Treatment Of Metastatic Urothelial Cancer Research Articles

Abstract 1872: A next generation treatment for Nectin-4 positive cancers - Preclinical characterization of LY4052031, an anti-Nectin-4 antibody, conjugated to a novel camptothecin payload

Abstract Nectin-4 is an immunoglobulin-like antigen overexpressed in a variety of cancers including bladder, breast, NSCLC, and gastric. Normal tissues including skin, salivary glands, bladder and esophagus express only low to medium levels of Nectin-4 making the protein an attractive target for cancer therapies. The approval of enfortumab vedotin-ejfv, an anti-Nectin-4 based antibody-drug conjugate (ADC) with a microtubule inhibitor payload, either as a single agent or in combination with pembrolizumab has been a significant advancement in the treatment of metastatic urothelial cancer. We have developed a novel anti-Nectin-4 ADC with a novel topoisomerase I (TOPO 1) inhibitor drug payload. Topoisomerase inhibitor payload-based ADCs offer potential advantages compared to microtubule payload-based ADCs including a different toxicity profile and the differentiated susceptibility to resistance mechanisms, such as P-gp mediated drug efflux. LY4052031 is a fully human monoclonal anti-Nectin-4 antibody conjugated to a novel TOPO 1 inhibitor by a cleavable peptide linker at a homogeneous drug antibody ratio (DAR) of 8:1. In vitro, both LY4052031 and its unconjugated parental antibody specifically bind to Nectin-4 expressing cell lines and are quickly and efficiently internalized. LY4052031 demonstrated potent cytotoxicity on tumor cells with high and low Nectin-4 expression. Additionally, bystander activity exerted by LY4052031 on antigen negative cells co-cultured with antigen positive cells was greater than that observed with the clinical benchmark enfortumab vedotin-ejfv. In vivo studies in xenografts expressing low to high levels of Nectin-4 showed significant tumor growth inhibition following treatment with LY4052031 as monotherapy. Overall, LY4052031 exhibits specificity, selectivity, potency, and effectiveness as a next generation therapy to treat Nectin-4 positive tumors. An IND submission is planned for 2024. Citation Format: Divya Sagar, Mohan Srinivasan, Kevin Lindquist, Qianxu Guo, Wailin Wong, Maria B. Lebron, Rose Marie Sattler, Jieyu Zhou, Whitney Helms, Jeffrey Boyles, Petra Verdino, Xuan Zhao, Yvonne Mak, Joshua Park, Rikke Holmgaard, Kyla Driscoll, Omar Duramad, Kristin Bedard. A next generation treatment for Nectin-4 positive cancers - Preclinical characterization of LY4052031, an anti-Nectin-4 antibody, conjugated to a novel camptothecin payload [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1872.

Abstract 5099: Prevalence of fibroblast growth factor receptor (FGFR) alterations (alts) and programmed death-ligand 1 (PD-L1) expression (exp) in Chinese solid tumor patients (pts)

