Immune Checkpoint Inhibitors for Urothelial Cancer: An Update on New Therapies.
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ABSTRACT:
SUBMITTER: El-Mouallem N
PROVIDER: S-EPMC6248150 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
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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:Bladder cancer is the sixth most common cancer in the US and most tumors have urothelial (transitional cell) histology. Platinum-based chemotherapy has long been the standard of care in advanced disease, but long-term outcomes have largely remained poor. Since the peak incidence of bladder cancer is in the eighth decade of life and beyond, medical comorbidities may often limit the use of chemotherapy. Immune checkpoint inhibitors with their favorable toxicity profiles and notable antitumor activity have ushered in a new era in the treatment of advanced urothelial cancer (UC) with five agents targeting the PD-1/PD-L1 pathway being recently approved by the US Food and Drug administration. A plethora of clinical trials are ongoing in diverse disease settings, employing agents targeting PD-1/PD-L1 and related immune checkpoint pathways. While reactivating anti-tumor immunity, these agents may lead to a unique constellation of immune-related adverse events, which may warrant discontinuation of therapy and potential use of immunosuppression. Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials and retrospective registries. At the era of precision molecular medicine, and since patients do not respond uniformly to these agents, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. This review discusses current updates and future directions of immunotherapy in advanced UC.
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Project description:Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant tool against cancer. HER2+ and triple-negative breast cancers (TNBCs) are considered more immunogenic and suitable for this kind of treatment due to the higher rate of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. In TNBC, genetic aberrations further favor immunogenicity due to more neo-antigens in cancer cells. Methods: This review summarizes the principal ongoing conventional and investigational immunotherapies in breast cancer. Particularly, immune checkpoint inhibitors (ICIs) and their use alone or combined with DNA damage repair inhibitors (DDRis) are described. Then, the issue on immunotherapy with monoclonal antibodies against HER-2 family receptors is updated. Other investigational immunotherapies include a new schedule based on the interferon beta-interleukin-2 sequence that was given in ER+ metastatic breast cancer patients concomitant with anti-estrogen therapy, which surprisingly showed promising results. Results: Based on the scientific literature and our own findings, the current evaluation of tumor immunogenicity and the conventional model of adjuvant chemotherapy (CT) are questioned. Conclusions: A novel strategy based on additional prolonged adjuvant immunotherapy combined with hormone therapy or alternated with CT is proposed.
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Project description:Urothelial carcinoma is one of the most common cancers in the United States, yet outcomes are historically suboptimal. Since 2016, the approval of five programmed cell death 1 and programmed death-ligand 1 immune checkpoint inhibitors for locally advanced and metastatic urothelial carcinoma has led to improved oncologic outcomes for many patients in the second-line setting. Two checkpoint inhibitors, pembrolizumab and atezolizumab subsequently earned approval for first-fine therapy with restricted indications. More recently, pembrolizumab was approved for bacillus Calmette-Guérin-unresponsive high-risk non-muscle invasive bladder cancer, opening the door for other immune checkpoint inhibitors to be integrated into treatment in earlier disease stages. Recent bacillus Calmette-Guérin shortages have highlighted the need for alternative treatment options for patients with non-muscle invasive bladder cancer. Currently, there are no FDA-approved checkpoint inhibitors for non-metastatic muscle-invasive bladder cancer. Furthermore, many patients are ineligible for standard cisplatin-based chemotherapy regimens. Numerous ongoing clinical trials are employing immune checkpoint inhibitors for muscle-invasive bladder cancer patients in the neoadjuvant, adjuvant, perioperative, and bladder-sparing setting. Although up to 10% of urothelial carcinoma tumors arise in the upper urinary tract, few studies are designed for this population. We highlight the need for more trials designed for patients with upper tract disease. Overall, there are numerous clinical trials investigating the safety and efficacy of immune checkpoint inhibitors in all stages of disease as single-agents and combined with dual-immune checkpoint inhibition, chemotherapy, radiotherapy, and other pharmacologic agents. As the field continues to evolve rapidly, we aim to provide an overview of recent and ongoing immunotherapy clinical trials in urothelial carcinoma.
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Project description:In recent years, progress in our understanding of immune-modulatory signaling pathways in immune cells and the tumor microenvironment (TME) has led to rejuvenated interest in cancer immunotherapy. In particular, immunotherapy targeting the immune checkpoint receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell-death 1 (PD-1), and programmed cell-death ligand 1 (PD-L1) have demonstrated clinical activity in a wide variety of tumors, including gynecological cancers. This review will focus on the emerging clinical data on the therapeutic role of immune checkpoint inhibitors, and potential strategies to enhance the efficacy of this class of compounds, in the context of gynecological cancers. It is anticipated that future biomarker-directed clinical trials will provide further insights into the mechanisms underlying response and resistance to immunotherapy, and help guide our approach to designing therapeutic combinations that have the potential to enhance the benefit of immunotherapy in patients with gynecologic cancers.
