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Locally advanced or metastatic urothelial carcinoma is a genomically and molecularly heterogeneous disease associated with various clinical outcomes. We aimed to evaluate the association between the status of p53/FGFR3 expression and the efficacy of enfortumab vedotin (EV) in metastatic urothelial carcinoma. We evaluated the association between p53 (abnormal vs. wild-type) or FGFR3 (high vs. low) expression determined by immunohistochemistry and response to EV in 28 patients with metastatic urothelial carcinoma. Overall, 60.7% showed abnormal p53, and 17.9% had high FGFR3 expression. The rates of objective response to EV were statistically higher in patients with abnormal p53 than in those with wild-type p53 (p = 0.038). Patients with pure urothelial carcinoma (n = 18) and low FGFR3 showed significantly better response to EV than those with high FGFR3. When the statuses of p53 and FGFR3 were combined, abnormal p53/low FGFR3 (vs. wild-type p53/high FGFR3) was strongly associated with favorable outcomes in both the entire cohort (p = 0.002) and in cases of pure urothelial carcinoma only (p = 0.023). Immunohistochemically abnormal p53 tumors were found to respond well to EV, while high FGFR3 tumors had a poorer response. Thus, p53 and FGFR3 are potential biomarkers for predicting response to EV treatment in patients with urothelial carcinoma. [ABSTRACT FROM AUTHOR]

Background and objective: The EV-302 trial found that the combination of enfortumab vedotin (EV) with pembrolizumab significantly improved survival for patients with metastatic urothelial carcinoma (mUC). However, given the high cost of the drugs, there is a need to assess its value by considering both efficacy and cost. This study assessed the cost-effectiveness of EV plus pembrolizumab as a first-line treatment for patients with mUC from the perspective of U.S. payers. Methods: A Markov model was developed to compare the lifetime costs and effectiveness of EV in combination with pembrolizumab with chemotherapy in the treatment of mUC patients from U.S. payer perspective. Life-years (LYs), quality-adjusted LYs (QALYs), and lifetime costs were estimated. One-way, twoway and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Additionally, subgroup analyses were performed. Results: Compared to chemotherapy, the combination of EV and pembrolizumab provided an additional 2.10 LYs and 1.72 QALYs, at an incremental cost of $962,240.8 per patient. The incremental cost-effectiveness ratio (ICER) is $558,973 per QALY. Subgroup analysis indicated that patients ineligible for cisplatin treatment had a lower ICER compared to those who were eligible for cisplatin. Conclusions: From the perspective of US payers, at a willingness-to-pay threshold of $150,000 per QALY, the combination of EV and pembrolizumab is estimated to not be cost-effective compared to traditional chemotherapy in the first-line treatment of mUC patients. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Enfortumab vedotin is an antibody drug conjugate approved for management of pretreated locally advanced or metastatic urothelial carcinoma, which is associated with a rare risk of drug extravasation and soft tissue reactions. CASE REPORT: We report two cases of EV extravasation with subsequent development of bullae and cellulitis. MANAGEMENT AND OUTCOME: They were both treated for cellulitis and had conservative management without surgical intervention and were able to resume treatment with Enfortumab vedotin without subsequent adverse events. DISCUSSION: We propose that EV acts as a vesicant upon extravasation, highlight measures to prevent extravasation events, and encourage appropriate measures when dealing such as attempt of aspiration, removal of catheter, application of compresses, and thorough documentation with photographic evidence.

• This ESMO Clinical Practice Guideline eUpdate addresses developments in first-line therapy in advanced urothelial carcinoma. • Enfortumab vedotin–pembrolizumab (EV–P) is the new standard of care in first-line advanced urothelial carcinoma. • Nivolumab–cisplatin–gemcitabine or platinum-based ChT and maintenance avelumab are alternatives if EV–P is not possible. [ABSTRACT FROM AUTHOR]

Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) targeting TROP2, which has recently been approved for treatment-refractory metastatic urothelial cancer (UC). However, the variability of TROP2 expression across different bladder cancer (BC) subtypes, as well as after enfortumab vedotin (EV) exposure, remains unknown. Using gene expression data from four clinical cohorts with >1400 patient samples of muscle-invasive BC and a BC tissue microarray, we found that TROP2 mRNA and protein are highly expressed across basal, luminal, and stroma-rich subtypes, but depleted in the neuroendocrine subtype. In addition, TROP2 mRNA levels are correlated with NECTIN4 mRNA but are more highly expressed than NECTIN4 mRNA in patient cohorts and BC cell lines. Moreover, CRISPR/Cas9-mediated knockdown of TROP2 demonstrates that its expression is one factor governing SG sensitivity. After prolonged EV exposure, cells can downregulate NECTIN4, leading to EV resistance, but retain TROP2 expression and remain sensitive to SG, suggesting nonoverlapping resistance mechanisms to these ADCs. While our findings warrant further validation, they have significant implications for biomarker development, patient selection, and treatment sequencing in the clinic as well as clinical trial design and stratification for metastatic BC patients. PATIENT SUMMARY: In this report, we investigated the expression levels of the drug target TROP2 across different molecular subtypes of bladder cancer in multiple patient cohorts and cell lines. We found high levels of TROP2 in most subtypes except in the neuroendocrine subtype. Overall, TROP2 gene expression is higher than NECTIN4 gene expression, and cells resistant to enfortumab vedotin (EV), a NECTIN4-targeting antibody-drug conjugate, remain sensitive to sacituzumab govitecan (SG). Our findings suggest that SG may be effective across most bladder cancer subtypes, including the bladder cancers previously treated with EV.

