-100 scale, respectively, p<0.001). Despite 38% of the cohort having advanced disease (defined as ≥T2 bladder cancer or metastatic urothelial cancer), only 25 respondents (9%) had PC raised by a provider as part of their cancer treatment plan, with heterogeneity in how, when in the disease course, and which provider brought up PC (Figure 1). Some patients expressed wanting PC to be brought up sooner in their disease course. Of the 247 respondents who did not have PC brought up with them by a provider, 30% (n=74) wished that it had been. 58% of the entire cohort somewhat (19%) or strongly agreed (39%) with the statement “It is a doctor’s obligation to inform all patients with cancer about the option of PC.” CONCLUSIONS: Based on patient- and caregiver-reported experiences, PC is discussed infrequently during the treatment of urothelial cancer. Patients and their caregivers expressed desire for PC to be introduced by providers more often and earlier than currently encountered. Source of Funding: PF is supported by the Urology Care Foundation Research Scholar Award and Society of Urologic Oncology Fund © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e330-e330 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pauline Filippou More articles by this author Lee A Hugar More articles by this author Rishi R Sekar More articles by this author Renata Louwers More articles by this author Ann Pomper More articles by this author Stephanie Chisolm More articles by this author Angela B Smith More articles by this author John L Gore More articles by this author Scott M Gilbert More articles by this author Expand All Advertisement Loading ...

The efficacy and safety of PD-1/PD-L1 immune checkpoint inhibitors in treating advanced urothelial cancer: a meta-analysis of clinical trials

Survival outcomes in advanced urothelial cancer (UC) are dismal. Over the past years, immunotherapy remains an evolving treatment modality for these patients. This meta-analysis was performed to comprehensively evaluate the efficacy and safety of immune checkpoint inhibitors. For this purpose, 18 clinical trials comprising a total of 3,144 patients were identified from the PubMed database up to September 2020. Overall, the objective response rate (ORR) to PD-1/PD-L1 inhibitors was 0.20 [95% confidence intervals (CI) 0.17–0.23]. Furthermore, the pooled 1-year overall survival (OS) and 1-year progression-free survival (PFS) rates were 0.43 (95% CI 0.33–0.53) and 0.19 (95% CI 0.17–0.21), respectively. The summary rates of any-grade and grade ≥3 adverse events (AEs) were 0.66 (95% CI 0.58–0.74) and 0.13 (95% CI 0.09–0.18), respectively. Among the different subgroups, PD-1/PD-L1 inhibitors elicited a promising ORR in patients with lymph node-only metastasis compared to those with visceral metastasis (0.41 VS. 0.17). Additionally, patients with primary tumor in the lower tract had higher ORR compared to those with primary tumor in the upper tract (0.24 VS. 0.15). Briefly speaking, this immunotherapy protocol showed an encouraging efficacy and acceptable safety profile in the treatment of advanced UC. Moreover, our findings provided potential clinical significance for patients with lymph node-only metastasis or primary tumor in the lower tract. However, these exciting findings need further confirmation.

Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer

Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP‐based chemotherapy is the first‐line treatment. WEE1, a G2/M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported. MK‐1775, a WEE1 inhibitor also known as AZD‐1775, blocked proliferation of UC cell lines in a dose‐dependent manner irrespective of TP53 status. MK‐1775 synergized with CDDP to block proliferation, inducing apoptosis and mitotic catastrophe in TP53‐mutant UC cells but not in TP53‐WT cells. Knocking down TP53 in TP53‐WT cells induced synergism of MK‐1775 and CDDP. In UMUC3 cell xenografts and two patient‐derived xenograft lines with MDM2 overexpression, in which the p53/cell cycle pathway was inactivated, AZD‐1775 combined with CDDP suppressed tumor growth inducing both M‐phase entry and apoptosis, whereas AZD‐1775 alone was as effective as the combination in RT4 cell xenografts. Drug susceptibility assay using an ex vivo cancer tissue‐originated spheroid system showed correlations with the in vivo efficacy of AZD‐1775 alone or combined with CDDP. We determined the feasibility of the drug susceptibility assay using spheroids established from UC surgical specimens obtained by transurethral resection. In conclusion, WEE1 is a promising therapeutic target in the treatment of UC, and a highly specific small molecule inhibitor is currently in early phase clinical trials for cancer. Differential antitumor efficacy of WEE1 blockade alone or combined with CDDP could exist according to p53/cell cycle pathway activity, which might be predictable using an ex vivo 3D primary culture system.

Pre-pembrolizumab neutrophil-to-lymphocyte ratio (NLR) predicts the efficacy of second-line pembrolizumab treatment in urothelial cancer regardless of the pre-chemo NLR.

Neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with prognosis of urothelial cancer (UC) patients receiving systemic chemotherapy or immunotherapy. However, it has not been elucidated how preceding first-line chemotherapy affects NLR and subsequent second-line pembrolizumab treatment. This multicenter study analyzed 458 patients with metastatic UC who received first-line chemotherapy and second-line pembrolizumab with regard to pre-chemotherapy and pre-pembrolizumab NLR in association with the efficacy of chemotherapy and pembrolizumab treatment. NLR was increased in 47% while decreased in 53% of patients before and after first-line chemotherapy. High pre-chemotherapy NLR (≥ 3) was significantly associated with unfavorable overall (OS, P = 0.0001) and progression-free (P < 0.0001) survivals after first-line chemotherapy. However, pre-chemotherapy NLR showed only modest influence on radiological response and survival after second-line pembrolizumab treatment, whereas pre-pembrolizumab NLR showed higher association. NLR decrease was associated with partial response or greater objective response by first-line chemotherapy, while NLR increase was associated with higher patient age. In conclusion, immediate pre-chemotherapy and pre-pembrolizumab NLR was significantly associated with efficacy of the following treatment, respectively. However, even patients with high pre-chemotherapy NLR achieved favorable OS if they had their NLR reduced by chemotherapy, whereas those with high pre-chemotherapy NLR yielded unfavorable OS if they had their NLR remained high after chemotherapy, suggesting that chemotherapy may have differential effect on the efficacy of subsequent pembrolizumab treatment in UC patients.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer

A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively...

NICE: avelumab not recommended for maintenance treatment of urothelial cancer

NICE: avelumab not recommended for maintenance treatment of urothelial cancer

A phase Ib single-arm study of bintrafusp alfa for the treatment of pretreated, locally advanced/unresectable or metastatic urothelial cancer.

TPS501 Background: Urothelial cancer (UC) is the most common histological subtype of bladder cancer. For patients with metastatic UC, platinum-containing chemotherapy (CT) is the first-line standard of care. With 5 PD-(L)1 inhibitors approved for second-line treatment of platinum-refractory advanced UC, objective response rates (ORRs) in this setting (15% to 21%) and in first-line cisplatin-ineligible patients (23% to 31%) suggest that there remains a significant unmet need for improved outcomes. TGF-β signaling has been associated with resistance to PD-(L)1 inhibitors in patients with UC. Bintrafusp alfa (BA) is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In murine models, BA resulted in improved antitumor activity vs TGF-β or PD-L1 monotherapies alone or in combination. In 2 phase I trials (NCT02517398 and NCT02699515), BA demonstrated a manageable safety profile and encouraging clinical efficacy in &gt;670 patients with advanced solid tumors. Here we describe a phase Ib study (NCT04349280) that will assess the clinical activity and safety profile of BA in platinum-experienced patients with locally advanced/unresectable or metastatic UC. Colocalized, simultaneous inhibition of the TGF-β and PD-L1 pathways by BA is hypothesized to elicit greater antitumor activity than anti–PD-(L)1 therapies in patients with UC. Methods: This open-label, multicenter, single-arm trial is accruing patients with histologically confirmed locally advanced/unresectable or metastatic UC (ECOG PS ≤1) with disease progression or recurrence after platinum-based CT. Patients must not have received &gt;2 lines of systemic therapy for metastatic disease or prior therapy targeting T-cell costimulation, or checkpoint or TGF-β pathways. Patients with pneumonitis or a history of noninfectious pneumonitis that required systemic immunosuppression are ineligible. Patients will receive BA 1200 mg every 2 weeks until progression, unacceptable toxicity, death, or study withdrawal, or for up to 2 years. The primary endpoint is investigator-assessed confirmed ORR per RECIST 1.1; key secondary endpoints include duration of response and progression-free survival per the investigator and IRC, overall survival, safety, immunogenicity, and pharmacokinetics. Exploratory biomarker analyses will be conducted using patient samples collected during screening and prior to administration of BA. The base ORR used for the null hypothesis is 21%, and the target ORR is 40%. Using a predictive probability design and an estimated enrollment of 40 patients, the type I error rate is 5.70% and the power is 85.39%. As of September 2020, 3 sites in 2 countries have been activated and no patients have been enrolled. Clinical trial information: NCT04349280.

Safety of same-day administration of gemcitabine plus cisplatin chemotherapy for urothelial carcinoma.

The present study aimed to examine the safety of a gemcitabine and cisplatin (GC) combination chemotherapy regimen with short hydration for the treatment of urothelial cancer administered on the same day (same day regimen). Patients with locally advanced or metastatic urothelial cancer received the same-day GC regimen with short hydration every 4 weeks, and their serum creatinine (Cr) level was measured to assess renal function using linear mixed model analysis. A total of 20 patients receiving the same-day regimen exhibited no significant change in their serum Cr level; nor was there any significant change in the serum Cr level between patients who received the same day regimen and those who received the drugs on different days. The present study demonstrated that the same-day regimen was safe for patients with urothelial cancer.

Clinical Perspectives of ERCC1 in Bladder Cancer.

ERCC1 is a key regulator of nucleotide excision repair (NER) pathway that repairs bulky DNA adducts, including intrastrand DNA adducts and interstrand crosslinks (ICLs). Overexpression of ERCC1 has been linked to increased DNA repair capacity and platinum resistance in solid tumors. Multiple single nucleotide polymorphisms (SNPs) have been detected in ERCC1 gene that may affect ERCC1 protein expression. Platinum-based treatment remains the cornerstone of urothelial cancer treatment. Given the expanding application of neoadjuvant and adjuvant chemotherapy in locally advanced bladder cancer, there is an emerging need for biomarkers that could distinguish potential responders to cisplatin treatment. Extensive research has been done regarding the prognostic and predictive role of ERCC1 gene expression and polymorphisms in bladder cancer. Moreover, novel compounds have been recently developed to target ERCC1 protein function in order to maximize sensitivity to cisplatin. We aim to review all the existing literature regarding the role of the ERCC1 gene in bladder cancer and address future perspectives for its clinical application.