Metastatic Urothelial Cancer: a rapidly changing treatment landscape.
Ontology highlight
ABSTRACT:
SUBMITTER: Stecca C
PROVIDER: S-EPMC8488509 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background:The treatment paradigm for metastatic nonsquamous non-small-cell lung cancer (nsclc) continues to change. Algorithms published only 6 months ago are outdated today and are dramatically different from those published a few years ago. New driver mutations continue to be identified, and the development of therapies to inhibit oncogenic addiction is ongoing. Patient survival is improving as treatments become more personalized and effective. Methods:This review looks at the outcomes of recent trials and discusses treatment options for patients with metastatic nsclc of nonsquamous histology. Algorithms continue to change quickly, and an attempt is made to keep the paradigm current and applicable into the near future. Results:Treatment algorithms for nsclc tumours with EGFR mutations, ALK rearrangements, and ROS1 rearrangements, and for wild-type tumours are presented. A future algorithm based on new immunotherapy data is proposed. Conclusions:The treatment algorithm for EGFR mutation is changing with the proven efficacy of osimertinib for the acquired T790M mutation. All patients taking first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors must be tested. The treatment algorithm for ALK rearrangement has changed with the proven superiority of alectinib compared with crizotinib in the first-line setting. The approval of crizotinib for ROS1 rearrangements now means that patients also must be tested for that mutation. The biomarker for checkpoint inhibitors continues to be PD-L1 by immunohistochemistry stain, but whether testing will be necessary for patient selection if chemotherapy combinations are implemented will be determined soon.
| S-EPMC6001773 | biostudies-literature
Project description:BackgroundMetastatic urothelial carcinoma (mUC) historically is treated with first-line platinum-based combination chemotherapy, preferably cisplatin plus gemcitabine whenever possible. In recent years, multiple classes of targeted therapy have demonstrated benefit, with some receiving approval in mUC. This review will summarize phase III efficacy and safety data for targeted agents, principally immune checkpoint inhibitors (ICIs), as either first-line or first-line switch-maintenance therapy for mUC and interpret these findings in the context of the current treatment landscape.Materials and methodsPublished and presented phase III data on targeted therapy for the first-line or first-line switch-maintenance treatment of mUC were identified using the key search terms "targeted therapy" AND "urothelial carcinoma" AND "advanced" OR respective aliases according to the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).ResultsOf the six eligible phase III targeted therapy trials, two assessing ICIs met their primary endpoints in platinum-eligible patients. First-line ICI plus chemotherapy combinations have not improved overall survival (OS), although final OS results of the IMVigor 130 trial are pending. Switch-maintenance using an ICI in patients achieving at least stable disease following platinum-based chemotherapy statistically significantly improved OS (21.4 vs. 14.3 months, hazard ratio, 0.69; 95% confidence interval, 0.56-0.86; p = .001). Current sequencing options for mUC include first-line platinum-based chemotherapy with a switch to ICI either immediately or upon disease progression.ConclusionRecent targeted therapy trials have expanded ICI sequencing options for mUC. The treatment landscape is likely to evolve rapidly, with results from multiple phase III trials expected in the next 5 years.Implications for practiceMultiple classes of targeted agents are approved for use in metastatic urothelial carcinoma (mUC). Six phase III trials have recently provided insight on the benefit of these agents in the first-line setting. In platinum-eligible patients, immune checkpoint inhibitors (ICIs) combined with first-line platinum-based chemotherapy failed to demonstrate improved survival, although ICI monotherapy as switch-maintenance significantly improved overall survival in patients with mUC who had achieved at least stable disease following first-line platinum-based chemotherapy. In patients ineligible for any chemotherapy, pembrolizumab, atezolizumab, or pembrolizumab in combination with enfortumab vedotin may be options.
| S-EPMC8342568 | biostudies-literature
Project description:The past few years have brought increasing advances in the therapeutic management of metastatic castration-resistant prostate cancer with the approval of several agents, including vaccine therapy with sipuleucel-T, second-line chemotherapy with cabazitaxel, the bone-targeted pharmaceutical denosumab, and the novel antiandrogen therapy abiraterone acetate. There are ongoing developments with other agents in the pipeline such as MDV3100 and alpharadin that have shown promising results. This review describes the clinical trials that brought about the drug approvals of various agents and offers some insights regarding a rational approach to optimal treatment sequencing for these drugs since national guidelines are currently lacking.