Objectives: To explore the characteristics of patients and assess the effectiveness of enfortumab vedotin (EV) in those with treatment‐resistant advanced urothelial cancer in a real‐world setting. Patients and Methods: A multicenter observational study was conducted on 103 evaluable patients with advanced urothelial cancer who received EV. Outcomes were assessed by radiographic response, progression‐free survival (PFS), and overall survival (OS), with treatment‐related adverse events (trAEs). Radiographic response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1, while trAEs were studied in line with Common Terminology Criteria for Adverse Events version 5.0. Results: The median follow‐up was 8.9 months (range, 0.1–16.4). The observed objective response rate was 50.5%. The median PFS was 6.0 months (95% CI: 4.7–9.8), and the median OS was 14.5 months (95% CI: 12.4–not reached). Out of the 103 patients, 19 (18.4%) had an Eastern Cooperative Oncology Group performance status of 2 or more, 14 (14.7%) had an non‐urothelial carcinoma histology, and 40 (38.3%) had at least one pre‐existing comorbidity. There were 26 (25.2%) patients who reported 49 trAEs, with 9 (18.3%) being grade 3 or higher. The most common trAEs included rash, occurring in 18.4%. Conclusions: This study describes the characteristics and outcomes of patients with previously treated advanced urothelial cancer receiving EV. The findings demonstrate that EV showed robust anti‐tumor activity and had manageable safety profiles outside the clinical trial setting. [ABSTRACT FROM AUTHOR]

Objectives: Enfortumab vedotin (EV) is a novel antibody–drug conjugate approved for metastatic urothelial carcinoma (UC) refractory to prior treatment with immune checkpoint inhibitors (ICIs). However, the difference in efficacy of EV after each ICIs and prognostic factors are not well known. We aimed to compare the efficacy of EV in patients with metastatic UC who were treated with avelumab or pembrolizumab and to identify the prognostic factors. Methods: The records of 100 patients with advanced metastatic UC who received EV after the administration of either avelumab or pembrolizumab were retrospectively collected from five academic hospitals in Japan. Results: The median follow-up period was 6.7 months. The median overall survival (OS) and progression-free survival (PFS) in the EV after avelumab/pembrolizumab group were not reached/14.7 months (p = 0.17) and 10.4/5.2 months (p = 0.039), respectively. The objective response rates (ORR) were 66.6% and 46.8% in EV after avelumab and EV after pembrolizumab groups, respectively (p = 0.14). Multivariate analysis identified histological variants, liver metastasis, low serum albumin levels, and high serum CRP level as significant poor prognostic factors. The median OS and PFS of cachexia patients with both low serum albumin levels and high serum CRP levels were 6.0 months and 0.93 months, respectively. Conclusion: PFS was superior in patients treated with EV after avelumab to EV after pembrolizumab. However, OS showed no significant difference between the two groups. Because the prognosis of patients with cachexia is extremely poor, the initiation of EV should be discussed in these patients. [ABSTRACT FROM AUTHOR]

Locally advanced or metastatic urothelial carcinoma is a genomically and molecularly heterogeneous disease associated with various clinical outcomes. We aimed to evaluate the association between the status of p53/FGFR3 expression and the efficacy of enfortumab vedotin (EV) in metastatic urothelial carcinoma. We evaluated the association between p53 (abnormal vs. wild-type) or FGFR3 (high vs. low) expression determined by immunohistochemistry and response to EV in 28 patients with metastatic urothelial carcinoma. Overall, 60.7% showed abnormal p53, and 17.9% had high FGFR3 expression. The rates of objective response to EV were statistically higher in patients with abnormal p53 than in those with wild-type p53 (p = 0.038). Patients with pure urothelial carcinoma (n = 18) and low FGFR3 showed significantly better response to EV than those with high FGFR3. When the statuses of p53 and FGFR3 were combined, abnormal p53/low FGFR3 (vs. wild-type p53/high FGFR3) was strongly associated with favorable outcomes in both the entire cohort (p = 0.002) and in cases of pure urothelial carcinoma only (p = 0.023). Immunohistochemically abnormal p53 tumors were found to respond well to EV, while high FGFR3 tumors had a poorer response. Thus, p53 and FGFR3 are potential biomarkers for predicting response to EV treatment in patients with urothelial carcinoma.

