FGFR2/3 genomic alterations and response to Enfortumab Vedotin in metastatic urothelial carcinoma.
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ABSTRACT:
SUBMITTER: Adib E
PROVIDER: S-EPMC8880907 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundEnfortumab vedotin shows promise as a targeted therapy for advanced urothelial carcinoma, particularly in patients who have previously received platinum-based chemotherapy and an immune-checkpoint inhibitor. The EV-301 phase III trial demonstrated significantly improved overall survival and response rates compared to standard chemotherapy. However, more data, especially from larger real-world studies, are needed to further assess its effectiveness in Japanese patients.MethodsA total of 6007 urothelial cancer patients inducted with pembrolizumab as a second-line treatment were analyzed. Among them, 563 patients received enfortumab vedotin after pembrolizumab, while 443 patients received docetaxel or paclitaxel after pembrolizumab, and all were included in the study for efficacy as a life prolonging agent.ResultsThe enfortumab vedotin group showed a longer overall survival than the paclitaxel/docetaxel group (p = 0.013, HR: 0.71). In multivariate analysis, enfortumab vedotin induction was the independent risk factor for overall survival (p = 0.013, HR: 0.70). There were no significant differences in cancer-specific survival.ConclusionsEnfortumab vedotin prolonged the overall survival for Japanese advanced or metastatic urothelial carcinoma patients compared to paclitaxel or docetaxel after pembrolizumab treatment.
| S-EPMC10486515 | biostudies-literature
Project description:Enfortumab vedotin (EV) is an antibody-drug conjugate and a promising agent for metastatic urothelial carcinoma (mUC). However, evaluations in end-stage renal disease patients undergoing hemodialysis are unreported. Here, we report such a case. A 74-year-old woman with mUC, on hemodialysis for complete urinary tract extirpation, was diagnosed with multiple pulmonary metastases after treatment with gemcitabine-carboplatin followed by pembrolizumab. As third-line therapy, she received a standard dose of EV. She achieved complete response after 2 cycles without grade 3 or higher adverse events, demonstrating the utility of EV in this setting.
| S-EPMC10294212 | biostudies-literature
Project description:BackgroundPatients with advanced urothelial carcinoma have poor overall survival after platinum-containing chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor treatment.MethodsWe conducted a global, open-label, phase 3 trial of enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. Patients were randomly assigned in a 1:1 ratio to receive enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight on days 1, 8, and 15 of a 28-day cycle) or investigator-chosen chemotherapy (standard docetaxel, paclitaxel, or vinflunine), administered on day 1 of a 21-day cycle. The primary end point was overall survival.ResultsA total of 608 patients underwent randomization; 301 were assigned to receive enfortumab vedotin and 307 to receive chemotherapy. As of July 15, 2020, a total of 301 deaths had occurred (134 in the enfortumab vedotin group and 167 in the chemotherapy group). At the prespecified interim analysis, the median follow-up was 11.1 months. Overall survival was longer in the enfortumab vedotin group than in the chemotherapy group (median overall survival, 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.56 to 0.89; P = 0.001). Progression-free survival was also longer in the enfortumab vedotin group than in the chemotherapy group (median progression-free survival, 5.55 vs. 3.71 months; hazard ratio for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001). The incidence of treatment-related adverse events was similar in the two groups (93.9% in the enfortumab vedotin group and 91.8% in the chemotherapy group); the incidence of events of grade 3 or higher was also similar in the two groups (51.4% and 49.8%, respectively).ConclusionsEnfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor. (Funded by Astellas Pharma US and Seagen; EV-301 ClinicalTrials.gov number, NCT03474107.).
| S-EPMC8450892 | biostudies-literature
Project description:The treatment landscape for metastatic urothelial cancer (mUC) beyond first-line platinum-based chemotherapy has changed significantly over the last 5 years with the recent approvals of the immune checkpoint inhibitors (ICIs), fibroblast growth factor receptor (FGFR) inhibitors and most recently Enfortumab Vedotin (EV). EV is a novel antibody-drug conjugate (ADC), that delivers monomethyl auristatin E (MMAE), a microtubule-disrupting agent, inside cells harboring the cell surface nectin-4 receptor. In mUC, EV has shown encouraging response rates and received accelerated approval from the Food and Drug Administration (FDA) in December 2019 in the post-platinum and ICI setting. EV is generally well tolerated, with the main toxicities being neuropathy, skin rash, alopecia and fatigue. Notably EV can also be administered to patients with renal dysfunction, which is commonly a concern in this patient population. EV is now being tested in combination strategies and in earlier disease settings in urothelial cancers. In this review, we will discuss its mechanism of action, clinical trials leading to FDA approval as well as ongoing trials and future directions.
| S-EPMC7780177 | biostudies-literature
Project description:BackgroundAntibody-drug conjugates have recently been introduced as a treatment for advanced urothelial carcinoma. The EV-301 study demonstrated that enfortumab vedotin (EV) improved overall survival compared with conventional chemotherapy. To assess the cost-effectiveness of EV for the treatment of advanced urothelial carcinoma (UC) from a payer perspective in middle- and high-income countries.MethodsA decision analysis model was developed to assess the efficacy and economic viability of EV as a subsequent-line treatment following disease progression in patients with advanced urothelial carcinoma already treated with PD-1 or PD-L1 inhibitors. Clinical and utility values were obtained from the published literature and available databases. Cost data were obtained from payer perspectives in the United States, United Kingdom, and China. Quality-adjusted life-years (QALYs) were used to measure health outcomes, and incremental cost-effectiveness ratios (ICERs) used to evaluate cost-effectiveness in comparison to willingness-to-pay in the United States, United Kingdom, and China. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the model.ResultsCompared with chemotherapy, EV increased the benefit by 0.16-0.17 QALYs, resulting in ICERs of $2,168,746.71, $2,164,494.38, and $1,775,576.56 per QALY in the United States, United Kingdom, and China, respectively. One-way sensitivity analysis indicated that the largest effect on outcome was the utility value for progression-free survival. Probabilistic sensitivity analysis demonstrated that the probability of EV being cost-effective was 0%.ConclusionsEV provides an additional health benefit over chemotherapy for patients with advanced urothelial carcinoma but is not cost-effective from a payer perspective in the United States, United Kingdom, or China.