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Project description:During the last 20 years, chemotherapy has improved survival rates of colorectal cancer (CRC). However, the majority of metastatic cases do not respond to or progress after first line conventional chemotherapy and contribute to the fatalities of patients with CRC. Insights into the immune contexture of the tumor microenvironment (TME) have enabled the development of new systemic treatments that boost the host immune system against the tumor-the immune checkpoint inhibitors (ICI). These promising drugs have already shown astonishing efficacies in other cancer types and have raised new hope for the treatment of metastatic CRC (mCRC). In this review, we will summarize the results of the clinical trials that led to their accelerated approval by the U.S. Food and Drug Administration (FDA) in 2017, as well as all relevant recent studies conducted since then-some of which are not published yet. We will focus on therapeutic efficacy, but also discuss the available data for drug safety and security, changes in quality of life indicators and predictive biomarkers for treatment response. The burgeoning evidence for a potential use of ICIs in other settings than mCRC will also be mentioned. For each trial, we have made a preliminary assessment of the quality of clinical trial design and of the "European Society of Medical Oncology (ESMO) magnitude of clinical benefit" (ESMO-MCBS) in order to provide the first evidence-based recommendation to the reader.
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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:BackgroundWe developed a novel risk scoring system for urothelial cancer (UC) patients receiving immune checkpoint inhibitors (ICI).MethodsWe conducted a retrospective review of 67 UC patients treated with ICI at Winship Cancer Institute of Emory University from 2015 to 2018. Using stepwise variable selection in Cox proportional hazard model and Sullivan's weighting schema, baseline platelet-to-lymphocyte ratio (PLR), presence of liver metastasis, baseline albumin, and baseline Eastern Cooperative Oncology Group performance status (ECOG PS) were used for risk scoring. Patients were categorized into good risk (risk score 0-1), intermediate risk (risk score 2-3), and poor risk (risk score 4-6). Univariable (UVA) and multivariable analysis (MVA) and Kaplan-Meier method were used to assess overall survival (OS) and progression free survival (PFS).ResultsThe Emory Risk Scoring System had C-statistics of 0.74 (Standard Error = 0.047) in predicting OS and 0.70 (Standard Error = 0.043) in predicting PFS. Compared to good risk patients, poor risk patients had significantly shorter OS and PFS in both UVA and MVA (all P < .001), and intermediate risk patients had significantly shorter OS and PFS in both UVA and MVA (all P < .03).ConclusionsRisk scoring using baseline PLR, presence of liver metastasis, baseline albumin, and baseline ECOG PS may effectively predict OS and PFS in UC patients receiving ICI.
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Project description:Bladder cancer (BC) is the most common malignancy of the genitourinary tract, with high morbidity and mortality rates. Until recently, the treatment of locally advanced or metastatic urothelial BC was based on the use of chemotherapy alone. Since 2016, five immune checkpoint inhibitors (ICIs) have been approved by the Food and Drug Administration (FDA) in different settings, i.e., first-line, maintenance and second-line treatment, while several trials are still ongoing in the perioperative context. Lately, pembrolizumab, a programmed death-1 (PD-1) inhibitor, has been approved for Bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC), using immunotherapy at an early stage of the disease. This review investigates the current state and future perspectives of immunotherapy in BC, focusing on the rationale and results of combining immunotherapy with other therapeutic strategies.
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Project description:Machine learning (ML) may enhance the efficiency of developing accurate prediction models for survival, which is critical in informing disease prognosis and care planning. This study aimed to develop an ML prediction model for survival outcomes in patients with urothelial cancer-initiating atezolizumab and to compare model performances when built using an expert-selected (curated) versus an all-in list (uncurated) of variables. Gradient-boosted machine (GBM), random forest, Cox-boosted, and penalised, generalised linear models (GLM) were evaluated for predicting overall survival (OS) and progression-free survival (PFS) outcomes. C-statistic (c) was utilised to evaluate model performance. The atezolizumab cohort in IMvigor210 was used for model training, and IMvigor211 was used for external model validation. The curated list consisted of 23 pretreatment factors, while the all-in list consisted of 75. Using the best-performing model, patients were stratified into risk tertiles. Kaplan-Meier analysis was used to estimate survival probabilities. On external validation, the curated list GBM model provided slightly higher OS discrimination (c = 0.71) than that of the random forest (c = 0.70), CoxBoost (c = 0.70), and GLM (c = 0.69) models. All models were equivalent in predicting PFS (c = 0.62). Expansion to the uncurated list was associated with worse OS discrimination (GBM c = 0.70; random forest c = 0.69; CoxBoost c = 0.69, and GLM c = 0.69). In the atezolizumab IMvigor211 cohort, the curated list GBM model discriminated 1-year OS probabilities for the low-, intermediate-, and high-risk groups at 66%, 40%, and 12%, respectively. The ML model discriminated urothelial-cancer patients with distinctly different survival risks, with the GBM applied to a curated list attaining the highest performance. Expansion to an all-in approach may harm model performance.
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