This study presents the enfortumab vedotin (EV) treatment analysis at our institution. We retrospectively analyzed patients with metastatic urothelial cancer (mUC) treated with EV between January 2021 and October 2023. EV was administered at 1.25 mg/kg on days 1, 8, and 15 in a 28-day cycle. Whole-body computed tomography scans were performed to assess the treatment response. Patient characteristics, treatment histories, response rates, progression-free survival, and adverse events were evaluated. Response rates were determined, and adverse events were recorded. Among the 20 patients, 70% were male and 65% had bladder tumors. Most patients had lung (65%) or lymph node (65%) metastases. The median follow-up was 11.2 months, with 45% of the patients succumbing to the disease. The overall response rate was 55%. The median progression-free and median overall survivals were 10.5 and 12.9 months, respectively. Severe adverse events occurred in 35% of patients. In this real-world study, EV demonstrated promising efficacy and manageable safety profiles in Japanese patients with mUC. The study's results were consistent with previous clinical trials, although a longer follow-up was required. Our findings support EV use as a treatment option for patients with mUC who exhibit disease progression after platinum-based chemotherapy and immune-checkpoint inhibitor therapy. [ABSTRACT FROM AUTHOR]

Objective: Enfortumab vedotin (EV) was approved for advanced urothelial carcinoma (UC) in 2021 after the EV‐301 trial showed its superiority to non‐platinum‐based chemotherapy as later‐line treatment after platinum‐based chemotherapy and immune checkpoint inhibitors including pembrolizumab. However, no study has compared EV with rechallenging platinum‐based chemotherapy (i.e., "platinum rechallenge") in that setting. Methods: In total, 283 patients received pembrolizumab for advanced UC after platinum‐based chemotherapy between 2018 and 2023. Of them, 41 and 25 patients received EV and platinum rechallenge, respectively, as later‐line treatment after pembrolizumab. After excluding two patients with EV without imaging evaluation, we compared oncological outcomes, including progression‐free survival (PFS) and overall survival (OS), between the EV (n = 39) and platinum rechallenge groups (n = 25) using propensity score matching (PSM). Results: Analyses on crude data (n = 64) showed no significant differences between the two groups regarding patients' baseline characteristics. PFS (5 months) and OS (11 months) in the EV group were comparable to those (8 and 12 months, respectively) in the platinum rechallenge group. After PSM (n = 36), the baseline characteristics between the two groups became more balanced, and PFS (not reached) and OS (not reached) in the EV group were comparable to those (8 and 11 months, respectively) in the platinum rechallenge group. Conclusions: EV and platinum rechallenge showed equivalent oncological outcomes, even after PSM, and both treatments should therefore be effective treatment options for post‐platinum, post‐pembrolizumab advanced UC. [ABSTRACT FROM AUTHOR]

Megan Giles,1 Simon J Crabb1,2 1Department of Medical Oncology, University Hospital Southampton NHS Foundation Trust, Southampton, UK; 2School of Cancer Sciences, University of Southampton, Southampton, UKCorrespondence: Simon J Crabb, University of Southampton, Mailpoint 824, Centre for Cancer Immunology, Southampton General Hospital, Southampton, SO16 6YD, UK, Email S.J.Crabb@southampton.ac.ukAbstract: Muscle-invasive bladder cancer has poor prognosis. If organ confined, it is potentially curable; however, across all prognostic groups, approximately half of patients will relapse. For patients with advanced disease, the median overall survival remains under two years. Systemic treatment options are centered on the use of platinum-based combination chemotherapy, with the choice of cisplatin- or carboplatin-based regimens determined on the basis of criteria including performance status and renal function. PD-1/PD-L1 checkpoint-directed immunotherapy has been established for use in advanced disease with modest overall improvements in survival outcomes. Based on current data, optimal utilization appears to be a switch maintenance strategy on completion of chemotherapy. In the curative setting, cisplatin-based chemotherapy provides modest improvements in cure rates in those fit to receive it. Data on the use of adjuvant immunotherapy are currently contradictory, with disease-free survival demonstrated for adjuvant nivolumab, but not atezolizumab, and no overall survival benefit has yet been confirmed. The Nectin-4 directed antibody drug conjugate enfortumab vedotin is an established treatment option for patients previously treated with both chemotherapy and immunotherapy. The emerging therapeutic targets under evaluation include Trop-2 with sacituzumab govitecan, fibroblast growth factor receptors, HER2, and DNA repair deficiency in biomarker-selected patients. The development of properly validated predictive biomarkers has proven challenging for this disease and should be a central priority in the future development of treatment options. This review summarizes the available systemic treatment options in both palliative and curative disease settings, and highlights the available evidence and current limitations for making treatment recommendations.Keywords: bladder cancer, urothelial carcinoma, chemotherapy, immunotherapy, enfortumab vedotin

