Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: 390(10), P. 875 - 888

Published: March 6, 2024

No treatment has surpassed platinum-based chemotherapy in improving overall survival patients with previously untreated locally advanced or metastatic urothelial carcinoma. Download a PDF of the Research Summary. We conducted phase 3, global, open-label, randomized trial to compare efficacy and safety enfortumab vedotin pembrolizumab Patients were randomly assigned 1:1 ratio receive 3-week cycles (at dose 1.25 mg per kilogram body weight intravenously on days 1 8) 200 day 1) (enfortumab vedotin–pembrolizumab group) gemcitabine either cisplatin carboplatin (determined basis eligibility cisplatin) (chemotherapy group). The primary end points progression-free as assessed by blinded independent central review survival. A total 886 underwent randomization: 442 group 444 group. As August 8, 2023, median duration follow-up for was 17.2 months. Progression-free longer than (median, 12.5 months vs. 6.3 months; hazard disease progression death, 0.45; 95% confidence interval [CI], 0.38 0.54; P<0.001), 31.5 16.1 0.47; CI, 0.58; P<0.001). number 12 (range, 46) 6 6) Treatment-related adverse events grade 3 higher occurred 55.9% 69.5% those Treatment resulted significantly better outcomes carcinoma, profile consistent that previous reports. (Funded Astellas Pharma US others; EV-302 ClinicalTrials.gov number, NCT04223856.) QUICK TAKE VIDEO SUMMARYEnfortumab Vedotin–Pembrolizumab Advanced Urothelial Cancer 02:22

Language: Английский

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Advances in diagnosis and treatment of bladder cancer

BMJ, Journal Year: 2024, Volume and Issue: unknown, P. e076743 - e076743

Published: Feb. 12, 2024

Abstract Bladder cancer remains a leading cause of death worldwide and is associated with substantial impacts on patient quality life, morbidity, mortality, cost to the healthcare system. Gross hematuria frequently precedes diagnosis bladder cancer. Non-muscle-invasive (NMIBC) managed initially transurethral resection tumor (TURBT), followed by risk stratified approach adjuvant intravesical therapy (IVe), an overall survival 90%. However, cure rates remain lower for muscle invasive (MIBC) owing variety factors. NMIBC MIBC groupings are heterogeneous have unique pathological molecular characteristics. Indeed, The Cancer Genome Atlas project identified genetic drivers luminal basal subtypes distinct treatment responses. For NMIBC, IVe immunotherapy (primarily BCG) gold standard high grade reduce or prevent both recurrence progression after initial TURBT; novel trials incorporate immune checkpoint inhibitors. gene combination chemotherapy recently been completed, promising results. localized MIBC, essential goals improving care reducing morbidity following cystectomy preserving strategies. In metastatic disease, advances in understanding genomic landscape microenvironment led implementation inhibitors, targeted treatments, antibody-drug conjugates. Defining better selection criteria identify patients most likely benefit from specific urgent need.

Language: Английский

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Targeted protein degradation: from mechanisms to clinic

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(9), P. 740 - 757

Published: April 29, 2024

Language: Английский

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The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Jan. 4, 2024

Antibody-drug conjugates (ADCs) represent an important class of cancer therapies that have revolutionized the treatment paradigm solid tumors. To date, many ongoing studies ADC combinations with a variety anticancer drugs, encompassing chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted in both preclinical clinical trial settings. Nevertheless, combination therapy does not always guarantee synergistic or additive effect may entail overlapping toxicity risks. Therefore, understanding current status underlying mechanisms is urgently required. This comprehensive review analyzes existing evidence concerning ADCs other classes oncology medicines. Here, we discuss biological different strategies, provide prominent examples, assess their benefits challenges. Finally, future opportunities for practice.

Language: Английский

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A review of the clinical efficacy of FDA-approved antibody‒drug conjugates in human cancers

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: March 23, 2024

Abstract While strategies such as chemotherapy and immunotherapy have become the first-line standard therapies for patients with advanced or metastatic cancer, acquired resistance is still inevitable in most cases. The introduction of antibody‒drug conjugates (ADCs) provides a novel alternative. ADCs are new class anticancer drugs comprising coupling antitumor mAbs cytotoxic drugs. Compared chemotherapeutic drugs, advantages good tolerance, accurate target recognition, small effects on noncancerous cells. occupy an increasingly important position therapeutic field. Currently, there 13 Food Drug Administration (FDA)‒approved more than 100 ADC at different stages clinical trials. This review briefly describes efficacy safety FDA-approved ADCs, discusses related problems challenges to provide reference work.

