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Emerging Treatment Options for the Treatment of Metastatic Urothelial Cancer: Therapeutic Potential of Enfortumab Vedotin.

ABSTRACT: Enfortumab vedotin (EV) is an antibody-drug conjugate with humanized anti-Nectin-4 antibody linked with a microtubule-disrupting agent called monomethyl auristatin E. Nectin-4 is a cellular adhesion protein that is overexpressed in urothelial cancer. EV was approved in December 2019 for patients with locally advanced or metastatic urothelial cancer who previously received platinum-based chemotherapy and immune checkpoint inhibitors. Here, we reviewed the clinical efficacy and safety data that led to the accelerated approval of EV for treating patients with metastatic urothelial cancer. Emerging clinical data on EV-based combinational therapeutic trials for metastatic urothelial cancer were also reviewed.

SUBMITTER: Jain RK

PROVIDER: S-EPMC7494003 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Emerging Treatment Options for the Treatment of Metastatic Urothelial Cancer: Therapeutic Potential of Enfortumab Vedotin.

Jain Rohit K RK Skelton William Paul WP Zhang Jingsong J

Cancer management and research 20200911

Enfortumab vedotin (EV) is an antibody-drug conjugate with humanized anti-Nectin-4 antibody linked with a microtubule-disrupting agent called monomethyl auristatin E. Nectin-4 is a cellular adhesion protein that is overexpressed in urothelial cancer. EV was approved in December 2019 for patients with locally advanced or metastatic urothelial cancer who previously received platinum-based chemotherapy and immune checkpoint inhibitors. Here, we reviewed the clinical efficacy and safety data that le ...[more]

PMID: 32982431

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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:IntroductionEnfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related toxicities and typically emerges in early cycles. This retrospective experience of patients with urothelial cancer treated with EV monotherapy evaluated whether EV-related cutaneous toxicity correlated with improved outcomes including progression-free (PFS) and overall (OS) survival and overall response rate (ORR).Patients and methodsPatients treated with EV monotherapy at Johns Hopkins were identified, and baseline characteristics, treatment, and toxicity details were extracted through chart review. Univariable Cox hazard ratios (HRs) were calculated for assessing the effect of baseline patient characteristics and cutaneous toxicity in PFS and OS. Based on the univariable analysis and known risk factors, all subsequent analyses were adjusted for: Eastern Cooperative Oncology Group performance status, visceral metastases at baseline, gender as well as EV dose, and weight to account for dosing differences. Multivariable Cox proportional HRs were used for comparing PFS and OS between patients with and without cutaneous toxicity, assessing toxicity and EV dose as a time-dependent variables. Adjusted p-values were calculated to compare ORR and disease control rate (DCR) between groups using the Poisson regression model.ResultsOf the 78 patients analyzed, 42 (53.8%) experienced EV-related cutaneous toxicity that appeared early during treatment (median time to occurrence 0.5 months from EV initiation). Cutaneous toxicity correlated with significantly improved OS [HR, 0.48; 95% confidence interval (CI), 0.25, 0.9; P = 0.0235], ORR (68.3% vs. 20.7%, P = 0.0033) and DCR (82.9% vs. 48.3%, P = 0.0122). Median PFS was numerically longer in the cutaneous toxicity group (6.3 vs. 1.7 months), although no significance was achieved in the multivariable analysis (HR, 0.62; 95% CI: 0.35, 0.108; P = 0.0925).ConclusionIn this retrospective study, EV-related cutaneous toxicity was associated with improved patient outcomes. Confirming this observation and understanding its mechanism could lead to discovery of a new clinical biomarker of EV response that can emerge in the first cycle.

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Emerging Treatment Options for the Treatment of Metastatic Urothelial Cancer: Therapeutic Potential of Enfortumab Vedotin.

Publications

Emerging Treatment Options for the Treatment of Metastatic Urothelial Cancer: Therapeutic Potential of Enfortumab Vedotin.

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