We report the case of a 68-year-old man who developed a sigmoidorectal fistula after marked response to enfortumab vedotin for advanced bladder cancer. The patient had undergone radical cystectomy with ileal conduit after neoadjuvant chemotherapy. Six months after surgery, local recurrence in the pelvic cavity and multiple lung metastases were found, and the patient was administered pembrolizumab as second-line therapy. Due to worsening local recurrence and suspected invasion of the sigmoid colon and rectum, enfortumab vedotin was initiated as third-line therapy and comprehensive genomic profiling was simultaneously performed. Enfortumab vedotin was remarkably effective, the lung metastases disappeared, and the local recurrent lesion shrank in volume although a sigmoidorectal fistula was found to form through the tumor cavity. Immunohistochemical analysis of the tumor specimens exhibited increased nectin-4 expression. This rare case of metastatic bladder cancer with sigmoidorectal fistula associated with effective enfortumab vedotin therapy suggests that nectin-4 expression and comprehensive genomic profiling might be useful in predicting treatment response to enfortumab vedotin. [ABSTRACT FROM AUTHOR]

The standard of care for advanced urothelial carcinoma includes platinum chemotherapy and immunotherapy. Antibody-drug conjugates (ADCs), originally developed for hematologic malignancies, involve potent cytotoxic agents linked to antibodies that recognize tumor-specific antigens; this rational drug design allows for more on-target efficacy, while mitigating systemic toxicity. Herein, we review the emerging landscape of ADCs in urothelial carcinoma. The anti-Nectin-4 ADC enfortumab vedotin has demonstrated efficacy in prospective studies in patients with advanced urothelial carcinoma in several settings either alone or in combination with pembrolizumab. The anti-Trop-2 ADC sacituzumab govitecan has also shown efficacy in single-armed studies. Both conjugates have full or accelerated approval from the Food and Drug Administration. Common adverse events include rash and neuropathy for enfortumab vedotin and myelosuppression and diarrhea for sacituzumab govitecan. Several anti-human epidermal growth factor receptor 2 ADCs are in clinical trials, and in localized bladder cancer, the anti-epithelial cell adhesion molecule ADC oportuzumab monatox is being studied in patients refractory to intravesical bacillus calmette-guerin therapy. Antibody-drug conjugates for urothelial carcinoma are approved and emerging as therapies for patients with advanced urothelial carcinoma, filling a prior void for treatment of progressive disease. Ongoing studies are also evaluating these agents in the neoadjuvant and adjuvant settings. [ABSTRACT FROM AUTHOR]

Metastatic urothelial carcinoma (mUC) is an aggressive malignancy with a dismal prognosis. Enfortumab vedotin (EV) is an antibody-drug conjugate consisting of an antibody targeting Nectin-4. This protein is highly expressed in UC cells. After binding, monomethyl auristatin E is released into cells, causing UC cell death. EV has been approved as a single agent for pre-treated mUC, with interesting improvements in response rate and survival in a setting with limited treatment options. More recently, EV approval occurred in cisplatin-ineligible naïve mUC patients in combination with pembrolizumab. Our review aims to summarize the pharmacological properties, clinical studies, and future developments of EV inmUC. [ABSTRACT FROM AUTHOR]

Enfortumab vedotin (EV) is an antibody-drug conjugate approved for the treatment of refractory advanced urothelial cancer. Cutaneous toxicity is well described but has not been correlated with response. In this retrospective single-center study, data from patients treated with more than one dose of EV between December 2017 and June 2022 were analyzed. Of 56 patients with a median age of 69 yr, 41 (73.2%) were male and 27 (48.2%) had any-grade skin toxicity. For all 51 patients evaluable by physician-assessed Response Evaluation Criteria in Solid Tumors (RECIST) criteria, the response rate was 41.2%. For those with cutaneous toxicity, the response rate was 57.7%; for those without cutaneous toxicity, it was 24.0% (p = 0.0145). All three patients with complete response experienced cutaneous toxicity, and two of these responses remain durable 5 and 24 mo off EV. The median starting weight and body mass index (BMI) were, respectively, 80.86 kg and 26.53 kg/m2 among patients with cutaneous toxicity, and 69.37 kg and 23.29 kg/m2 in patients without (p = 0.0129 and 0.0014, respectively). In this small dataset, EV-related cutaneous toxicity was more common in patients with higher weight and BMI at baseline, and was associated with disease response. Confirmation in prospective trials may confirm this association and lead to an important clinical biomarker of response. Patient summary: We evaluated patients with urothelial cancer who were treated at our institution with enfortumab vedotin (EV). We found that patients who experienced the common side effect of any type of skin toxicity, such as rash or itching, were more likely to have improvement in their cancer from EV treatment than those who did not experience skin toxicity. Patients with higher weight and body mass index when starting EV tended to have more skin toxicity. We conclude that presence of skin toxicity might help doctors make decisions about how to manage the care of patients with EV in the future.

Metastatic urothelial carcinoma (mUC) is an aggressive malignancy with a dismal prognosis. Enfortumab vedotin (EV) is an antibody-drug conjugate consisting of an antibody targeting Nectin-4. This protein is highly expressed in UC cells. After binding, monomethyl auristatin E is released into cells, causing UC cell death. EV has been approved as a single agent for pre-treated mUC, with interesting improvements in response rate and survival in a setting with limited treatment options. More recently, EV approval occurred in cisplatin-ineligible naïve mUC patients in combination with pembrolizumab. Our review aims to summarize the pharmacological properties, clinical studies, and future developments of EV in mUC.