Abstract Background: PD-L1 expression drives anti-PD(L)-1 treatment decisions across many cancer indications. FGFR inhibitors have been approved for the treatment of metastatic urothelial cancer (UC) and cholangiocarcinoma with FGFR alts. BALVERSA (erdafitinib), a selective pan-FGFR kinase inhibitor, has shown clinical activity against FGFR altered solid tumors in pts who exhausted standard treatment options. It is important to understand the prevalence of FGFR alts and relationship between FGFR alts and PD-L1 expression levels in different cancer types. Methods: In this real-world study, 9937 Chinese solid tumor pts with the PD-L1 (22C3) immunohistochemistry and OrigiMed 450-gene next-generation sequencing panel results were selected. Chi-square test and Fisher test were used to explore the association between the FGFR alts and PD-L1 expression. Results: FGFR1-4 somatic alts were found in 9.0% of Chinese cancer pts evaluated. FGFR1 amplification (amp) was the most prevalent alts identified (1.9%). There were no significant differences in frequency of FGFR alts between the Chinese cohort and MSK-IMPACT cohort in each cancer type tested. Up to 40.6% of pts evaluated were PD-L1 positive (CPS ≥1 or TPS ≥1%). The PD-L1 positive rate (TPS ≥1%) in SCLC (12.4%, n=121) and NSCLC adenocarcinoma tumors (LUAD) (26.1%, n=2902) was relatively low. In few tumor types, higher expression of PD-L1 in FGFR altered samples was observed compared with FGFR unaltered samples in pan-tumor (mean TPS 14.8% vs.8.6%, P=6.0*E-9; mean CPS 6.3 vs. 6.1, P=3*E-4). Those includes LUAD (mean TPS 14.2% vs. 7.4%, P = 1.7*E-16), colorectal tumor (mean CPS 4.6 vs. 3.9, P = 4.6*E-8), and uterine tumor (mean CPS 8.1 vs. 6.5, P = 9.6*E-5). While PD-L1 expression is lower in FGFR altered samples than FGFR unaltered samples in UC (n=154; mean CPS 3.9 vs. 6.8, P = 0.004). No relationship was observed between FGFR alts and PD-L1 expression in cholangiocarcinoma (n=610). Specific FGFR alts eligible for erdafitinib UC treatment were further investigated in UC and observed with rate 10.4%, including FGFR3 short variants (9.7%) as main alts. Specific FGFR altered tumors showed similar trend with lower PD-L1 expression than FGFR unaltered tumors in UC. The inverse relationship between FGFR alts and PD-L1 expression in UC compared to other solid tumors may explain variable role of FGFRs since the predominant FGFR alt types vary among different cancer types (FGFR3 short variants enriched in UC vs no such predominant FGFR alt types in other cancer types). Conclusion: The large Chinese solid tumor cohort analysis showed comparable FGFR alts prevalence between Chinese and Western population. Differences in relationship between FGFR alts and PD-L1 expression across tumor types reflect the differential role of predominant FGFR types in each tumor type. Citation Format: Min Qing, Fei Yang, Xiaowei Chen, Xuesong Lyu, Aodi Wang, Yanfei Yu, Shibu Thomas, Longen Zhou. Prevalence of fibroblast growth factor receptor (FGFR) alterations (alts) and programmed death-ligand 1 (PD-L1) expression (exp) in Chinese solid tumor patients (pts) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5099.

Phase 2 trial of tremelimumab in patients with metastatic urothelial cancer previously treated with programmed death 1/programmed death ligand 1 blockade.

Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade has changed the landscape of treatment for metastatic urothelial cancer, but single-agent cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade in metastatic urothelial cancer has been underexplored. A prior phase 2 trial of tremelimumab in PD-1/PD-L1-blockade naive patients with metastatic urothelial cancer revealed activity comparable to that observed with PD-1/PD-L1 blockade raising the hypothesis that these classes of immune checkpoint inhibitors might be non-cross-resistant. The current phase 2 trial treated patients with PD-1/PD-L1 blockade-resistant metastatic urothelial cancer with single-agent tremelimumab (750mg intravenously every 28days for up to 7 cycles). The primary end point was objective response rate. Twenty-six patients were enrolled and 24 patients were evaluable for response. The objective response rate was 8.3%, composed of a total of two partial responses that lasted 10.9 and 24.0months. Stable disease was observed in another 20.8% of patients, with a median duration of stable disease of 5.4months. Diarrhea occurred in 15 patients (58%), elevated hepatic transaminases occurred in seven patients (27%), and adrenal insufficiency occurred in two patients (8%); one patient died after experiencing immune-related hepatitis. High dose CTLA-4 blockade in patients with PD-1/PD-L1-resistant metastatic urothelial cancer has modest activity and is associated with treatment-related toxicity similar to prior reports.

A unique dermatologic adverse event from enfortumab vedotin

Enfortumab vedotin (EV) is a novel chemotherapeutic agent used in the treatment of metastatic urothelial cancer. Although rashes are reported as a common adverse event from this therapy, a paucity of literature is available on dermatologic toxicities to EV, especially with respect to bullous dermatoses. This case report will review a unique bullous dermatosis in the setting of EV therapy, including the diagnostic workup and management. Because cutaneous adverse events to chemotherapy and immunotherapy are common and can often result in dose reduction and treatment withdrawal for cancer patients, awareness of these manifestations and understanding how to manage them is crucial to providing quality care to this patient population.

Do Cancer Genetics Impact Treatment Decision Making? Immunotherapy and Beyond in the Management of Advanced and Metastatic Urothelial Carcinoma.