Language: Английский

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NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(20), P. 2446 - 2455

Published: April 24, 2024

PURPOSE The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit only achieved in a small, yet uncharacterized patient subset. NECTIN4 located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) cancer. Here, we aimed to evaluate amplifications as genomic biomarker predict EV response mUC. MATERIALS AND METHODS We established NECTIN4-specific fluorescence situ hybridization (FISH) assay assess the predictive value of CNVs multicenter EV-treated mUC cohort (mUC-EV, n = 108). were correlated membranous protein expression, treatment responses, outcomes. also assessed prognostic measured biopsies non–EV-treated (mUC-non-EV, 103). Furthermore, queried Cancer Genome Atlas (TCGA) data sets (10,712 across 32 types) CNVs. RESULTS are events muscle-invasive bladder (TCGA set: approximately 17%) (approximately 26% our cohorts). In mUC-EV, amplification represents stable alteration during progression associates enhanced expression. Ninety-six percent (27 28) demonstrated objective responses compared 32% (24 74) nonamplified subgroup ( P < .001). multivariable Cox analysis adjusted age, sex, Bellmunt risk factors, led 92% reduction death (hazard ratio, 0.08 [95% CI, 0.02 0.34]; mUC-non-EV, not associated TCGA Pan-Cancer that occur frequently other cancers, example, 5%-10% breast lung cancers. CONCLUSION predictors long-term survival

Language: Английский

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Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study

The Lancet Oncology, Journal Year: 2023, Volume and Issue: 25(1), P. 29 - 45

Published: Dec. 12, 2023

Language: Английский

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Development of antibody‐drug conjugates in cancer: Overview and prospects

Cancer Communications, Journal Year: 2023, Volume and Issue: 44(1), P. 3 - 22

Published: Dec. 30, 2023

Abstract In recent years, remarkable breakthroughs have been reported on antibody‐drug conjugates (ADCs), with 15 ADCs successfully entering the market over past decade. This substantial development has positioned as one of fastest‐growing domains in realm anticancer drugs, demonstrating their efficacy treating a wide array malignancies. Nonetheless, there is still an unmet clinical need for wider application, better efficacy, and fewer side effects ADCs. An ADC generally comprises antibody, linker payload, combination profound drug structure, pharmacokinetic profile efficacy. Hence, optimization key components provides opportunity to develop higher potency effects. this review, we comprehensively reviewed current prospects ADC, provided analysis marketed ongoing pipelines globally well China, highlighted several platforms technologies specific different pharmaceutical enterprises biotech companies, also discussed new related technologies, possibility next‐generation directions research.

Language: Английский

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Therapeutic prospects of nectin-4 in cancer: applications and value

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

Published: March 28, 2024

Nectin-4 is a Ca 2+ -independent immunoglobulin-like protein that exhibits significantly elevated expression in malignant tumors while maintaining extremely low levels healthy adult tissues. In recent years, overexpression of has been implicated tumor occurrence and development various cancers, including breast cancer, urothelial lung cancer. 2019, the Food Drug Administration approved enfortumab vedotin, first antibody–drug conjugate targeting Nectin-4, for treatment carcinoma. This emphasized value targeted therapy promoted implementation more clinical trials vedotin. addition, many new drugs have entered trials, with aim exploring potential indications. However, exact mechanisms by which affects tumorigenesis progression are still unclear, emergence drug resistance treatment-related adverse reactions poses challenges. article reviews diagnostic potential, prognostic significance, molecular role tumors, focus on field Nectin-4-related Nectin-4.

Language: Английский

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Unlocking the Potential: Biomarkers of Response to Antibody-Drug Conjugates

American Society of Clinical Oncology Educational Book, Journal Year: 2024, Volume and Issue: 44(3)

Published: June 1, 2024

Antibody-drug conjugates (ADCs) have reshaped the cancer treatment landscape across a variety of different tumor types. ADCs' peculiar pharmacologic design combines cytotoxic properties chemotherapeutic agents with selectivity targeted therapies. At present, approval many ADCs used in clinical practice has not always been biomarker-driven. Indeed, predicting activity and toxicity through demonstration specific biomarkers is still great unmet need, identification patients who can derive significant benefit from may often be uncertain. With lack robust predictive to anticipate primary, intrinsic resistance no consolidated aid early (ie, acquired resistance), determination precise biologic mechanisms ADC safety becomes priority quest for better patient-centric outcomes. Of relevance, whether target antigen expression determinant primary clarified, available data remain quite controversial. Antigen assessment typically performed on tissue biopsy, hence only providing information site, therefore unable capture heterogeneous patterns expression. Quantifying all sites would help understand heterogeneity, whereas molecularly characterizing tumor-intrinsic features over time might provide mechanisms. In addition, represent critical concern, since most profile that resembles chemotherapies, unique adverse events requiring special management, possibly because differential pharmacokinetics between small-molecule agent versus payload similar class (eg, deruxtecan conjugate–related interstitial lung disease). As such, potential improve patient selection enrich population likely substantial benefit, especially those disease settings where happen approved competing indications, undefined make decision making unclear how sequence ADCs. this point, clinically actionable space remains top research priority.

Language: Английский

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