We report a 76-year-old man who was treated for hyperglycemia and metabolic acidosis after chemotherapy with enfortumab vedotin and pembrolizumab administered after his surgery for bladder cancer. He had an approximately 20-year history of diabetes. His body mass index was 18.6, and he received metformin 1000 mg/day, sitagliptin 50 mg/day, mitiglinide 30 mg/day, and voglibose 0.6 mg/day with hemoglobin A1c was approximately 7%. He underwent total cystectomy and ileal conduit reconstruction. After relapse, he received chemotherapy but later developed hyperglycemia and metabolic acidosis. His hyperglycemia was caused by enfortumab vedotin, and metabolic acidosis was attributable to the ileocecal canal. These symptoms should be remembered as important complications of this standard treatment, which prompted this case report. [ABSTRACT FROM AUTHOR]

Urothelial carcinoma is a common malignancy that affects the urinary system, with bladder cancer being the most prevalent form. Although the management of early-stage disease has seen significant improvements, the treatment of locally advanced and metastatic urothelial carcinoma remains challenging. Over the past decade, there has been an explosion in the number of therapies available for the treatment of advanced disease, with immune checkpoint inhibitors and antibody-drug conjugates leading the way. Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, a protein that is overexpressed in urothelial carcinoma cells. In clinical trials, it has shown promising outcomes for the treatment of advanced urothelial carcinoma that has progressed after chemotherapy or immunotherapy. The US Food and Drug Administration has granted expedited approval for enfortumab vedotin in the treatment of advanced urothelial carcinoma. This review provides an overview of the current and emerging treatments for urothelial carcinoma, with a particular focus on enfortumab vedotin. We discuss the mechanisms of action, clinical efficacy, safety, and ongoing research of enfortumab vedotin, along with the current landscape of other approved therapies and promising agents in development. The aim of this review is to provide a comprehensive and up-to-date summary of the available treatment options for urothelial carcinoma, including their limitations and future prospects. [ABSTRACT FROM AUTHOR]

This article, titled "Editorial: Innovative molecular therapeutic approaches in urothelial carcinoma," discusses various innovative molecular therapeutic approaches in the treatment of urothelial cell carcinoma (UCC). UCC is a common cancer, with a higher incidence in men compared to women. The article highlights the use of targeted therapies and antibody drug conjugates (ADCs) in the treatment of UCC, as well as the potential biomarkers for targeted therapy. It also explores the efficacy of enfortumab-vedotin (EV) in metastatic UCC and the expression of HER2 in UCC. Additionally, the article discusses the impact of antibiotic use on the efficacy of intravesical Bacillus Calmette-Guerin (BCG) therapy and the characteristics of upper tract UCC. The authors emphasize the importance of molecularly targeted therapies in improving treatment outcomes for UCC. [Extracted from the article]

The therapeutic landscape in advanced urothelial carcinoma (aUC) has been rapidly evolving over the last 6 years. Enfortumab vedotin (EV) is an antibody–drug conjugate that targets Nectin-4, which is widely expressed in UC. EV is approved by the US Food and Drug Administration for patients with aUC refractory to prior therapy. EV is now being investigated in combination with other therapeutic agents, such as immune checkpoint inhibitors, both in first-line and refractory settings in aUC as well as earlier therapy settings. In this review, we summarized the role of EV in the rapidly evolving therapeutic landscape of aUC. [ABSTRACT FROM AUTHOR]

• This study is the first to explore the impact of organ-specific tumor response to enfortumab vedotin in patients with metastatic urothelial carcinoma. • The most prominent organ-specific response rate was found in liver metastasis, and the least in bone metastasis. • Tumor burden reduced by 50% or more in lymph node, lung, and liver metastases. • No prognostic differences were found with respect to the organ-specific overall survival. To evaluate the organ-specific therapeutic effect of enfortumab vedotin (EV) after chemotherapy and immunotherapy failed for advanced urothelial carcinoma. At 6 institutions between December 2021 and July 2023, we retrospectively analyzed patients with metastatic upper and lower urinary tract cancer who received EV monotherapy after platinum-based chemotherapy and immune checkpoint blockade therapy. Objective response rate (ORR) and organ-specific response rate (OSRR) were evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1. This study analyzed 58 patients with 210 tumor lesions, of which 24% were females and 48% had upper urinary tract cancer. The ORR and disease control rate were 53.5% and 74.1%. Moreover, we found 15 target lesions in the primary site, 7 in local recurrence, 93 in the lymph nodes, 46 in the lung, 29 in the liver, and 20 in the bone, with OSRRs of 40%, 71.4%, 61.1%, 70.6%, 90.9%, and 18.2%, respectively. Over time from baseline, the reduction rate (median) in tumor burden was 50% or more in the lymph node, lung, and liver metastases. The organ-specific tumor response to EV in patients with metastatic urothelial carcinoma was almost favorable. The antitumor activity of EV monotherapy may be less in bone metastasis than in other organ sites. Conversely, EV showed remarkably high efficacy against liver metastasis. Advanced urothelial carcinoma with metastasis is clinically aggressive. We evaluated the organ-specific response to enfortumab vedotin treatment after platinum-based chemotherapy and immune checkpoint blockade therapy failed in patients with metastatic bladder and upper urinary tract cancer. A promising antitumor activity was observed regardless of the organ involved. [ABSTRACT FROM AUTHOR]

