Nectin-4 inhibitors: An ace up our sleeve against advanced urothelial carcinoma.
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ABSTRACT:
SUBMITTER: Kumaraswamy S
PROVIDER: S-EPMC8555568 | biostudies-literature | 2021 Oct-Dec
REPOSITORIES: biostudies-literature
Publications
Nectin-4 inhibitors: An ace up our sleeve against advanced urothelial carcinoma.
Indian journal of urology : IJU : journal of the Urological Society of India 20211001 4
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Project description:Urothelial carcinoma is an aggressive cancer and development of metastases remains a challenge for clinicians. Immune checkpoint inhibitors (ICIs) are significantly improving the outcomes of patients with metastatic urothelial cancer (mUC). These agents were first used in monotherapy after failure of platinum-based chemotherapy, but different strategies explored the optimal use of ICIs in a first-line metastatic setting. The "maintenance" strategy consists of the introduction of ICIs in patients who experienced benefit from first-line chemotherapy in a metastatic setting. This allows an earlier use of ICIs, without waiting for disease progression. We review the optimal management of mUC in the era of ICIs, based on the key clinical messages arising from the pivotal trials.
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Project description:Metastatic urothelial cancer is an aggressive disease associated with a poor prognosis. In the first-line setting, platinum-based chemotherapy is the standard of care but resistance rapidly occurs. After failure of platinum-based therapy and in cisplatin-ineligible patients, therapeutic options are limited. Malignant cells evolve mechanisms to evade immune recognition, including the expression of cell-surface molecules, named immune checkpoints, on tumor and tumor-specific lymphocytes. Immunotherapy, by targeting these checkpoints, represents a new tool to improve the patient outcome in advanced urothelial carcinoma (UC). Recently, the US FDA approved, in a short time, several immune checkpoint inhibitors in metastatic UC, both after failure of platinum-based therapy and in first-line setting in cisplatin-ineligible patients. This article aims to review the place of immunotherapy in advanced UC.
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Project description:Enfortumab vedotin is a novel antibody-drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between Nectin-4 and Programmed Death Ligand 1 (PD-L1) in UTUC is also ambiguous. We performed immunohistochemical analysis of 99 UTUC tissue microarray to assess the expression of Nectin-4 and PD-L1 in UTUC. Nectin-4-positivity was detected in 65 (65.7%) samples, and PD-L1 was detected in 24 (24.2%) samples. There was no correlation between the expression of Nectin-4 and PD-L1. Patients with strong Nectin-4-expressing tumors had a significantly higher risk of progression (p = 0.031) and cancer-specific mortality (p = 0.036). Strong Nectin-4 expression was also an independent predictor of disease progression in the high-risk group (pT3 ≤ or presence of lymphovascular invasion or lymph node metastasis) (Hazard ratio, 3.32 [95% confidence interval, 1.20-7.98; p = 0.027]). In conclusion, we demonstrated that Nectin-4 expression rate in UTUC was 65.7% and independent of PD-L1 expression. Strong Nectin-4 expression was associated with worse progression-free survival in high-risk UTUC. These findings suggested that enfortumab vedotin may be effective in a broad range of patients with UTUC, regardless of PD-L1 expression.
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Project description:ObjectiveTo evaluate the effects of the concomitant use of proton pump inhibitors (PPIs) and/or antibiotics (Abs) on oncological outcomes in patients with advanced urothelial carcinoma.Patients and methodsWe retrospectively evaluated 155 patients with advanced urothelial carcinoma who were treated with immune checkpoint inhibitors (ICIs) between August 2015 and April 2021. The concomitant use of PPI or Abs was defined as any PPI or Abs administered within 30 days before ICI initiation and during ICI therapy. The primary outcomes were the effect of PPI and/or Abs use on the objective response rate (ORR) and immune-related adverse events (irAEs). The secondary outcomes were the effects of PPI and/or Abs use on progression-free survival (PFS) and overall survival (OS) after ICI therapy analyzed using the inverse probability of treatment weighting-adjusted Cox regression analysis.ResultsOf the 155 patients enrolled in the study, 99 (64%) were PPI users and 56 (36%) Abs users. PPI users were associated with a significantly poorer ORR than non-PPI users (41% vs. 20%, respectively), whereas Abs use was not significantly associated with changes in ORR. The rate of irAEs was not significantly associated with the use of PPIs or Abs. Multivariate inverse probability of treatment weighting-adjusted Cox regression analysis revealed significantly poorer PFS and OS in PPI users than in non-PPI users, whereas Abs use was not associated with poorer outcomes.ConclusionThe concomitant use of PPI may adversely affect oncological outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with ICI therapy.
| S-EPMC8988833 | biostudies-literature
Project description:IntroductionNectin-4 is a tumor-associated antigen overexpressed in urothelial carcinoma and several other malignancies. It has emerged as a compelling target for novel tumor-directed therapies, particularly as a component of antibody-drug conjugates (ADCs), a growing class of anti-cancer therapeutic agents. Development of nectin-4-directed therapies has been led by enfortumab vedotin (EV), an ADC comprised of a fully human monoclonal antibody specific for nectin-4 conjugated via a cleavable linker to the microtubule inhibitor MMAE. EV was approved in 2019 as a first-in-class agent for the treatment of urothelial carcinoma.Areas coveredThis article discusses general principles relevant to ADC design and our current understanding of nectin-4 in normal physiology and malignancy, followed by a review of the development of EV as well as additional drug conjugate strategies targeting nectin-4.Expert opinionEV offers proof-of-concept for the clinical utility of nectin-4-directed therapies and provides further support for ADCs as an important class of anti-cancer agents. Future development of nectin-4-targeted approaches will benefit from a deeper understanding of nectin-4 biology in both health and disease, as well as a detailed exploration of the mechanisms underlying therapeutic activity and resistance.
