Treatment Of Urothelial Cancer Research Articles

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

Abstract 6644: aPD1 treatment of urothelial cancers is synergistically enhanced by activating anti tumor immunity using vascular targeted photodynamic therapy

Abstract Background: Recurrence and progression rate following surgical treatment of locally advanced urothelial cancer is high, underscoring the unmet need to develop an effective, well tolerated treatment strategies, particularly for high grade upper tract urothelial cancer (HG-UTUC). The treatment success of low grade UTUC by vascular targeted photodynamic therapy (VTP) with WST11 (Padeliporfin) in phase I clinical trials led the FDA to approve Phase 3 trial in a fast track, orphan drug designation for low grade UTUC (ENLIGHT). Recently, treatment with immune checkpoint inhibitor (ICIs) of the PD1/PD-L1 axis has been approved for treatment of HG-UTUC. Yet, the failure rate of aPD1 therapy in HG-UTUC is high.We hypothesized that immune checkpoint inhibition needs to be complemented by the massive priming and accrual of newly activated anti-tumor immune cells through tumor immunogenic cell death. Early evidence indicated that WST11 VTP promotes anti-tumor immunity suggesting that VTP/aPD1 combinations may significantly improve the treatment success of HG-UTUC. Methods: Mice bearing s.c. MB49-Luc, were subjected to WST11 VTP at 14d post implantation at suboptimal dose of drug or partial area of illumination. 4 or 5 doses of aPD1 were intraperitonealy administrated every 3 days starting at 1d post VTP (aPD1+1), or every 3 days till 10 days post-treatment starting at 2 days before VTP (aPD1-2). Tumor progression was followed up to 90 days post treatment using IVIS. Hematoxylin-eosin staining, and multiplex immunohistochemistry (mIHC) were performed on controls and treated animals. Results: WST11 VTP with suboptimal drug dose, aPD1+1, and aPD1-2 resulted in 17%, 23% and 43% cure at day 90 post VTP. VTP at suboptimal drug dose combined with aPD1+1 or aPD1-2, resulted in 50% and 77% cure rate at 90 days, respectively. VTP with optimal drug dose (5mg/kg) but partial illumination resulted in 20% cure rate while combining this treatment modality with aPD1-2 resulted in 90% animal cure rate at day 90.At 24h post VTP mIHC showed a 2-3 fold increase of cytotoxic T cells, dendritic and NK cells, and a ~4 folds overexpression of PD1 and PD-L1 in the treated tumor tissue. At 2 days post aPD1-2 initiation, PD1 and PD-L1 apparent expression dropped to 0 and 2 folds higher than control, respectively. Following the combined VTP and aPD1-2 treatment, both PD1 and PDL-1 contents dropped down to zero and the CD8 content reached 3 folds enhancement compared to control. Conclusions: These observations indicate that elevating the content of anti-tumor immune cells in the tumor microenvironment by VTP in combination with ICI synergistically enhances the therapeutic effect providing a much higher complete cure compared with the individual therapies. The cure rate extent strongly depends on the synchronization of the two modalities providing guidelines for the clinical management of HG-UTUC treatment. Citation Format: Lilach Agemy, Keren Sasson, Tamar Yechezkel, Rachel Hamri, Raz Robas, David Kain, Avigdor Scherz. aPD1 treatment of urothelial cancers is synergistically enhanced by activating anti tumor immunity using vascular targeted photodynamic therapy [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 6644.

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.

Peripheral neuropathy and nerve electrophysiological changes with enfortumab vedotin in patients with advanced urothelial carcinoma: a prospective multicenter cohort study.