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 agent linked 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. [ABSTRACT FROM AUTHOR]

Metastatic urothelial carcinoma is an aggressive malignancy with a poor prognosis. Research in recent years has led to the approval of new treatments that offer improved survival for patients. Enfortumab vedotin-ejfv is a first-in-class monoclonal antibody drug conjugate that binds Nectin-4, a protein expressed on bladder cancer cells, and delivers the tubulin toxin, monomethyl auristatin E, into the cell causing cell death. Enfortumab vedotin-ejfv has changed the standard of care treatment in urothelial carcinoma with a high response and disease-control rate, acceptable toxicity profile and improved overall survival for patients who previously had limited options after failure of chemotherapy and/or immunotherapy. We review the pharmacology, clinical efficacy, safety, and tolerability of enfortumab vedotin. Enfortumab vedotin-ejfv has shown promising efficacy and safety in pretreated patients with advanced urothelial carcinoma. It is currently being evaluated in clinical trials in earlier lines of treatment and in combination therapy. [ABSTRACT FROM AUTHOR]

Purpose The treatment landscape of advanced bladder cancer continues to evolve with novel therapeutics approved in recent years and many in the pipeline. Here we review the role of the novel agents enfortumab vedotin and sacituzumab govitecan in treatment of advanced disease. Summary Patients with advanced bladder cancer often first receive platinum-based therapy, while immune checkpoint inhibitors offer a maintenance option following cytotoxic chemotherapy or a second-line option. Despite various first- and second-line options, patients with significant comorbidities and treatment-related adverse events will experience disease progression requiring alternative treatment. Enfortumab vedotin and sacituzumab govitecan are novel antibody-drug conjugates approved in patients with advanced bladder cancer following platinum-based and immune checkpoint inhibitor therapy. Following platinum-based therapy and immunotherapy in patients with advanced bladder cancer, enfortumab vedotin, targeting Nectin-4, improves overall survival while sacituzumab govitecan, targeting Trop-2, is associated with a 27% response rate. With these new approaches to disease management, however, it remains critical to understand safety, efficacy, and operational considerations to optimize outcomes. Conclusion When selecting an antibody-drug conjugate to treat patients with bladder cancer, it is important to note the adverse event profile of each agent to optimize outcomes and safety for patients. [ABSTRACT FROM AUTHOR]

Background: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for advanced urothelial cancer (aUC) refractory to prior therapy. In the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study, the authors looked at the experience with EV in patient subsets of interest for which activity had not been well defined in clinical trials.Methods: UNITE was a retrospective study of patients with aUC treated with recently approved agents. This initial analysis focused on patients treated with EV. Patient data were abstracted from chart reviews by investigators at each site. The observed response rate (ORR) was investigator-assessed for patients with at least 1 post-baseline scan or clear evidence of clinical progression. ORRs were compared across subsets of interest for patients treated with EV monotherapy.Results: The initial UNITE analysis included 304 patients from 16 institutions; 260 of these patients were treated with EV monotherapy and included in the analyses. In the monotherapy cohort, the ORR was 52%, and it was >40% in all reported subsets of interest, including patients with comorbidities previously excluded from clinical trials (baseline renal impairment, diabetes, and neuropathy) and patients with fibroblast growth factor receptor 3 (FGFR3) alterations. Progression-free survival and overall survival were 6.8 and 14.4 months, respectively. Patients with a pure urothelial histology had a higher ORR than patients with a variant histology component (58% vs 42%; P = .06).Conclusions: In a large retrospective cohort, responses to EV monotherapy were consistent with data previously reported in clinical trials and were also observed in various patient subsets, including patients with variant histology, patients with FGFR3 alterations, and patients previously excluded from clinical trials with an estimated glomerular filtration rate < 30 mL/min and significant comorbidities.Lay Summary: Enfortumab vedotin, approved by the Food and Drug Administration in 2019, is an important new drug for the treatment of patients with advanced bladder cancer. This study looks at the effectiveness of enfortumab vedotin as it has been used at multiple centers since approval, and focuses on important patient populations previously excluded from clinical trials. These populations include patients with decreased kidney function, diabetes, and important mutations. Enfortumab vedotin is effective for treating these patients. Previously reported clinical trial data have been replicated in this real-world setting, and support the use of this drug in broader patient populations. [ABSTRACT FROM AUTHOR]