| S-EPMC8796084 | biostudies-literature
Project description:BackgroundTreatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited and survival is short. Enfortumab vedotin (EV) is a monoclonal anti-NECTIN4 antibody conjugated to monomethyl auristatin. It was recently approved because of superior survival in comparison to standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than patients included in clinical trials.ObjectiveTo analyze the efficacy and safety of EV in a cohort of real-world patients.Design setting and participantsRetrospective data were collected from 23 hospitals and private practices for patients with metastatic and previously treated UC who received EV either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within a compassionate use program, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards.Outcome measurements and statistical analysisAdverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.Results and limitationsThe median age for the 125 eligible patients was 66 yr (range 31-89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 for 76.0%, 2-4 for 13.6%, and unknown for 10.4% of patients. EV was administered in the fourth or later line for 44.8% of patients. The overall response rate was 41.6% (partial response 39.2%, complete response 2.4%). Median OS was 10.0 months (mo) (95% confidence interval 7.20-12.80) and median PFS was 5.0 mo (95% confidence interval 4.34-5.67). For patients with ECOG PS of 0-1, median OS was 14 mo. Any-grade AEs were observed in 67.2% and CTCAE grade ≥3 AEs in 30.4%. The most common AEs were peripheral sensory neuropathy and skin toxicity. Three fatal events (pneumonia, pneumonitis) occurred. Limitations include the retrospective design and short follow-up.ConclusionsAdministration of EV for real-world patients was feasible with an acceptable toxicity profile. No new safety signals were reported. Antitumor activity in our cohort was comparable to data previously reported for trials. In summary, our results support the use of EV in patients with metastatic UC.Patient summaryEnfortumab vedotin is a medication that improved the survival of patients with bladder cancer in comparison to standard chemotherapy in clinical trials. However, patients included in clinical trials are highly selected and results for toxicities and improvements in survival do not always transfer to the real-world setting. We analyzed data for 125 patients who were treated with enfortumab vedotin. Our results are comparable to the outcomes from clinical trials regarding the safety and efficacy of this treatment.
| S-EPMC10334227 | biostudies-literature
Project description:Locally advanced or metastatic urothelial cancer is an aggressive form of cancer with high recurrence rates and low survival. Nectin-4 is a cell adhesion molecule commonly expressed in several tumors, including high expression in urothelial cancer. Enfortumab vedotin is an antibody-drug conjugate composed of an anti-Nectin-4 humanized monoclonal antibody linked to the microtubule disrupting agent, monomethyl auristatin E. In this phase I study (NCT03070990), Japanese patients with locally advanced/metastatic urothelial cancer treated with prior chemotherapy, or ineligible for cisplatin, were randomized 1:1 to receive 1.0 mg/kg (Arm A) or 1.25 mg/kg (Arm B) enfortumab vedotin on Days 1, 8, and 15 of each 28-day cycle. Assessing the pharmacokinetic and safety/tolerability profiles of enfortumab vedotin were primary objectives; investigator-assessed antitumor activity (RECIST v1.1) was a secondary objective. Seventeen patients (n = 9, Arm A; n = 8, Arm B) received treatment. Pharmacokinetic data suggest a dose-dependent increase in enfortumab vedotin maximum concentration and area under the concentration-time curve at Day 7. Enfortumab vedotin was well tolerated across both doses. Dysgeusia and alopecia (n = 9 each) were the most common treatment-related adverse events. Regardless of attribution, grade ≥ 3 adverse events occurring in ≥2 patients were anemia and hypertension (n = 2 each). One patient achieved a confirmed complete response (Arm A) and five achieved confirmed partial responses (n = 3, Arm A; n = 2, Arm B). Objective response and disease control rates were 35.3% and 76.5%, respectively. In Japanese patients with locally advanced/metastatic urothelial cancer, enfortumab vedotin is well tolerated with preliminary antitumor activity and a pharmacokinetic profile consistent with prior reports.
| S-EPMC7340645 | biostudies-literature
Project description:Enfortumab vedotin (EV) is a novel antibody-drug conjugate that is the first in class to be FDA-approved for use in patients with treatment-refractory urothelial cancer. Enfortumab is comprised of an antibody targeting nectin-4, widely expressed in urothelial cancers, with an monomethyl auristatin E (MMAE) chemotherapy payload. To date, trials in urothelial cancers refractory to platinum-based chemotherapy, and or checkpoint inhibitors, have shown the drug is very active, with overall responses ranging from 40% to 52%. This includes patients with visceral metastasis, a known predictor of poor prognosis. EV is fairly well tolerated, including in patients who are not candidates for cisplatin, a common urothelial cancer population with significant unmet need. Side effects such as skin toxicity, fatigue, and blood sugar elevations are generally manageable with supportive care and dose modifications. Peripheral neuropathy is common and can be dose-limiting in responding patients, and rare serious skin toxicities have been reported. Trials in various disease states and in combination with checkpoint inhibitors and other agents are ongoing, with additional indications likely in the future for EV in urothelial cancer.
| S-EPMC9762760 | biostudies-literature
Project description: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.
| S-EPMC10362867 | biostudies-literature
Project description: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.
| S-EPMC10262920 | biostudies-literature