Enfortumab vedotin is a novel antibody-drug conjugate used as a third-line therapy for the treatment of urothelial cancer. We aimed to elucidate the effect of enfortumab vedotin-related peripheral neuropathy on its efficacy and whether enfortumab vedotin-induced early electrophysiological changes could be associated with peripheral neuropathy onset. Our prospective multicenter cohort study enrolled 34 patients with prior platinum-containing chemotherapy and programmed cell death protein 1/ligand 1 inhibitor-resistant advanced urothelial carcinoma and received enfortumab vedotin. The best overall response, progression-free survival, overall survival, and safety were assessed. Nerve conduction studies were also performed in 11 patients. The confirmed overall response rate and disease control rate were 52.9% and 73.5%, respectively. The median overall progression-free survival and overall survival were 6.9 and 13.5months, respectively, during a median follow-up of 8.6months. The patients with disease control had significantly longer treatment continuation and overall survival than did those with uncontrolled disease. Peripheral neuropathy occurred in 12.5% of the patients. The overall response and disease control rates were 83.3% and 100%, respectively: higher than those in patients without peripheral neuropathy (p = 0.028 and p = 0.029, respectively). Nerve conduction studies indicated that enfortumab vedotin reduced nerve conduction velocity more markedly in sensory nerves than in motor nerves and the lower limbs than in the upper limbs, with the sural nerve being the most affected in the patients who developed peripheral neuropathy (p = 0.011). Our results indicated the importance of focusing on enfortumab vedotin-induced neuropathy of the sural nerve to maximize efficacy and improve safety.

Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer.

Antibody-drug conjugates and bicycle toxin conjugates represent a tremendous advance in drug delivery technology and have shown great promise in the treatment of urothelial cancer. Previously approved systemic therapies, including chemotherapy and immunotherapy, are often impractical due to comorbidities, and outcomes for patients with advanced disease remain poor, even when receiving systemic therapy. In this setting, antibody-drug and bicycle toxin conjugates have emerged as novel treatments, dramatically altering the therapeutic landscape. These drugs harness unique designs consisting of antibody or bicycle peptide, linker, and cytotoxic payload with more targeted delivery than conventional chemotherapy, thus eliminating malignant cells while reducing systemic toxicities. Potential targets investigated in urothelial cancer include Nectin-4, TROP2, HER2, and EphA2. Initial clinical trials demonstrated efficacy in treatment of refractory advanced urothelial cancer, as well as improvement in quality of life. These initial studies led to FDA approval of two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. Moreover, antibody-drug and bicycle toxin conjugates are being studied in ongoing clinical trials in frontline treatment of advanced disease as well as for localized cancer. These studies highlight the potential for additional future therapies with novel targets, novel antibodies, cytotoxic and immunomodulatory payloads, and unique structural designs enhancing efficacy and safety. There is increasing evidence that combinations with other cancer therapies, especially immunotherapy, improve treatment outcomes. The combination of enfortumab vedotin and pembrolizumab was recently approved for first-line treatment of advanced urothelial carcinoma. Despite the great promise of these novel drugs, robust predictive biomarkers are needed to determine the patients who would maximally benefit. This review surveys the rationale and current state of the evidence for these new drugs and describes future directions actively being explored.

Expression of Nectin-4 in Chromophobe Renal Cell Carcinoma in a Multicenter Cohort: Early Prognostic and Therapeutic Considerations

Introduction: Nectin-4 is a member of the nectin family and a calcium-independent immunoglobulin-like transmembrane protein that contributes to tumor growth and angiogenesis in malignant tumors. A nectin-4-directed antibody drug conjugate, enfortumab vedotin-ejf, has recently been approved for treatment in urothelial cancer and is currently under investigation in other tumor entities such as breast, lung, and prostate cancer. In non-clear cell renal cell carcinoma (RCC), vascular endothelial growth factor (VEGF)-directed tyrosine kinase inhibitors and checkpoint inhibitors are currently treatments of choice. However, due to the rarity of disease treatment recommendations for chromophobe RCC (chRCC) are limited and new therapeutic agents urgently needed. In this study, we investigated the expression and prognostic impact of nectin-4 in a large cohort of chRCC. Methods: Patients who underwent renal surgery due to chRCC were recruited. Clinical data were retrospectively evaluated. Tumor specimen was analyzed for nectin-4 expression by immunohistochemistry. Results: Eighty-one chRCC patients were eligible for analysis. In 15 (18.5%) samples, tumors were positive for nectin-4. No significant associations were found for nectin-4 expression and clinical attributes in patients with chRCC. Kaplan-Meier analysis disclosed a 5-year overall survival for nectin-4-negative and nectin-4-positive tumors of 91.8% versus 100.0% (p = 0.316, log rank). Conclusions: In chRCC, a small subset of tumors expresses nectin-4 potentially amenable to nectin-4-directed treatment. Expression of nectin-4 is not associated with parameters of aggressiveness or survival. Due to the rare incidence of chRCC, further studies with larger cohorts are warranted.