Bladder cancer is one of the most commonly diagnosed genitourinary malignancies. For many years, the primary treatment for metastatic urothelial cancer (mUC) was predicated on the use of platinum-based chemotherapy. More recently, immune checkpoint inhibitors (ICIs) were approved by regulatory agencies such as the US FDA for use in both the first- and second-line settings. This review outlines the approved ICIs for mUC in the second-line setting and as an alternative to chemotherapy in the first-line setting, as well as the novel agents that have also been incorporated into the treatment of this malignancy. Single-agent ICIs are often used in second-line settings in mUC, and there are three drugs currently approved for those who progress after receiving platinum-based chemotherapy. In the first-line setting, the preferred treatment regimen remains cisplatin-based chemotherapy. However, single-agent ICI can be an alternative first-line treatment for those who are not candidates for cisplatin-based therapy. There are also clinical trials adding ICIs to chemotherapy as combination regimens. However, treatment for mUC has now expanded even beyond immunotherapy. Newer targeted agents such as erdafitinib, a fibroblast growth factor receptor inhibitor, and two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan, have been recently approved. As new drug agents are discovered, it will be important to assess both the treatment outcomes as well as the effects on patients' quality of life. Furthermore, integrating genetic and molecular information can help guide treatment decisions as next-generation sequencing is more commonly acquired during the evaluation of newly diagnosed patients with advanced and metastatic cancer.

Emerging Therapies in the Treatment of Bladder Cancer

The advent of targeted agents, such as enfortumab vedotin, erdafitinib, and sacituzumab govitecan, have revolutionized the treatment of metastatic urothelial cancer. Although these novel therapies have demonstrated favorable efficacy outcomes, their toxicity must be carefully monitored. The NCCN Guidelines for Bladder Cancer recommend platinum-based chemotherapy in this clinical context, but the combination of targeted and immunotherapeutic agents may have the potential to replace it as frontline standard of care.

The role of switch maintenance therapy in urothelial cancers.

Maintenance therapy with immune checkpoint inhibitors (ICIs) has changed the treatment paradigm of metastatic urothelial carcinoma (mUC). The JAVELIN Bladder 100 trial established avelumab, one of several ICIs in use today, as a life-prolonging maintenance therapy for patients with advanced urothelial carcinoma. Platinum-based chemotherapy is most often used in the first-line treatment of mUC, and while response rates approach about 50%, disease control is usually short-lived upon completion of the standard three to six cycles of chemotherapy. Much progress has been made in recent years in the second-line space and beyond with the use of ICIs, antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs) in eligible patients at the time of disease progression post-platinum-based chemotherapy. However, many patients with progressive mUC after first-line chemotherapy suffer from rapid progression of disease, treatment toxicity with subsequent lines of therapy, and a limited life expectancy. Until the results of the JAVELIN Bladder 100 trial were presented in 2020, there were no maintenance strategies proven to be beneficial over best supportive care after disease control is achieved with first-line platinum-based chemotherapy. To date, standard of care frontline treatment of metastatic urothelial cancer remains to be four to six cycles of platinum-based chemotherapy followed by maintenance avelumab. This review summarizes the current evidence available on maintenance therapies in mUC, as well as several highly anticipated clinical trials that we hope will result in further progress in the management of this aggressive cancer and improve patient outcomes.

153P Efficacy and toxicity of HER2-targeted antibody-drug conjugates (ADCs) in the treatment of metastatic urothelial cancer (mUC): A systematic review

mUC is an aggressive disease with limited overall survival. HER2 overexpression is associated with poor prognosis and occurs in a significant number of patients (pts) with mUC. HER2-targeted ADCs represent a promising strategy in mUC, with multiple ongoing clinical trials. We aimed to realize a systematic review of efficacy and toxicity of anti-HER2 ADCs in mUC.

Efficacy and toxicity of antibody-drug conjugates in the treatment of metastatic urothelial cancer: A scoping review.