This retrospective study demonstrates poor outcomes of metastatic urothelial carcinoma patients following discontinuation of Enfortumab Vedotin (EV). Only 51% received therapy after discontinuation of EV. Benchmarks for the interpretation of activity of new agents following EV were identified. The duration of EV was identified as a potential prognostic factor following discontinuation of EV. Background: Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue. Methods: Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors. Objective response rate (ORR) was evaluated in those who received therapy post-EV. Statistical analyses were performed to describe the overall survival (OS) and compare patient characteristics and outcomes of those who did or did not receive treatment post-EV. Results: Data were available for 63 patients from 6 institutions: 46 (73%) were male and median age was 68 years (range 43-83). The median OS was 32 weeks. Thir ty-t wo patients (51%) received therapy after EV. The OS of those who did vs. did not receive post-EV therapy was significantly different (median 43.1 vs. 16.9 weeks, P = .015). Longer duration of prior EV therapy was associated with receipt of post-EV therapy (P = .0437) as well as OS in both the treated (P = .045) and untreated groups (P = .012). Objective response was observed in 3 of 32 patients (9.4%) who received therapy post-EV. Conclusion: Outcomes of patients with mUC following discontinuation of EV are dismal and only 51% received therapy after discontinuation of EV. This study identifies benchmarks for the interpretation of activity of new agents following EV and raises the hypothesis for duration of EV as a potential prognostic factor following discontinuation of EV. [ABSTRACT FROM AUTHOR]

Enfortumab vedotin (EV) was FDA approved in December 2019 for platinum- and checkpoint-refractory urothelial cancer based on an exceptional 44% response rate, and is currently approved for use after platinum and checkpoint inhibitor therapy. Enfortumab is an antibody-drug conjugate that targets Nectin-4, which is widely expressed in urothelial cancer. Despite this ample target, clinical benefit is not achieved by all patients, and mechanisms of treatment resistance are undescribed. Herein we summarize what is known to date regarding coorelative findings and subgroup analysis and EV response, including novel biopsy data in patients with tumor progression post EV. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the pharmacology, pharmacokinetics, clinical efficacy, safety, dosing, cost, and clinical implications of enfortumab vedotin-ejfv (EV) in the treatment of locally advanced or metastatic urothelial carcinoma (UC).Data Sources: A literature search of PubMed (inception to August 2020) was conducted using the terms enfortumab, vedotin, Padcev, and Nectin. Data were also obtained from package inserts, meeting abstracts, and ongoing studies from ClinicalTrials.gov.Study Selection and Data Extraction: All relevant published articles, package inserts, and meeting abstracts evaluating EV for the treatment of UC were analyzed.Data Synthesis: Antibody-drug conjugates (ADCs) deliver potent cytotoxic agents using highly selective monoclonal antibodies. Targeting the near-universal expression of Nectin-4 on UC cells is a viable therapeutic strategy. In a pivotal phase II trial, EV demonstrated an overall response rate of 44%, and a median duration of response of 7.6 months. Estimated overall survival was 11.7 months with a median estimated progression-free survival of 5.6 months. Results were similar among difficult-to-treat patients, including those with liver metastases. Unique toxicity concerns with EV require careful consideration and monitoring.Relevance To Patient Care and Clinical Practice: EV, a first-in-class anti-Nectin-4 ADC, provides impressive response rates with manageable toxicities, making it a promising treatment option for patients with multiply relapsed or refractory UC.Conclusion: The US Food and Drug Administration-approved EV demonstrates antitumor activity in heavily pretreated patients with UC but harbors important adverse effects and financial concerns. Additional studies are required to identify the optimal sequencing, patient population, and place in therapy for EV. [ABSTRACT FROM AUTHOR]

Enfortumab vedotin is a Nectin-4 directed antibody-drug conjugate approved in metastatic urothelial carcinoma following progression on a platinum-containing chemotherapy and immune checkpoint blockade. On-target dermatologic toxicity may occur from Nectin-4 expression in the skin. We highlight a case of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis following enfortumab infusions that was ultimately fatal. The second case describes an erythema multiforme-like rash with interface dermatitis related to enfortumab. Dermatologic findings, immunohistochemistry studies, and immune profiling are detailed. These cases demonstrate the potentially catastrophic outcomes in some patients treated with enfortumab. Patients must be monitored for cutaneous toxicities with early involvement of dermatology and dermatopathology.