| S-EPMC3539272 | biostudies-literature
Project description:The practising clinician treating a patient with metastatic clear cell renal cell carcinoma (CCRCC) faces a difficult task of choosing the most appropriate therapeutic regimen in a rapidly developing field with recommendations derived from clinical trials. NCCN guidelines for kidney cancer initiated a major shift in risk categorization and now include emerging treatments in the neoadjuvant setting. Updates of European Association of Urology clinical guidelines also include immune checkpoint inhibition as the first-line treatment. Randomized trials have demonstrated a survival benefit for ipilimumab and nivolumab combination in the intermediate and poor-risk group, while pembrolizumab plus axitinib combination is recommended not only for unfavorable disease but also for patients who fit the favorable risk category. Currently vascular endothelial growth factor (VEGF) targeted therapy based on tyrosine kinase inhibitors (TKI), sunitinib and pazopanib is the alternative regimen for patients who cannot tolerate immune checkpoint inhibitors (ICI). Cabozantinib remains a valid alternative option for the intermediate and high-risk group. For previously treated patients with TKI with progression, nivolumab, cabozantinib, axitinib, or the combination of ipilimumab and nivolumab appear the most plausible alternatives. For patients previously treated with ICI, any VEGF-targeted therapy, not previously used in combination with ICI therapy, seems to be a valid option, although the strength of this recommendation is weak. The indication for cytoreductive nephrectomy (CN) is also changing. Neoadjuvant systemic therapy does not add perioperative morbidity and can help identify non-responders, avoiding unnecessary surgery. However, the role of CN should be investigated under the light of new immunotherapeutic interventions. Also, markers of response to ICI need to be identified before the optimal selection of therapy could be determined for a particular patient.
| S-EPMC6770566 | biostudies-literature
Project description: Not available
| S-EPMC6881185 | biostudies-literature
Project description:Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.
| S-EPMC8773703 | biostudies-literature
Project description:BRAF-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. BRAF alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I BRAFV600E mutation occurring most frequently in colorectal cancer. Functional categorization of BRAF mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with BRAFV600E-mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in BRAFV600E-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in BRAF-mutated advanced colorectal cancer.
| S-EPMC9390817 | biostudies-literature
Project description:Bladder cancer is the 10th most common cancer type in the world. There were more than 573,000 new cases of bladder cancer in 2020. It is the 13th most common cause of cancer death with an estimated more than 212,000 deaths worldwide. Low-grade non-muscle-invasive bladder cancer (NMIBC) is usually successfully managed with transurethral resection (TUR) and overall survival for NMIBC reaches 90% according to some reports. However, long-term survival for muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer remains low. Treatment options for bladder cancer have undergone a rapid change in recent years. Immune checkpoint inhibitors (ICI), targeted therapies, and antibody-drug conjugates are available now. As bladder cancer is genetically heterogeneous, the optimization of patient selection to identify those most likely to benefit from a specific therapy is an urgent issue in the treatment of patients with bladder cancer.
| S-EPMC9604712 | biostudies-literature
Project description:Esophagogastric cancer (EGC) is a heterogeneous group of malignancies that collectively represent the 2nd leading cause of cancer deaths worldwide. While surgery in combination with chemotherapy and/or radiation therapy represents the primary curative treatment for early stage disease, survival outcomes for the majority of patients with later-stage disease remain poor. Cytotoxic chemotherapy with platinum doublets such as 5-FU/leucovorin/oxaliplatin is the mainstay of treatment with incremental benefits provided by targeted therapy (trastuzumab, trastuzumab deruxtecan, ramucirumab) and immunotherapy (pembrolizumab, nivolumab). In this article, we provide an updated review and perspectives on the management of advanced EGC. We examine the distinct epidemiological, etiological and molecular features of each disease entity comprising EGC. After reviewing the critical studies that established conventional systemic cytotoxic and targeted therapeutics, we elaborate on recent promising and complex data with immune checkpoint inhibition focusing on implications of tumor histology and PD-L1 expression in the tumor microenvironment. We also highlight novel diagnostic and therapeutic strategies to build on these recent advances.
| S-EPMC8352646 | biostudies-literature
Project description:Background and objectivesEndometrial cancer is a common malignancy and recurrences can be fatal. Although platinum-pretreated endometrial tumors are commonly treated with anthracyclines and taxanes, there is no current standard of care. Both immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) have been extensively assessed in this setting, including tumors selected for DNA mismatch repair (MMR)/microsatellite instability (MSI) and programmed death-ligand 1 expression status. This review will provide evidence-based guidance on use of ICIs alone or in combination with TKIs in patients with pretreated advanced, persistent, or recurrent metastatic endometrial cancer.Data sources and methodsRandomized phase II-III trials in unselected populations pretreated, recurrent, or metastatic endometrial cancer and phase I-II trials in biomarker selected populations were identified from PubMed as well as conference proceedings using the key search terms 'immune checkpoint inhibitors', 'endometrial cancer', and 'advanced'.ResultsA total of nine eligible studies were identified assessing ICI monotherapy for biomarker-selected or ICI plus TKI combinations and a dual ICI regimen for biomarker-unselected patients with pretreated recurrent or metastatic endometrial cancer. In MMR/MSI-selected tumors, five phase I/II studies evaluated ICI monotherapy indicating benefit in these patients. Only the phase III KEYNOTE-775 trial reported a statistically significant overall survival improvement for the combination of pembrolizumab plus lenvatinib compared with docetaxel or paclitaxel regardless of MMR/MSI status.ConclusionsPembrolizumab plus lenvatinib is indicated for patients with unselected pretreated metastatic endometrial cancer and pembrolizumab monotherapy is a preferred option for patients with MMRd/MSI-H tumors.
| S-EPMC10026109 | biostudies-literature