Metastatic urothelial cancer (mUC) is an aggressive disease with limited overall survival and treatment options. Antibody-drug conjugates (ADCs) were designed with the intent to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells by linking cytotoxins to monoclonal antibodies (mAbs) and have emerged as new treatment options in mUC, mainly in chemotherapy (CT) and immune-checkpoint inhibitors (ICI)-exposed patients. We aimed to perform a scoping review to assess activity, efficacy, treatment-related adverse events (TRAEs), and impact on quality of life of ADCs in mUC. A review of the literature was performed in January 2022 using Pubmed and Embase databases according to the recommendations of the Joanna Briggs Institute. The search method involved querying for the terms "bladder carcinoma" or "urothelial carcinoma" with any of the following: "enfortumab vedotin" (EV), "sacituzumab govitecan" (SG), antibody-drug conjugate. Only prospective clinical trials were included. Ultimately, eleven clinical trials with 1417 patients were selected for inclusion, and five drugs were identified: enfortumab vedotin (EV), sacituzumab govitecan (SG), disitamab vedotin (RC48-ADC), ASG-15ME (anti-SLITRK6), and trastuzumab deruxtecan. The different ADCs have been tested mainly in phase 1 or phase 2 trials, as monotherapy or in combination with ICI. Response rate ranged from 27% with SG in previously treated patients to 73.3% with EV plus pembrolizumab in cisplatin-ineligible patients as first-line treatment. The phase 3 trial, EV-301, confirmed EV superiority over investigator-chosen CT after failure to platinum-based CT and ICI, improving overall survival (12.88 vs. 8.97 months; HR 0.70; 95% CI, 0.56-0.89; P=0.001). TRAEs of any grade occurred in more than 90% of patients in phase 2 or 3 trials, with high rates of grade 3 ≥ events ranging from 51.4 to 73.5% in different trials. TRAEs of particular interest related to EV were rash, neuropathy, and hyperglycemia. SG was associated with diarrhea and hematologic toxicity. Data from phase 2 and 3 trials of EV suggest no impact on quality of life but an improvement in pain symptoms compared to the control arm. ACDs represent a new therapeutic option for the treatment of mUC. Level-1 evidence has already been achieved by EV in the post-CT and post-ICI settings. A high incidence of potential adverse events was observed in phase 2 and 3 trials, including rash, neutropenia, hematologic toxicity, and neuropathy. Clinicians should be aware of possible adverse events and their optimal management.

Atezolizumab plus platinum-based chemotherapy as first-line therapy for metastatic urothelial cancer: A cost-effectiveness analysis.

Purpose: According to the IMvigor130 trial, adding atezolizumab to platinum-based chemotherapy was effective in the treatment of metastatic urothelial cancer (mUC). Based on the perspective of the United States and China, the current study evaluated cost-effectiveness of atezolizumab plus chemotherapy for mUC patients in the first-line setting. Methods: A partitioned survival model was adopted for mUC patients. The survival data were derived from the IMvigor130 trial. Direct cost values were collected from the Centers for Medicare and Medicaid Services (CMS), Chinese Drug Bidding Database, and published literatures. The utility and toxicity data were gathered from related research studies and IMvigor130 trial. The incremental cost–utility ratios (ICURs) and incremental cost-effectiveness ratios (ICERs) were calculated and analyzed. Scenario analyses and sensitivity analyses were performed to observe the outputs and uncertainties. Results: The base-case analysis showed that the ICUR of atezolizumab plus chemotherapy versus chemotherapy in American and Chinese settings is $ 737,371 /QALY and $ 385,384 /QALY, respectively. One-way sensitivity analyses showed that the ICUR ranged from $ 555,372/QALY to $ 828,205/QALY for the United States. Also, the range was from $ 303,099/QALY to $ 433,849/QALY in the Chinese setting. A probabilistic sensitivity analysis showed the likelihood that atezolizumab plus chemotherapy becoming the preferred strategy was a little low even if the price reduction strategy was applied. Conclusion: Adding atezolizumab to chemotherapy improved survival time, but it is not a cost-saving option compared to chemotherapy for metastatic urothelial cancer patients in the American and Chinese settings.

Personalisierte Therapie beim metastasierten Urothelkarzinom – Vision oder Wirklichkeit?

BackgroundFor many years personalized treatment of metastatic urothelial cancer (mUC) was not a priority topic in clinical treatment and research. This has changed in recent years and gene sequencing as well as the development of predictive biomarkers have also become important for UC. Alterations in fibroblast growth factor receptor 2/3 (FGFR2/3) have become established as tumor drivers and patient selection according to FGFR mutations and fusions is already included in the European guidelines of oncological and urological societies.ObjectiveThe aim of this narrative review is the presentation of the current data situation and the clinical relevance of personalized treatment for mUC.Material and methodsNo systematic review was performed.ResultsPatients with selective alterations should be included in studies or treated in the sense of individual treatment attempts according to the decision of the molecular tumor board. The data of the FGFR inhibitor erdafitinib, which has already been approved in the USA, show a response rate of 40% in pretreated patients. Other mutations, such as in the BRCA1/2 gene or TSC1, could also be therapeutically groundbreaking; however, the clinical evidence for this is still lacking. Studies involving genomically selected patients with monotherapy or combinations in treatment naïve and pretreated patients are currently ongoing and will provide more information about future treatment options and strategies.ConclusionPersonalized treatment for mUC in selected patients is a promising and effective approach and will improve the prognosis of UC patients, which has stagnated for many years.

