Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer

Journal of Clinical Oncology, Journal Year: 2022, Volume and Issue: 41(1), P. 22 - 31

Published: Aug. 30, 2022

Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic urothelial cancer (la/mUC); however, toxicity is substantial, responses are rarely durable, and many patients with la/mUC ineligible. Each enfortumab vedotin pembrolizumab have shown a survival benefit versus in UC, not restricted by cisplatin eligibility, warrant investigation as first-line (1L) therapy ineligible cisplatin.

Language: Английский

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Mechanisms of ADC Toxicity and Strategies to Increase ADC Tolerability

Cancers, Journal Year: 2023, Volume and Issue: 15(3), P. 713 - 713

Published: Jan. 24, 2023

Anti-cancer antibody-drug conjugates (ADCs) aim to expand the therapeutic index of traditional chemotherapy by employing targeting specificity monoclonal antibodies (mAbs) increase efficiency delivery potent cytotoxic agents malignant cells. In past three years, number ADCs approved Food and Drug Administration (FDA) has tripled. Although several have demonstrated sufficient efficacy safety warrant FDA approval, clinical use all leads substantial toxicity in treated patients, many failed during development due their unacceptable profiles. Analysis data that dose-limiting toxicities (DLTs) are often shared different deliver same payload, independent antigen is targeted and/or type cancer treated. DLTs commonly associated with cells tissues do not express (i.e., off-target toxicity), limit ADC dosage levels below those required for optimal anti-cancer effects. this manuscript, we review fundamental mechanisms contributing toxicity, summarize common treatment-related adverse events, discuss approaches mitigating toxicity.

Language: Английский

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

Journal of Clinical Oncology, Journal Year: 2023, Volume and Issue: 41(25), P. 4107 - 4117

Published: June 27, 2023

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 improved therapies. Enfortumab vedotin (EV) pembrolizumab (Pembro) individually shown a survival benefit in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV Pembro) 1L setting.

Language: Английский

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Exploration of the antibody–drug conjugate clinical landscape

mAbs, Journal Year: 2023, Volume and Issue: 15(1)

Published: Aug. 28, 2023

The antibody–drug conjugate (ADC) field has undergone a renaissance, with substantial recent developmental investment and subsequent drug approvals over the past 6 y. In November 2022, ElahereTM became latest ADC to be approved by US Food Drug Administration (FDA). To date, 260 ADCs have been tested in clinic against various oncology indications. Here, we review clinical landscape of that are currently FDA (11), agents trials but not yet (164), candidates discontinued following testing (92). These clinically further analyzed their targeting tumor antigen(s), linker, payload choices, highest stage achieved, highlighting limitations associated candidates. Lastly, discuss biologic engineering modifications preclinically demonstrated improve therapeutic index if incorporated may increase proportion molecules successfully transition regulatory approval.

Language: Английский

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Rise of Antibody-Drug Conjugates: The Present and Future

American Society of Clinical Oncology Educational Book, Journal Year: 2023, Volume and Issue: 43

Published: May 1, 2023

Antibody-drug conjugates (ADCs) embody a simple, but elegant, vision for cancer therapy—the delivery of potent cytotoxic agent to tumor cells with minimal damage normal cells—so-called smart chemo. Although there were significant challenges in achieving this milestone culminating the first Food and Drug Administration approval 2000, subsequent advancements technology have led rapid drug development regulatory approvals ADCs targeting variety types. The most successful application solid tumors has been breast cancer, becoming standard care across traditional human epidermal growth factor receptor 2 (HER2)+, hormone receptor+ (HR+) triple-negative disease subtypes. Moreover, improved features gains potency expanded treatment-eligible population those low/heterogeneous expression target antigen on trastuzumab deruxtecan or case sacituzumab govitecan, agnostic expression. Despite their antibody-directed homing, these novel agents come share toxicities obligating appropriate patient selection vigilant monitoring while treatment. As more are included treatment armamentarium, mechanisms resistance need be studied understood optimal sequencing. Modifying payload use immune-stimulating combination therapies immunotherapy other effective targeted may further extend utility tumors.

Language: Английский

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Enfortumab Vedotin–related Cutaneous Toxicity and Radiographic Response in Patients with Urothelial Cancer: A Single-center Experience and Review of the Literature

European Urology Open Science, Journal Year: 2023, Volume and Issue: 49, P. 100 - 103

Published: Feb. 6, 2023

Enfortumab vedotin (EV) is an antibody-drug conjugate approved for the treatment of refractory advanced urothelial cancer. Cutaneous toxicity well described but has not been correlated with response. In this retrospective single-center study, data from patients treated more than one dose EV between December 2017 and June 2022 were analyzed. Of 56 a median age 69 yr, 41 (73.2%) male 27 (48.2%) had any-grade skin toxicity. For all 51 evaluable by physician-assessed Response Evaluation Criteria in Solid Tumors (RECIST) criteria, response rate was 41.2%. those cutaneous toxicity, 57.7%; without it 24.0% (p = 0.0145). All three complete experienced two these responses remain durable 5 24 mo off EV. The starting weight body mass index (BMI) were, respectively, 80.86 kg 26.53 kg/m2 among 69.37 23.29 0.0129 0.0014, respectively). small dataset, EV-related common higher BMI at baseline, associated disease Confirmation prospective trials may confirm association lead to important clinical biomarker response.We evaluated cancer who our institution enfortumab (EV). We found that side effect any type such as rash or itching, likely have improvement their did experience Patients when tended conclude presence might help doctors make decisions about how manage care future.

