Outlook into the future of front-line immune checkpoint inhibition in metastatic urothelial carcinoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Brown JR
PROVIDER: S-EPMC8053833 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
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.
| S-EPMC5993034 | biostudies-literature
Project description:IntroductionSynergistic effects have been discussed for tyrosine kinase (TKI) and immune checkpoint inhibitors (ICI). Primary resistance to TKI might disturb subsequent ICI effectiveness. The objective was to investigate, if primary resistance to 1st line TKI monotherapy predicts response to ICI in subsequent therapy lines and impacts overall survival (OS) in advanced renal cell carcinoma (aRCC).Materials and methodsRetrospectively, aRCC patients which received front-line TKI from 2016 to 2019 were analyzed for the outcomes primary resistance (1LR), response to sequential ICI therapy, progression free survival (PFS) and overall survival (OS). Kaplan-Meier-estimates, Cox proportional hazards and logistic regression were used.ResultsPrimary resistance to front-line TKI was observed in 27 (53%) of 51 patients. Groups with disease control (DC) and 1st line TKI resistance (1LR) were not different at baseline with regard to clinicopathological features. Median duration on 1st line therapy was significantly shorter in the 1LR (5.1 months) than in the DC (14.7 months) group (p = 0.01). Sequential therapy was started in 21 (75%) and 12 (52%) patients of 1LR and DC groups using nivolumab in 16 (76%) vs. 11 (92%) cases (p > 0.05). Logistic regression revealed that 1LR status, neutrophil-to-lymphocyte ratio < 3, IMDC favorable prognosis and clear cell histology had no significant impact on responsiveness to ICI in subsequent therapy lines. Cox proportional hazards demonstrated no significant association of 1LR status with PFS and OS in patients who received subsequent ICI treatment.ConclusionPrimary TKI resistance of aRCC was neither significantly associated with responsiveness to ICI during sequential therapy nor with PFS and OS. This adds the evidence for ICI based sequential therapy in primary TKI resistant aRCC.
| S-EPMC10517909 | biostudies-literature
Project description:Treatment strategies for metastatic urothelial carcinoma (mUC) have evolved dramatically over the last decade. The emergence of immunotherapeutic agents, especially immune checkpoint inhibitors, has been the most significant development. Immunotherapy increased the overall survival rate of patients with mUC and provided a durable response. The success of immune checkpoint inhibitors further led to the development of novel agents that regulate the immune system within the tumor microenvironment. However, despite some success with immune checkpoint inhibitors, researchers are still developing new agents, including small molecule tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and novel fusion proteins, tailored for targets other than immune checkpoint inhibitors. Novel treatment strategies are being developed rapidly with ongoing pre-clinical trials. Here, we outline promising new therapies that are expected to improve survival rates for patients with mUC.
| S-EPMC8799034 | biostudies-literature
Project description:The mechanisms underlying the resistance to immune checkpoint inhibitors (ICIs) therapy in metastatic urothelial carcinoma (mUC) patients are not clear. It is of great significance to discern mUC patients who could benefit from ICI therapy in clinical practice. In this study, we performed machine learning method and selected 10 prognostic genes for constructing the immunotherapy response nomogram for mUC patients. The calibration plot suggested that the nomogram had an optimal agreement with actual observations when predicting the 1- and 1.5-year survival probabilities. The prognostic nomogram had a favorable discrimination of overall survival of mUC patients, with area under the curve values of 0.815, 0.752, and 0.805 for ICI response (ICIR) prediction in the training cohort, testing cohort, and combined cohort, respectively. A further decision curve analysis showed that the prognostic nomogram was superior to either mutation burden or neoantigen burden for overall survival prediction when the threshold probability was >0.35. The immune infiltrate analysis indicated that the low ICIR-Score values in mUC patients were significantly related to CD8+ T cell infiltration and immune checkpoint-associated signatures. We also identified differentially mutated genes, which could act as driver genes and regulate the response to ICI therapy. In conclusion, we developed and validated an immunotherapy-responsive nomogram for mUC patients, which could be conveniently used for the estimate of ICI response and the prediction of overall survival probability for mUC patients.
| S-EPMC7477044 | biostudies-literature
Project description:Treatment of metastatic urothelial carcinoma (mUC) after failure with platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) remains controversial. To explore the role of subsequent systemic therapy, medical records from 436 patients who were consecutively treated with chemotherapy for mUC between May 2017 and April 2021 were collected from a single-center cancer registry. The primary endpoint was overall survival (OS), and progression-free survival (PFS) and response rate (RR) were also assessed. Among the 318 patients who failed both platinum and ICIs, subsequent therapy was delivered to 166 (52%) patients: taxanes (n = 56), platinum rechallenge (n = 46), pemetrexed (n = 39), and clinical trials (n = 25). Objective responses to third-line therapy were noted in 50 patients (RR, 30%; 95% CI, 23-37%). The patients who were enrolled in clinical trials and treated with platinum rechallenge were significantly more likely to respond than those treated with taxanes or pemetrexed. The median PFS and OS were 3.5 months (95% CI, 2.9-4.2 months) and 9.5 months (95% CI, 8.1-11.0 months), respectively. Similar to RR, PFS and OS were longer for the patients who were enrolled in clinical trials. Based on multivariate analyses, good performance status and enrollment in clinical trials are associated with benefits from subsequent therapy for pretreated mUC.
| S-EPMC9405748 | biostudies-literature
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.