Abstract B128: Preclinical characterization of ETx-22, a next-generation antibody drug conjugate (ADC) targeting nectin-4

Abstract Nectin-4 is overexpressed in a variety of cancers including urothelial, breast, cervix, lung and ovarian, with low level of expression in normal tissues. Enfortumab vedotin (EV), an anti-Nectin-4 ADC with a monomethyl auristatin (MMAE) payload, has been a significant advancement in the treatment of urothelial cancer. Yet, it is associated with important skin toxicity owing to the expression of nectin-4 in the skin, and peripheral neuropathy secondary to its toxin. We have developed a next-generation anti-nectin-4 ADC, ETx-22, which consists of a humanized IgG1, Fcg-silent antibody that is bound via maleimide-ß-glucuronide poly-sarcosine linkers to 8 molecules of the topoisomerase-I inhibitor, exatecan. Here, we describe the key pharmacological experiments, in-vivo efficacy and results from the good laboratory practice (GLP) toxicology studies. In-vitro studies have shown that the ETx-22 antibody exhibits a high affinity for tumor-expressed Nectin-4, but 10-fold lower affinity for nectin-4 expressed on skin, with significantly higher internalization in tumor cells. In-vivo efficacy was evaluated in various patient-derived xenograft models. ETx-22 was shown to be consistently superior to EV as well as chemotherapy, in a broad array of tumors, including urothelial, ovarian, cervical and triple negative breast cancer irrespective of the degree of nectin-4 expression. Antitumor activity was also observed in MMAE-resistant models. GLP studies evaluated repeated doses of ETx-22 in cynomolgus monkeys at two doses, 10 and 20 mg/kg. The treatment was administered as 30-minute intravenous infusions once every 2 weeks for a total of three cycles. The ETx-22 antibody alone was also evaluated at 20 mg/kg. Both ETx-22 doses were well tolerated and all animals survived up to scheduled euthanasia. The common observation at both doses was mild multifocal skin hyperpigmentation, which was reversible. No skin rash or pruritus was reported. Mild transient decrease in red blood cells was observed in between cycles. No gastrointestinal toxicities were observed. No signs of interstitial lung disease or eye toxicity were detected. Based on these findings, the highly non- severely toxic dose (HNSTD) is at least 20 mg/kg. The half-life of ETx-22 ranged from 3.36 – 3.6 days. In conclusion, preclinical and pharmacological shows that ETx-22 has better tolerance, longer half-life, and higher efficacy to EV. No skin rash was reported in toxicology studies. A first in human study (EXCEED) is planned to start in 2023. Citation Format: Hatem Azim, Florence Lhospice, Xavier Preville, Joanna Fares, Marc Lopez, Emerence Crompot, Emmanuelle Josselin, Remy Castellano, Maria Wehbeh, Yves Collette, Jack Elands, Daniel Olive. Preclinical characterization of ETx-22, a next-generation antibody drug conjugate (ADC) targeting nectin-4 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B128.

Vaccination against Extracellular Vimentin for Treatment of Urothelial Cancer of the Bladder in Client-Owned Dogs.

It was recently shown that targeting extracellular vimentin (eVim) is safe and effective in preclinical models. Here, we report the safety and efficacy in client-owned dogs with spontaneous bladder cancer of CVx1, an iBoost technology-based vaccine targeting eVim in combination with COX-2 inhibition. This was a single-arm prospective phase 1/2 study with CVx1 in 20 client-owned dogs with spontaneous UC which involved four subcutaneous vaccinations with CVx1 at 2-week intervals for induction of antibody titers, followed by maintenance vaccinations at 2-month intervals. Additionally, daily cyclooxygenase (COX)-2 inhibition with meloxicam was given. The response was assessed by antibody titers, physical condition, abdominal ultrasound and thorax X-ray. The primary endpoints were the development of antibody titers, as well as overall survival compared to a historical control group receiving carboplatin and COX-2 inhibition with piroxicam. Kaplan-Meier survival analysis was performed. All dogs developed antibodies against eVim. Titers were adequately maintained for the duration of this study. A median overall survival of 374 days was observed, which was 196 days for the historical control group (p < 0.01). Short-term grade 1-2 toxicity at the injection site and some related systemic symptoms peri-vaccination were observed. No toxicity was observed related to the induced antibody response. A limitation of this study is the single-arm prospective setting. CVx1 plus meloxicam consistently induced efficient antibody titers, was well tolerated and showed prolonged survival. The results obtained merit further development for human clinical care.

