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Targeted Treatment of Locally Advanced and Metastatic Urothelial Cancer: Enfortumab Vedotin in Context.

ABSTRACT: 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.

SUBMITTER: Hoffman-Censits J

PROVIDER: S-EPMC9762760 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Targeted Treatment of Locally Advanced and Metastatic Urothelial Cancer: Enfortumab Vedotin in Context.

Hoffman-Censits Jean J Maldonado Laneisha L

OncoTargets and therapy 20221215

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 ...[more]

PMID: 36545447

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Project description:BackgroundBladder cancer is the 10th most common cancer globally. The majority of bladder cancers are urothelial carcinomas (UCs), which, if locally advanced or metastatic, carry poor long-term prognosis. Cancer cells can evade the immune system by expressing the programmed cell death ligand 1 protein (PD-L1). Programmed cell death ligand 1 protein binds to programmed cell death protein 1 (PD-1) on T cells, inhibiting their antitumor action. Bladder tumor cells also overexpress nectin-4, a cell adhesion polypeptide that contributes to metastasis, worsening prognosis. Current platinum-based chemotherapy treatments are suboptimal. This review aimed to assess novel treatments for locally advanced or metastatic UC that specifically target PD-L1 or nectin-4, namely, the PD-1 inhibitor pembrolizumab and the anti-nectin-4 antibody-drug conjugate enfortumab vedotin (EV).Materials and methodsRelevant English-language peer-reviewed articles and conference abstracts from the last 5 years were identified through MEDLINE and EMBASE database searches. A narrative review was performed, with key results outlined below.ResultsPembrolizumab was demonstrated to be superior to chemotherapy as a second-line treatment for platinum-unresponsive participants in the KEYNOTE-045 trial, resulting in its Food and Drug Administration (FDA) approval. Enfortumab vedotin therapy resulted in superior outcomes compared with chemotherapy in the EV-301 trial, resulting in FDA approval for its use for patients with locally advanced or metastatic UC who had previously undergone treatment with platinum-based chemotherapy and PD-1/PD-L1 inhibitors. Positive preliminary results for pembrolizumab and EV combination therapy have led to FDA approval in patients with locally advanced or metastatic UC who are not eligible for platinum chemotherapy.ConclusionsPembrolizumab and EV represent novel treatment options for patients with locally advanced or metastatic UC with documented superior outcomes and tolerability as compared with standard chemotherapy.

Project description:BackgroundEnfortumab vedotin, a fully human monoclonal antibody-drug conjugate (ADC) directed to Nectin-4, prolonged overall survival (OS) versus standard chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma (mUC) previously receiving a programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitor and platinum-based chemotherapy in the pivotal, phase 3 EV-301 clinical trial, supporting global approvals of enfortumab vedotin monotherapy. This bridging study was the first to evaluate enfortumab vedotin monotherapy in previously treated Chinese patients with locally advanced or mUC.MethodsEV-203 was a multicenter, open-label, phase 2 study (NCT04995419) assessing efficacy, safety/tolerability, pharmacokinetics (PK), and immunogenicity of enfortumab vedotin in 40 Chinese patients (PK analysis set, n = 13) with previously treated locally advanced or mUC. Patients received enfortumab vedotin 1.25 mg/kg (Days 1, 8, and 15). Primary endpoints included confirmed objective response rate (ORR) by the independent review committee (IRC) and PK parameters of ADC, total antibody (TAb), and free monomethyl auristatin E (MMAE). Secondary endpoints included investigator-assessed confirmed ORR; investigator-/IRC-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); OS; immunogenicity; and safety/tolerability.ResultsAs of May 13, 2022, the median follow-up was 6.5 months. Confirmed ORR was 37.5% (n/N = 15/40; 95% CI: 22.7%-54.2%) by IRC and 42.5% (n/N = 17/40; 95% CI: 27.0%-59.1%) by investigator assessment. By IRC, DCR was 72.5% (n = 29), median DOR was not reached, and median PFS was 4.7 months. Median OS was not reached. Endpoints assessed by investigators were consistent with IRC assessments. Two patients discontinued treatment for treatment-related adverse events. No new safety signals were identified. ADC, TAb, and free MMAE were characterized in Chinese patients and consistent with previously characterized populations. The incidence of positive antitherapeutic antibodies postbaseline was 0%.ConclusionEnfortumab vedotin demonstrated meaningful clinical activity with a manageable safety profile in Chinese patients with previously treated locally advanced or mUC.Trial registrationClinicalTrials.gov identifier: NCT04995419.

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.).

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Targeted Treatment of Locally Advanced and Metastatic Urothelial Cancer: Enfortumab Vedotin in Context.

Publications

Targeted Treatment of Locally Advanced and Metastatic Urothelial Cancer: Enfortumab Vedotin in Context.

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