Atezolizumab with chemotherapy in first-line treatment for metastatic urothelial cancer: a cost-effectiveness analysis.

Purpose: To evaluate the cost-effectiveness of atezolizumab plus chemotherapy as first-line treatment for metastatic urothelial cancer (mUC). Materials & methods: A Markov model was established for the analysis. Parametric survival models were used to fit to progression-free survival and overall survival data in the IMvigor130 study. A series of one-way and probabilistic sensitivity analyses were performed to test the robustness of the model. Results: The incremental cost-effectiveness ratios for atezolizumab plus chemotherapy versus chemotherapy alone were US$475,633.17 and $207,488.17 per quality-adjusted life year in the USA and China, respectively. Utility for the progression-free survival and progressive disease states, the cost of atezolizumab had the most significant impact on the incremental cost-effectiveness ratio. Conclusion: Atezolizumab plus chemotherapy is not a cost-effective treatment option as a first-line treatment for metastatic urothelial cancer.

First-line avelumab for patients with PD-L1-positive metastatic or locally advanced urothelial cancer who are unfit for cisplatin

Cisplatin-based chemotherapy is the most recommended treatment for metastatic urothelial cancer (mUC). However, about 50% of patients are considered to be cisplatin ineligible. Anti-programmed cell death protein 1/programmed death-ligand 1 (PD-L1) therapies have, nevertheless, increased the options available to clinicians and are especially valuable for treating these patients. This study therefore tested the activity and safety of avelumab as first-line therapy for mUC. Patients with mUC who were ineligible for cisplatin-based chemotherapy were screened centrally for PD-L1 expression and only those with a tumour proportion score ≥ 5% were enrolled in the trial. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were median OS, median progression-free survival, overall response rate, duration of the response, safety and tolerability. All the survival rates were estimated with the Kaplan-Meier product-limit methodology and compared across groups using the log-rank test. A total of 198 patients were screened, with 71 (35.9%) whose PD-L1 expression was ≥5% enrolled in the study. The median age was 75 years, bladder cancer was the primary tumour in 73.2% of cases and 25.3% had liver metastases. The main reasons for the cisplatin ineligibility were a low rate of creatinine clearance (<60 ml/min), present in 70.4% of patients, and an Eastern Cooperative Oncology Group performance status of 2, which affected 31%. The median OS was 10.0 months (95% confidence interval 5.5-14.5 months) and 43% of patients were alive at 1 year. A complete response was achieved in 8.5% of cases, and 15.5% had a partial response. Adverse any-grade and high-grade events occurred in 49.3% and 8.5% of patients, respectively. A grade 3 infusion reaction was the only high-grade treatment-related adverse event. No treatment-related deaths were reported. This ARIES trial confirmed the activity and safety of avelumab for treating mUC, adding a new therapy option to the armamentarium of checkpoint inhibitors already approved for platinum-ineligible, locally advanced/mUC.

Second line therapy for metastatic urothelial carcinoma. Clinical case of vinflunine use

Urothelial cancer occupies a significant place in the routine practice of cancer treatment. Systemic antitumor treatment of patients with metastatic urothelial cancer in the first line is currently well studied, has its own standards, implemented in clinical practice. However, the problem of choosing antitumor treatment for patients with metastatic urothelial cancer in the second line remains relevant. Vinflunine is one of the treatment options for such patients. This article presents the case of successful treatment of metastatic urothelial cancer in the second line with vinflunine. A 63-year-old patient with a diagnosis of C65 Urothelial cancer of the pelvis of the left kidney T3N0M1, stage IV, bone metastases. Condition after cytoreductive left-sided nephrectomy, para-aortic lymphadenectomy from 04/16/2021. Concomitant pathology: Anemia. Diabetes mellitus type 2 Hypertonic disease. As the 1st line of treatment, 6 courses of CT were performed according to the scheme: Cisplatin + Gemcitabine. The effect was evaluated according to MSCT data of 3 zones and bone scintigraphy in accordance with Recist 1.1. The best response was obtained after the 4th cycle in August 2021 in the form of stabilization. October 2021 follow-up examination revealed progression. Since October 2021, chemotherapy of the 2nd line with Vinflunin is carried out in mono mode. All AEs are well controlled and do not require discontinuation of the drug. According to the results of the control examination, stabilization was achieved. Thereby vinflunine has been shown to be effective as a second-line treatment for platinum-resistant recurrent urothelial cancer.