Antibody-Drug Conjugates in the Treatment of Urothelial Cancer.

Antibody-drug conjugates (ADCs) have transformed the treatment landscape in oncology and become an essential therapeutic modality. In urothelial carcinoma (UC), the two ADCs that have been especially successful in clinical practice are enfortumab vedotin and sacituzumab govitecan. These drugs are currently approved as monotherapy for later lines of treatment in locally advanced or metastatic UC and have had a significant impact for patients with limited treatment options. Combinational trials, as well as additional ADCs, are currently being investigated in the treatment of UC for subsequent lines of therapy as overall survival rates remain dismal.

Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for Treatment of Nectin-4-expressing Cancers.

Overexpression of nectin cell adhesion protein 4 correlates with cancer progression and poor prognosis in many human malignancies. Enfortumab vedotin (EV) is the first nectin-4-targeting antibody-drug conjugate (ADC) approved by the FDA for the treatment of urothelial cancer. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV. Furthermore, ocular, pulmonary, and hematologic toxic side effects are common in nectin-4-targeted therapy, which frequently results in dose reduction and/or treatment termination. Thus, we designed a second generation nectin-4-specific drug, 9MW2821, based on interchain-disulfide drug conjugate technology. This novel drug contained a site specifically conjugated humanized antibody and the cytotoxic moiety monomethyl auristatin E. The homogenous drug-antibody ratio and novel linker chemistry of 9MW2821 increased the stability of conjugate in the systemic circulation, enabling highly efficient drug delivery and avoiding off-target toxicity. In preclinical evaluation, 9MW2821 exhibited nectin-4-specific cell binding, efficient internalization, bystander killing, and equivalent or superior antitumor activity compared with EV in both cell line-derived xenograft and patient-derived xenograft (PDX) models. In addition, 9MW2821 demonstrated a favorable safety profile; the highest nonseverely toxic dose in monkey toxicologic studies was 6 mg/kg, with milder adverse events compared with EV. Overall, 9MW2821 is a nectin-4-directed, investigational ADC based on innovative technology that endowed the drug with compelling preclinical antitumor activity and a favorable therapeutic index. The 9MW2821 ADC is being investigated in a phase I/II clinical trial (NCT05216965 and NCT05773937) in patients with advanced solid tumors.

Molecular Urothelial Tumor Cell Subtypes Remain Stable During Metastatic Evolution

Urothelial cancer (UC) care is moving toward precision oncology. For tumor biology–driven treatment of metastatic UC (mUC), molecular subtypes play a crucial role. However, it is not known whether subtypes change during metastatic evolution. To address this, we analyzed a UC progression cohort (N = 154 patients) with 138 matched primary tumors (PRIM) and synchronous or metachronous distant metastasis (MET) by immunohistochemistry, and mRNA sequencing in a subgroup of 20 matched pairs. Protein-based tumor cell subtypes and histomorphology remained stable during metastatic progression (concordance: 94%, 95% confidence interval [CI] 88–97%). In comparison, transcriptome-based molecular consensus subtypes exhibited higher heterogeneity between PRIM and MET (concordance: 45%, 95% CI 23–69%), with switches particularly occurring between luminal and stroma-rich tumors. Of note, all tumors classified as stroma rich showed luminal tumor cell differentiation. By an in-depth analysis, we found a negative correlation of luminal gene and protein expression with increasing desmoplastic stroma content, suggesting that luminal tumor cell differentiation of “stroma-rich tumors” is superimposed by gene expression signals stemming from the stromal compartment. Immunohistochemistry allows tumor cell subtyping into luminal, basal, or neuroendocrine classes that remain stable during metastatic progression. These findings expand our biological understanding of UC MET and have implications for future subtype-stratified clinical trials in patients with mUC. Patient summaryUrothelial carcinomas (UCs) occur in different appearances, the so-called molecular subtypes. These molecular subtypes will gain importance for the therapy of metastatic UCs in the future. We could demonstrate that the subtype remains stable during metastasis, which is highly relevant for future studies.

