Dataset Information

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer.

ABSTRACT:

Purpose

Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting.

Patients and methods

In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms.

Results

The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%).

Conclusion

EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.

SUBMITTER: O'Donnell PH

PROVIDER: S-EPMC10852367 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer.

O'Donnell Peter H PH Milowsky Matthew I MI Petrylak Daniel P DP Hoimes Christopher J CJ Flaig Thomas W TW Mar Nataliya N Moon Helen H HH Friedlander Terence W TW McKay Rana R RR Bilen Mehmet A MA Srinivas Sandy S Burgess Earle F EF Ramamurthy Chethan C George Saby S Geynisman Daniel M DM Bracarda Sergio S Borchiellini Delphine D Geoffrois Lionnel L Maroto Rey Jose Pablo JP Ferrario Christiano C Carret Anne-Sophie AS Yu Yao Y Guseva Maria M Homet Moreno Blanca B Rosenberg Jonathan E JE

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20230627 25

<h4>Purpose</h4>Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting.<h4>Patients and methods</h4> ...[more]

PMID: 37369081

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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: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.).

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:ImportanceMetastatic urothelial carcinoma (mUC) presents a therapeutic challenge with poor outcome. Enfortumab vedotin has emerged as a promising treatment, necessitating a comprehensive evaluation of its effectiveness and safety.ObjectiveTo synthesize the available evidence on enfortumab vedotin, both as monotherapy and in combination with pembrolizumab, as an mUC treatment for the purpose of guiding clinical decision-making and future research.Data sourcesCochrane Library, MEDLINE (via PubMed), Google Scholar, and Web of Science were searched from database inception to August 31, 2024. Major conference abstracts from 2019 to 2024 were also included. Search strategy used a combination of Medical Subject Heading terms and free-text keywords related to mUC and enfortumab vedotin.Study selectionRandomized clinical trials and prospective studies investigating enfortumab vedotin in adult patients with mUC were included. Eleven studies met the inclusion criteria.Data extraction and synthesisTwo independent reviewers extracted data and assessed study quality using the Cochrane Risk of Bias tool 2 and Risk of Bias in Non-Randomized Studies of Interventions tool. The meta-analysis used a random effects model, while a network meta-analysis was performed using a frequentist approach.Main outcomes and measuresPrimary outcomes were disease control rate (DCR), objective response rate (ORR), and 1-year survival rate.ResultsThe 11 included studies (3 randomized clinical trials [27.3%] and 8 nonrandomized prospective studies [72.7%]) involved 2128 patients. Of these patients, 563 (26.5%) received enfortumab vedotin plus pembrolizumab, 814 (38.3%) received enfortumab vedotin without pembrolizumab, and 751 (35.3%) received chemotherapy. Enfortumab vedotin plus pembrolizumab was associated with a pooled DCR of 86% (95% CI, 83%-89%), ORR of 68% (95% CI, 64%-71%), and a 1-year survival rate of 79% (95% CI, 75%-82%). Enfortumab vedotin monotherapy had a pooled DCR of 73% (95% CI, 70%-76%), ORR of 43% (95% CI, 40%-47%), and a 1-year survival rate of 52% (95% CI, 48%-56%). Network meta-analysis revealed that enfortumab vedotin plus pembrolizumab significantly outperformed chemotherapy in ORR (odds ratio [OR], 3.47; 95% CI, 1.49-8.09; P = .004) and 1-year survival (OR, 2.32; 95% CI, 1.75-3.06; P < .001).Conclusions and relevanceIn this systematic review and meta-analysis, enfortumab vedotin plus pembrolizumab showed high response rates in first-line settings, while enfortumab vedotin monotherapy was associated with clinical benefit in later lines of therapy. These findings underscore the importance of personalized treatment approaches, and future research is warranted to refine enfortumab vedotin-based therapies for mUC management.

Dataset Information

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer.

Purpose

Patients and methods

Results

Conclusion

Publications

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer.

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