Efficacy and toxicity of antibody-drug conjugates (ADCs) in the treatment of metastatic urothelial cancer (mUC): A systematic review.

e16536 Background: mUC is an aggressive disease with limited overall survival. Recently, immunotherapy with checkpoint inhibitors (ICI) has dramatically improved outcomes but with limited response rates and overall survival. ADC were designed with the intent to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells by linking cytotoxins to mAbs and have emerged as a new option of treatment with promising results. We aimed to realize a systematic review of efficacy, treatment-related AEs (trAEs) and impact on quality of life of ADC in mUC. Methods: A systematic review of the literature has been performed in January 2022 using Pubmed and Embase database according to the Preferred Reported Items for Systematic Reviews and Meta-analyses (PRISMA) statement. After excluding review, duplicate and non-relevant articles, 10 clinical trials were included in the analysis. The search method involved querying for the terms bladder carcinoma or urothelial carcinoma with any of the following: enfortumab vedotin (EV), sacituzumab govitecan (SG), antibody-drug conjugate. Only prospective clinical trials were included. Results: The systematic review yielded 1103 records using MEDLINE (741 records) and EMBASE (362 records). Ultimately, 9 phase 1, 2 or 3 clinical trials with 1355 patients were selected for inclusion and 4 drugs were identified: Enfortumab vedotin (EV), sacituzumab govitecan (SG), an anti-HER2 compound (RC48-ADC), and an anti- SLITRK6 drug (ASG-15ME). Efficacy outcomes are presented in table 1. Phase 2 trials have reported promising response rates in mUC and one randomized phase 3 trial showed the superiority of EV vedotin over CT after failure to platinum-based CT and ICI with improvement in overall survival. TRAEs of any grade occurred in more than 90% of patients in phase 2 or 3 trials, with high rates of discontinuation (table 2). TRAEs of special interest related to EV were rash, neuropathy, and hyperglycemia. SG is associated with diarrhea and hematologic toxicity. Data from phase 2 and 3 trials of EV suggest no impact on quality of life and an improvement in some parameters. Conclusions: ACDs represent a very promising new option for the treatment of mUC. A phase 3 trial confirmed the superiority of EV over CT after platinum and IO failure. A high incidence of potential adverse events was observed in phase 2 and 3 trials, including rash, neutropenia, hematologic toxicity, and neuropathy. Practitioners’ oncologists should be aware of potential adverse events and optimal management. Quality of life is preserved during the treatment with EV.

Chemoimmunotherapy in urothelial cancer: concurrent or sequential?

Advances in immuno-oncology in the treatment of metastatic urothelial cancer have overturned current perspectives on the treatment of this type of tumor. The success of using Immune checkpoint inhibitors in metastatic urothelial cancer raised the question of effectiveness of immunotherapy added to standard first-line chemotherapy. This review presents data coming from actual studies examining chemotherapy and immunotherapy in urothelial cancer, or a combination of these methods. Ongoing and planned clinical studies should help identify the optimal sequencing, feasibility of combination, and best duration of treatment with checkpoint inhibitors in urothelial cancer.

Biomarkers for therapy selection in metastatic urothelial cancer

The treatment of metastatic urothelial cancer (mUC) has been transformed by recent progress in clinical trials and drug development. There are now three therapeutic classes with proven benefits in mUC: chemotherapy, immunotherapy, and targeted therapy. The optimal sequence and combination of these classes remain to be defined. Biomarker development is essential to guide treatment selection at each therapeutic juncture. Two biomarkers, programmed death-ligand 1 expression and fibroblast growth factor receptor alterations, have been incorporated into the mUC treatment paradigm thus far. This review discusses predictive biomarkers in development and their potential to influence mUC treatment selection moving forward.

Role of immunotherapy in localized muscle invasive urothelial cancer.