Enfortumab vedotin is a Nectin-4 directed antibody-drug conjugate approved in metastatic urothelial carcinoma following progression on a platinum-containing chemotherapy and immune checkpoint blockade. On-target dermatologic toxicity may occur from Nectin-4 expression in the skin. We highlight a case of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis following enfortumab infusions that was ultimately fatal. The second case describes an erythema multiforme-like rash with interface dermatitis related to enfortumab. Dermatologic findings, immunohistochemistry studies, and immune profiling are detailed. These cases demonstrate the potentially catastrophic outcomes in some patients treated with enfortumab. Patients must be monitored for cutaneous toxicities with early involvement of dermatology and dermatopathology. [ABSTRACT FROM AUTHOR]

Introduction: In December 2019, the US Food and Drug Administration granted accelerated approval to the novel nectin-4-targeting antibody-drug conjugate, enfortumab vedotin, for the treatment of platinum-refractory and immune checkpoint blockade-refractory locally advanced or metastatic urothelial carcinoma. Antibody-drug conjugates represent a new therapeutic modality in urothelial cancer; and beyond nectin-4, agents targeting Trop-2, HER2, and EpCAM are also in clinical development.Areas Covered: This review outlines the biologic rationale and the clinical development of novel antibody-drug conjugates for the treatment of urothelial cancer across the spectrum of disease from non-muscle-invasive bladder cancer through treatment-refractory metastatic disease.Expert Opinion: The high response rates observed with enfortumab vedotin - both as monotherapy and in combination with checkpoint blockade immunotherapy - suggest this and other antibody-drug conjugates may have efficacy similar to or even exceeding that of traditional cytotoxic chemotherapy. Ongoing clinical development of antibody-drug conjugates in urothelial cancer will address the optimal combination or sequencing strategy with anti-PD-1/L1 immunotherapy and platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

Urothelial Carcinoma (UC) is the second most common malignancy of the genitourinary system and is the sixth most common cancer in the USA. Over a decade prior to 2016, the standard of care for early disease consisted of transuretheral resection of the bladder tumor with or without intravesicular chemotherapy or immunotherapy. Systemic chemotherapies such as gemcitabine and cisplatin combinations or dose-dense methotrexate, vinblastine, doxorubicin, cisplatin were reserved for recurrent, muscle-invasive, advanced or metastatic disease. Novel treatment approaches for UC have significantly impacted the management of patients. In 2016–2017, five immune checkpoint inhibitors marked a new paradigm in the treatment of UC for patients with advanced or metastatic disease or who are unable to tolerate platinum-based chemotherapy. Most recently, the U.S. Food and Drug Administration set restrictions on two commonly utilized checkpoint inhibitors, atezolizumab and pembrolizumab, in the first-line setting in patients with UC due to decreased survival associated with low expression of the protein programmed death ligand 1. Furthermore, Breakthrough Therapy Designations have been granted for enfortumab vedotin and erdafitinib for patients following platinum-based chemotherapy and those with fibroblast growth factor receptor mutated UC, respectively. Additional updates include dose-dense gemcitabine and cisplatin for muscle-invasive bladder cancer and preoperative checkpoint blockade. This article will review the available data on updates in the treatment of UC and future direction of therapies. [ABSTRACT FROM AUTHOR]

The fact that there are now five immune checkpoint inhibitor (ICI) monoclonal antibodies approved since 2016 that target programmed cell death protein 1 or programmed death ligand-1 for the treatment of metastatic and refractory bladder cancer is an outstanding achievement. Although patients can display pronounced responses that extend survival when treated with ICIs, the main benefit of these drugs compared to traditional chemotherapy is that they are better tolerated and result in reduced adverse events (AEs). Unfortunately, response rates to ICI treatment are relatively low and, these drugs are expensive and have a high economic burden. As a result, their clinical efficacy/cost-value relationship is debated. Long sought after targeted molecular therapeutics have now emerged and are boasting impressive response rates in heavily pre-treated, including ICI treated, patients with metastatic bladder cancer. The antibody-drug conjugates (ADCs) enfortumab vedotin (EV) and sacituzumab govitecan (SG) have demonstrated the ability to provide objective response rates (ORRs) of 44% and 31% in patients with bladder tumor cells that express Nectin-4 and Trop-2, respectively. As a result, EV was approved by the U.S. Food and Drug Administration for the treatment of patients with advanced or metastatic bladder cancer who have previously received ICI and platinum-containing chemotherapy. SG has been granted fast track designation. The small molecule Erdafitinib was recently approved for the treatment of patients with advanced or metastatic bladder cancer with genetic alterations in fibroblast growth factor receptors that have previously been treated with a platinum-containing chemotherapy. Erdafitinib achieved an ORR of 40% in patients including a proportion who had previously received ICI therapy. In addition, these targeted drugs are sufficiently tolerated or AEs can be appropriately managed. Hence, the early performance in clinical effectiveness of these targeted drugs are substantially increased relative to ICIs. In this article, the most up to date follow-ups on treatment efficacy and AEs of the ICIs and targeted therapeutics are described. In addition, drug price and cost-effectiveness are described. For best overall value taking into account clinical effectiveness, price and cost-effectiveness, results favor avelumab and atezolizumab for ICIs. Although therapeutically promising, it is too early to determine if the described targeted therapeutics provide the best overall value as cost-effectiveness analyses have yet to be performed and long-term follow-ups are needed. Nonetheless, with the arrival of targeted molecular therapeutics and their increased effectiveness relative to ICIs, creates a potential novel paradigm based on ‘targeting’ for affecting clinical practice for metastatic bladder cancer treatment.