| S-EPMC6121021 | biostudies-literature
Project description:BackgroundLimited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1)-negative patients receiving immunotherapy. Final results from these trials are unknown.ObjectiveTo compare survival in cisplatin-ineligible mUC patients receiving first-line immunotherapy versus those receiving carboplatin-based chemotherapy.Design, setting, and participantsWe conducted a retrospective cohort study of 2017 mUC patients receiving first-line carboplatin-based chemotherapy (n = 1530) or immunotherapy (n = 487) from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record-derived database.Outcome measurements and statistical analysisThe primary outcomes were overall survival (OS), comparing 12- and 36-mo OS, and hazard ratios before and after 12 mo. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression model estimates of comparative effectiveness.Results and limitationsIPTW-adjusted OS rates in the immunotherapy group were lower at 12 mo (39.6% [95% confidence interval {CI} 34.0-45.3%] vs 46.1% [95% CI 43.4-48.8%]) but higher at 36 mo (28.3% [95% CI 21.8-34.7%] vs 13.3% [95% CI 11.1-15.5%]) relative to the chemotherapy group. Immunotherapy treatment demonstrated inferior OS during the first 12 mo relative to carboplatin-based chemotherapy (IPTW-adjusted hazard ratio [HR] 1.37, 95% CI 1.15-1.62), but superior OS beyond 12 mo (IPTW-adjusted HR 0.50, 95% CI 0.30-0.85). Limitations include retrospective design and potential unmeasured confounding.ConclusionsIn the setting of mUC, clinicians and patients should carefully consider how to balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy.Patient summaryTo determine the optimal first-line therapy for metastatic bladder cancer patients who are unfit for cisplatin, we compared carboplatin-based chemotherapy versus immunotherapy using real-world data. Survival in the 1st year of treatment was lower with immunotherapy relative to chemotherapy, but for patients surviving beyond the 1st year, immunotherapy was superior.
| S-EPMC6822167 | biostudies-literature
Project description:IntroductionClinical trials investigating efficacy of immune checkpoint inhibitors (ICI) revealed sex-specific divergent outcomes in urothelial cancer (UC), suggesting that sex hormones might play an important role in gender-specific dimorphisms of response upon ICI. However, further clinical investigations are still needed to understand the influence of sex hormones in UC. The aim of this study was to get further insights on the prognostic and predictive value of sex hormone levels in patients with metastatic UC (mUC) who underwent ICI.Material and methodsSex hormone levels of patients with mUC including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, prolactin, testosterone and 17β-estradiol (E2) were evaluated at baseline and during ICI at 6/8 weeks and 12/14 weeks.ResultsTwenty-eight patients (10 women, 18 men) with a median age of 70 years were included. Metastatic disease was confirmed in 21 patients (75%) after radical cystectomy while seven patients showed mUC at first diagnosis. Twelve patients (42.8%) received first line and 16 patients second line pembrolizumab. The objective response rate (ORR) was 39% (CR in 7%). The median progression-free survival (PFS) and overall survival (OS) was 5.5 and 20 months. Focusing on changes of sex hormone levels during ICI, a significant increase in FSH levels and decrease of the LH/FSH ratio was noticed in responders (p = 0.035), yet without sex-specific significance. When adjusted for sex and treatment line, a significant increase of FSH levels was confirmed in men during second line pembrolizumab. Focusing on baseline levels, LH/FSH ratio was significantly higher in female responders (p = 0.043) compared to non-responders. In women, increased LH levels and LH/FSH ratio were associated with better PFS (p = 0.014 for LH, p = 0.016 for LH/FSH ratio) and OS (p = 0.026 and p = 0.018). In male patients, increased E2 levels were linked with improved PFS (p < 0.001) and OS (p = 0.039).ConclusionIncreased LH and LH/FSH values in women as well as high E2 levels in men were significant predictors of better survival. Elevated LH/FSH ratio was predictive of better response to ICI in women. These results show first clinical evidence of the potential role of sex hormones as prognostic and predictive biomarker in mUC. Further prospective analyses are needed to corroborate our findings.
| S-EPMC10243034 | biostudies-literature
Project description:Over the last decade, the treatment paradigm of metastatic renal cell carcinoma has rapidly evolved, with notable changes in the front-line setting. Combination therapies involving the use of either doublet therapy with immune checkpoint inhibitors or combination VEGFR-directed therapies with immune checkpoint inhibitors have significantly improved clinical outcomes, including prolonged overall survival and durable response to treatment. We aim to highlight the Food and Drug Administration-approved front-line therapy options, the navigation of treatment selection, and the future directions of metastatic renal cell carcinoma therapies.
| S-EPMC9106028 | biostudies-literature
Project description:The incidence of renal cell carcinoma (RCC) is rising and metastatic RCC carries a very poor prognosis. The treatment paradigm for metastatic RCC has shifted dramatically in the last decade with multi-targeted tyrosine kinase inhibitors (TKI) previously used as first-line treatment but its utility is limited by short-lived efficacy and rapid disease progression. The dysregulation of immune cells in the tumour microenvironment contributes to unregulated growth of RCC. Thus, the use of immune checkpoint inhibitors has become first-line treatment for metastatic RCC and has offered dramatic improvement in clinical benefit and survival. Treatment with immune checkpoint inhibitor in combination with TKI appears to be promising in offering even greater response rates. The treatment for metastatic RCC continues to evolve and ongoing advances with new targeted agents and biomarkers are needed to continue to improve prognosis in the future.
| S-EPMC8435744 | biostudies-literature