The standard treatment for non-metastatic muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy or trimodality therapy with chemoradiation in select patients. Pathologic complete response (pCR) to neoadjuvant chemotherapy is a reliable predictor of overall and disease-specific survival in MIBC. A pCR rate of 35–40% is attained with neoadjuvant cisplatin-based chemotherapy. With the approval of immune checkpoint inhibitors (ICIs) for the treatment of metastatic urothelial cancer, these agents are now being studied in the neoadjuvant setting for MIBC. We describe the results from clinical trials using single agent ICI, ICI/ICI and ICI/chemotherapy combination therapies in the neoadjuvant setting for MIBC. These single-arm clinical trials have demonstrated safety and pCR comparable to cisplatin-based chemotherapy. Neoadjuvant ICI is a promising approach for cisplatin-ineligible patients, and the role of adding ICIs to cisplatin-based chemotherapy is also being investigated in randomized phase III clinical trials. Ongoing biomarker research to suggest a response to neoadjuvant ICIs will also guide appropriate treatment selection. We also describe the studies using ICIs for adjuvant therapy and in combination with chemoradiation.

BPI21-004: A Qualitative Study Describing Oncology Practitioners’ Approaches to First-Line (1L) Treatment of Metastatic Urothelial Cancer (mUC) in the United States

"BPI21-004: A Qualitative Study Describing Oncology Practitioners’ Approaches to First-Line (1L) Treatment of Metastatic Urothelial Cancer (mUC) in the United States" published on 17 Mar 2021 by National Comprehensive Cancer Network.

Prognostic impact of serum cytokeratin 19 fragments in patient with metastatic urothelial cancer (mUC) treated with first-line chemotherapy.

473 Background: Even today, when several immune checkpoint Inhibitors have been approved for the treatment of metastatic urothelial cancer (mUC), cytotoxic chemotherapy (CTC) still remains the mainstay for first-line treatment. We believe that the prognostic factors for the first-line CTC have become more important again and need to be re-analyzed. Current guidelines do not yet provide recommendations for any serum tumor markers in patients with mUC. Previous studies have shown that serum cytokeratin 19 fragments levels (sCK) were correlated with depth of tumor invasion and metastatic burden in patients with bladder cancer. In this study we evaluated whether sCK, and other clinical parameters could predict overall survival (OS) in patients with mUC treated with CTC. Methods: Two hundreds fifty two patients with mUC received CTC from December 2006 to 2016 at our institution. sCK had been measured in 128 patients at diagnosis of mUC. OS rate were analyzed by Kaplan–Meier curves and log–rank test. Multivariate analysis was carried out using the Cox hazards model. Tumor burden (TB) was measured based on Response Evaluation Criteria In Solid Tumor (version 1.1). Results: Of 128 patients, with median age of 72 (44-93), 36 (28%) had lung metastasis, 11 (9%) had bone metastasis, 10 (8%) had liver metastasis (LM). Ninety five (74%) patients received platinum based chemotherapy as a first-line treatment. During the median follow-up period of 19 (1-89) months, 72 patients (70%) had died. A 1-year (1y) OS was 51% and a 2y-OS was 36%. On univariate analysis, performance status (PS) (HR2.0, p&lt;0.005), sCK (HR3.9, p&lt;0.001), CRP (HR4.0, p&lt;0.001), neutrophil-lymphocyte ratio (HR1.9, p&lt;0.049), LM (HR2.0, p=0.042) and TB (HR2.4, p&lt;0.001) were the significant prognostic factors for OS. On multivariate analysis, PS (HR2.0, 95%CI (1.05-3.85) p=0.036 ), sCK (HR3.1, 95%CI (1.3-8.3), p=0.011), and LM (HR3.0, 95%CI (1.06-6.98), p=0.022) were the independent prognostic factors for OS. Based on these 3 factors we divided patients into three groups, good risk (G, 0 factor), intermediate risk (I, 1 factor) and poor risk (P, 2-3 factors). There was a significant difference between the three groups. (G vs I: p&lt;0.001, I vs P: p=0.001). Conclusions: PS, sCK, and LM were the independent prognostic factors for OS in patients with mUC receiving CTC. For the patients in good or intermediate risk with this score, early exposure of ICIs should be performed after CTCs. Treatment strategy should be changed in patients with poor risk since CTC is primary refractory in such population.