Dataset Information

Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.

ABSTRACT:

Purpose

The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET).

Experimental design

Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4-negative/weak (H-score 0-99) versus moderate/strong (H-score 100-300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts.

Results

In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0-140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001).

Conclusions

Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377.

SUBMITTER: Klumper N

PROVIDER: S-EPMC10102834 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.

Klümper Niklas N Ralser Damian J DJ Ellinger Jörg J Roghmann Florian F Albrecht Julia J Below Eduard E Alajati Abdullah A Sikic Danijel D Breyer Johannes J Bolenz Christian C Zengerling Friedemann F Erben Philipp P Schwamborn Kristina K Wirtz Ralph M RM Horn Thomas T Nagy Dora D Toma Marieta M Kristiansen Glen G Büttner Thomas T Hahn Oliver O Grünwald Viktor V Darr Christopher C Erne Eva E Rausch Steffen S Bedke Jens J Schlack Katrin K Abbas Mahmoud M Abbas Mahmoud M Zschäbitz Stefanie S Schwab Constantin C Mustea Alexander A Adam Patrick P Manseck Andreas A Wullich Bernd B Ritter Manuel M Hartmann Arndt A Gschwend Jürgen J Weichert Wilko W Erlmeier Franziska F Hölzel Michael M Eckstein Markus M

Clinical cancer research : an official journal of the American Association for Cancer Research 20230401 8

<h4>Purpose</h4>The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET).<h ...[more]

PMID: 36534531

Similar Datasets

Project description:PurposeTo assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4.MethodsEV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4-expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti-PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective.ResultsEnrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti-PD-(L)1 treatment, liver metastases, or upper-tract disease.ConclusionSingle-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.

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: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

Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.

Purpose

Experimental design

Results

Conclusions

Publications

Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.

Similar Datasets

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