Treatment of metastatic bladder cancer: current and historical aspects

The “state-of-art” treatment approach for patients with metastatic urothelial cancer (eg, bladder cancer or other urothelial tumors of urinary tract) is platinum-containing chemotherapy, however, despite the high immediate efficacy of therapy (up to 70% of the objective response rate), long-term results of treatment remain unsatisfactory, median progression-free and overall survival usually do not exceed 6 and 12 months respectively, patients with visceral metastases or poor performance status have a particularly dismal prognosis. The most effective treatment for this disease is cisplatin-containing chemotherapy, ddMVAC (methotrexate, vinblastine, doxorubicin, cisplatin) and GC (gemcitabine, cisplatin) regimens are most effective, however, in real world setting a minority of patients can tolerate these treatment options. Recent advances in the treatment of urothelial cancer are associated with discoveries in the field of immunotherapy for this disease by targeting the PD-1/PD-L1 pathway. The most promising results in the first line of treatment for this disease based on the sequential use of cisplatin-containing chemotherapy with maintenance avelumab therapy, the latter drug has been proven to increase the overall survival of patients with metastatic urothelial cancer. This article discusses key data on the immediate and long-term effectiveness of systemic therapy for metastatic urothelial cancer, as well as potential ways to improve the results of treatment of patients with this disease, primarily through the introduction of maintenance immunotherapy into real world clinical practice and expanding the category of patients who are eligible for platinum-containing chemotherapy.

BCG downregulates PD1 and PD-L1 expression in bladder cancer cells co-cultivated with peripheral blood mononuclear cells

PurposeBCG is the standard of care to treat high risk non-muscle invasive bladder cancer (NMIBC), reducing recurrence. PD-L1 is a ligand of the co-inhibitory receptor PD1 that has been shown to be expressed by tumor cells of distinct origin related to unfavorable prognosis. The development of a new class of target drugs that inhibit PD-L1 and PD1 has opened a new perspective for urothelial cancer treatment. Although there are few studies searching for the role of BCG over PD1 and PD-L1, many clinical trials are in course using the immune checkpoint inhibitors together with BCG as a new regime to treat NMIBC.Material and methodsWe analyzed the expression of PD1 and PD-L1 using qRT-PCR in RT4 bladder cancer (BCa) epithelial cells co-cultivated with peripheral blood mononuclear cells (PBMC) after treatment with BCG.ResultsThere was a significantly reduction in PD1 and PD-L1 expression by BCa epithelial cells after BCG treatment. In PBMC PD1 was significantly overexpressed.ConclusionOur results suggest that one of the mechanisms related to the success of BCG in reducing tumor recurrence in NMIBC may be related to the negative control of PD1 and PD-L1 in tumor cells.

Urine protects urothelial cells against killing with nanosecond pulsed electric fields

The quest for safe and effective ablation resulted in the development of nanosecond pulsed electric fields (nsPEF) technology for tumor treatment. For future applications of nsPEF in urothelial cancer treatment, we evaluated the effect of urine presence at the ablation site. We prepared artificial urine (AU) with compounds commonly present in the healthy human urine at physiological concentrations. We compared nsPEF cytotoxicity for cancerous (T24) and non-cancerous (SV-HUC-1) human urothelial cell lines pulsed either in the AU or in a physiological solution (PS). Cell monolayers were exposed to trains of 300-ns, 10-Hz pulses using a two-needle electrode assembly placed orthogonal to the monolayer. The assembly produced the electric field gradually weakening with the distance from the electrodes. The electric field which killed 50 % of cells (LD50) was measured by staining with propidium iodide and matching the stained area with the simulated electric field strength. nsPEF exposure in PS was more cytotoxic to cancer cells. The AU protected both healthy and cancer urothelial cells, increasing their LD50 1.4 and 1.6 times, respectively. Omitting urea from the AU reduced the LD50 for healthy and cancer urothelial cells. Testing the role of other AU components, we found that it was the high concentration of phosphates what also rendered the protective effect of the AU. Our findings suggest that the nsPEF ablation of bladder cancer will be less efficient if the bladder is filled with urine.

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.