Language: Английский

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Enfortumab Vedotin in Metastatic Urothelial Carcinoma: Survival and Safety in a European Multicenter Real-world Patient Cohort

European Urology Open Science, Journal Year: 2023, Volume and Issue: 53, P. 31 - 37

Published: May 17, 2023

Treatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited survival is short. Enfortumab vedotin (EV) a monoclonal anti-NECTIN4 antibody conjugated monomethyl auristatin. It was recently approved because of superior in comparison standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than included clinical trials.To analyze the efficacy safety EV cohort real-world patients.Retrospective data were collected from 23 hospitals private practices metastatic previously treated UC who received either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within compassionate use program, or as SOC treatment after EMA approval. Imaging therapy management accordance local standards.Adverse events (AEs) reported according Common Terminology Criteria Adverse Events (CTCAE) version 5.0 criteria. Objective responses evaluated Response Evaluation Solid Tumors 1.1. Progression-free (PFS) overall (OS) estimated using Kaplan-Meier method.The median age 125 eligible 66 yr (range 31-89). The Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 76.0%, 2-4 13.6%, unknown 10.4% patients. administered fourth later line 44.8% response rate 41.6% (partial 39.2%, complete 2.4%). Median OS 10.0 months (mo) (95% confidence interval 7.20-12.80) PFS mo 4.34-5.67). For ECOG PS 0-1, 14 mo. Any-grade AEs observed 67.2% CTCAE grade ≥3 30.4%. most common peripheral sensory neuropathy skin toxicity. Three fatal (pneumonia, pneumonitis) occurred. Limitations include retrospective design short follow-up.Administration feasible an acceptable toxicity profile. No new signals reported. Antitumor activity our comparable trials. In summary, results support UC.Enfortumab medication that improved bladder standard chemotherapy However, trials highly selected toxicities improvements do not always transfer setting. We analyzed enfortumab vedotin. Our outcomes regarding this treatment.

Language: Английский

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Enfortumab vedotin following platinum-based chemotherapy and immune checkpoint inhibitors for advanced urothelial carcinoma: response, survival and safety analysis from a multicentre real-world Japanese cohort

Japanese Journal of Clinical Oncology, Journal Year: 2023, Volume and Issue: 54(3), P. 329 - 338

Published: Nov. 20, 2023

Real-world evidence regarding enfortumab vedotin for unresectable or metastatic urothelial carcinoma is scarce, particularly in Japan. We investigated real-world data focusing on patient background, previous treatments, response, survival and adverse events patients receiving vedotin.

Language: Английский

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Drug conjugates for the treatment of lung cancer: from drug discovery to clinical practice

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: March 1, 2024

Abstract A drug conjugate consists of a cytotoxic bound via linker to targeted ligand, allowing the delivery one or more tumor sites. This approach simultaneously reduces toxicity and increases efficacy, with powerful combination efficient killing precise targeting. Antibody‒drug conjugates (ADCs) are best-known type conjugate, combining specificity antibodies cytotoxicity chemotherapeutic drugs reduce adverse reactions by preferentially targeting payload tumor. The structure ADCs has also provided inspiration for development additional conjugates. In recent years, such as ADCs, peptide‒drug (PDCs) radionuclide (RDCs) have been approved Food Drug Administration (FDA). scope application expanding, including therapy delivery, variety new conjugation technology concepts emerged. Additionally, technology-based developed in industry. addition chemotherapy, immunotherapy, undergone continuous made significant progress treating lung cancer offering promising strategy treatment this disease. review, we discuss advances use treatment, structure-based design, mechanisms action, clinical trials, side effects. Furthermore, challenges, potential approaches future prospects presented.

Language: Английский

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Managing potential adverse events during treatment with enfortumab vedotin + pembrolizumab in patients with advanced urothelial cancer

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: April 22, 2024

Cisplatin-based chemotherapy has been the standard of care for patients with locally advanced or metastatic urothelial cancer (la/mUC). Enfortumab vedotin, an antibody-drug conjugate directed to Nectin-4, and pembrolizumab, immune checkpoint inhibitor, are two therapies that have individually provided a survival benefit in la/mUC. The combination regimen enfortumab vedotin plus pembrolizumab was evaluated EV-302 (KEYNOTE-A39; NCT0422385), phase 3 study showed statistically significant clinically meaningful improvement overall survival, progression-free key secondary endpoint response rate versus chemotherapy. Based on these results those from EV-103 (KEYNOTE-869; NCT03288545) Dose Escalation cohort, Cohort A, K, granted approval US Food Drug Administration treatment adults While guidelines recommendations management adverse events (AEs) developed inhibitor monotherapy monotherapy, additional guidance is needed managing AEs occur pembrolizumab. As monotherapies, both associated some observed combination, such as skin reactions, pneumonitis, diarrhea, which may confound attribution AE specific agent thereby complicate clinical management. In this manuscript, we aim provide best practice patient interest la/mUC receiving including peripheral neuropathy, hyperglycemia, pneumonitis. These were based published guidelines, expert opinions, experience authors, include oncologist, provider, nursing, pharmacy perspectives. addition, education communication provided. With vigilant monitoring, early detection, prompt intervention treatment-emergent recommended approaches described herein, it authors' most can be managed supportive therapy dose modification/interruptions, allowing continue treatment.

Language: Английский

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