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Project description:The ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase 1 (CHK1) pathway is intricately involved in protecting the integrity of the human genome by suppressing replication stress and repairing DNA damage. ATR is a promising therapeutic target in cancer cells because its inhibition could lead to an accumulation of damaged DNA preventing further replication and division. ATR inhibition is being studied in multiple types of cancer, including advanced urothelial carcinoma where there remains an unmet need for novel therapies to improve outcomes. Herein, we review preclinical and clinical data evaluating 4 ATR inhibitors as monotherapy or in combination with chemotherapy. The scope of this review is focused on contemporary studies evaluating the application of this novel therapy in advanced urothelial carcinoma.
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Project description:GC (cisplatin and gemcitabine) and MVAC (methotrexate, vinblastine, Adriamycin [doxorubicin], and cisplatin) have been the standard systemic chemotherapy in advanced urothelial carcinoma. These regimens have shown significant response rates in this patient population. Nevertheless, disease does recur with most patients who unfortunately do succumb to the disease. Research efforts are focused in several different areas of therapy, targeted therapy, and immunotherapy. Further efforts include those in improving understanding of the molecular biology of urothelial carcinoma which may lead development of biomarkers that may enhance therapeutic index. This paper reviews recent advances in the treatment and ongoing study of molecular biology of urothelial carcinoma.
| S-EPMC4009980 | biostudies-other
Project description:Urothelial carcinoma (UC), originating in the bladder or upper urinary tract, is the most common histological type of cancer. Currently, platinum-based cytotoxic chemotherapy is the standard treatment for metastatic UC (mUC) and the preferred treatment option in the perioperative (neoadjuvant and/or adjuvant) setting of muscle invasive bladder cancer (MIBC). In addition, intravesical bacillus Calmette-Guerin immunotherapy or chemotherapy is applied as the adjuvant therapeutic option in non-muscle invasive bladder cancer (NMIBC) after transurethral resection, to prevent recurrence and progression. In recent years, with an increased understanding of cancer immunobiology, systemic immunotherapies targeting immune checkpoint inhibition has been explored and clinically used in the area of UC. The programmed cell death 1 receptor (PD-1) and its ligand (PD-L1) are important negative regulators of immune activity, preventing the destruction of normal tissues and autoimmunity. To date, five immune checkpoint inhibitors blocking PD-1 (pembrolizumab, nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved by the United States Food and Drug Administration (US-FDA) for first- or second-line use in mUC, based on durable therapeutic response and manageable safety profiles observed in relevant clinical trials. In addition, the clinical use of several immune checkpoint inhibitors is currently being tested for MIBC and NMIBC. In this article, we review the current and ongoing clinical trials, regarding immune checkpoint inhibitors, being conducted in various clinical settings of UC, including mUC, MIBC, and NMIBC.
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Project description:BackgroundSites of metastasis have prognostic significance in advanced urothelial carcinoma (aUC), but more information is needed regarding outcomes based on metastatic sites in patients treated with immune checkpoint inhibitors (ICI). We hypothesized that presence of liver/bone metastases would be associated with worse outcomes with ICI.MethodsWe identified a retrospective cohort of patients with aUC across 26 institutions, collecting demographics, clinicopathological, treatment, and outcomes information. Outcomes were compared with logistic (observed response rate; ORR) and Cox (progression-free survival; PFS, overall survival; OS) regression between patients with/without metastasis beyond lymph nodes (LN) and those with/without bone/liver/lung metastasis. Analysis was stratified by 1st or 2nd+ line.ResultsWe identified 917 ICI-treated patients: in the 1st line, bone/liver metastases were associated with shorter PFS (Hazard ratio; HR: 1.65 and 2.54), OS (HR: 1.60 and 2.35, respectively) and lower ORR (OR: 0.48 and 0.31). In the 2nd+ line, bone/liver metastases were associated with shorter PFS (HR: 1.71 and 1.62), OS (HR: 1.76 and 1.56) and, for bone-only metastases, lower ORR (OR: 0.29). In the 1st line, LN-confined metastasis was associated with longer PFS (HR: 0.53), OS (HR:0.49) and higher ORR (OR: 2.97). In the 2nd+ line, LN-confined metastasis was associated with longer PFS (HR: 0.47), OS (HR: 0.54), and higher ORR (OR: 2.79); all associations were significant.ConclusionBone and/or liver metastases were associated with worse, while LN-confined metastases were associated with better outcomes in patients with aUC receiving ICI. These findings in a large population treated outside clinical trials corroborate data from trial subset analyses.
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