Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer.

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

Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial.

BACKGROUND: Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population. METHODS: We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged ≥18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or 75 mg/m2 docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on <1% [IC0] or 1% to <5% [IC1] of tumour-infiltrating immune cells vs ≥5% of tumour-infiltrating immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver metastases (yes vs no), and number of prognostic factors (none vs one, two, or three). Patients and investigators were aware of group allocation. Patients, investigators, and the sponsor were masked to PD-L1 expression status. The primary endpoint of overall survival was tested hierarchically in prespecified populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. This study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT02302807. FINDINGS: Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11·1 months [95% CI 8·6-15·5; n=116] vs 10·6 months [8·4-12·2; n=118]; stratified hazard ratio [HR] 0·87, 95% CI 0·63-1·21; p=0·41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15·9 months [95% CI 10·4 to not estimable] vs 8·3 months [5·6-13·2]; HR 0·57, 95% CI 0·26-1·26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients). INTERPRETATION: Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting. FUNDING: F Hoffmann-La Roche, Genentech.

Hyperprogression after pembrolizumab treatment in two patients with metastatic urothelial carcinoma.

Hyperprogression has recently been recognized as a new pattern of progression in patients undergoing immune checkpoint inhibitor treatment. Here, we report two cases that showed hyperprogression during the initial phase of pembrolizumab treatment for metastatic urothelial carcinoma. The first patient, who received pembrolizumab as a second-line treatment, developed severe respiratory failure due to the rapid progression of lung metastases on the ninth day after the third pembrolizumab treatment. The second patient developed jaundice and hepatic dysfunction due to the progression of a metastatic lymph node of the liver hilum after the first administration of pembrolizumab. She developed multiple brain metastases with intraventricular bleeding on the 10th day after the second administration of pembrolizumab. It is important to be aware that hyperprogression sometimes occurs quite a while after starting treatment, and that both pseudoprogression and hyperprogression may occur in the early stage of treatment.

Tumour multifocality and grade predict intravesical recurrence after nephroureterectomy in patients with upper urinary tract urothelial carcinoma without a history of bladder cancer.

OBJECTIVE: Patients with upper urinary tract urothelial carcinoma (UUT-UC) without a history of bladder cancer have a different natural history of intravesical recurrence after nephroureterectomy compared with those with a history of bladder cancer. The aim of this study was to identify predictive factors for post-operative intravesical recurrence in patients with non-metastatic upper urinary tract-localized urothelial carcinoma without a history of bladder cancer and who were not taking medication during the perioperative period. METHODS: This retrospective study included 133 patients who were treated between 1995 and 2012. Univariate and multivariate analyses were used to evaluate the clinical and pathological factors associated with the cumulative incidence of bladder cancer. RESULTS: Of the 133 patients, 51 (38.3%) developed intravesical recurrence during a median follow-up of 71 months (range, 0.8-210.8). In the multivariate analysis, multifocality (P = 0.03) and high tumour grade (P = 0.007) were significantly associated with the cumulative incidence of bladder cancer. We constructed a prediction classification model on the basis of the total number of risk factors. The 2-year cumulative incidence rates were 5.6, 34.8 and 50.0% in individuals with no, one and two risk factors, respectively. There was a significant difference between patients with no risk factors and those with two risk factors (P = 0.01). CONCLUSIONS: Although this retrospective study had several limitations, tumour multifocality and tumour grade were found to be potential risk factors for intravesical recurrence in our cases.

[Analysis of the treatment and prognosis for gestational trophoblastic neoplasia patients with urinary system and adrenal glands metastasis].

OBJECTIVE: To analyze the treatment and prognosis of patients with gestational trophoblastic neoplasia with urinary system and adrenal glands metastasis. METHODS: The treatment and prognoses of 32 patients with gestational trophoblastic neoplasia with urinary system and adrenal glands metastasis from Dec. 1990 to Dec. 2010 at Peking Union Medical College Hospital, Chinese Academy of Medical Sciences were respectively reviewed. RESULTS: Treatment methods: all 32 patients received 9 courses(in average) of a multi- drug chemotherapy in our hospital (range 1-24 coures). Among them, 3 patients with bladder metastasis received intravesical chemotherapy of fluorouracil. 9 patients received surgical treatments in other hospital and 15 patients received surgical treatments while undergoing chemotherapy in our hospital. Treatment results: after the treatments, of the 32 patients, 21 (66%) patients achieved complete remission, 3(9%) exhibited partial remission and 8 (25%) progressed. Seven patients with renal metastasis achieved complete remission. Two patients with adrenal glands metastasis achieved complete remission. Nine patients with urinary bladder metastasis achieved complete remission. Seven patients with ureters metastasis achieved complete remission. Two (10% ) of 21 patients with complete remission relapsed. CONCLUSIONS: Multidrug and multiroute chemotherapy is the main strategy for patients with gestational trophoblastic neoplasia with urinary system and adrenal glands metastasis. The prognoses of patients with renal or adrenal glands metastasis are much worse than those in patients with bladder and ureters metastasis because of concomitant multiogran metastasis. Adequate attention should be given to patients with renal or adrenal glands metastasis. Individual treatment, assisted by surgery when necessary, may be carried out for these patients to achieve a better outcome.

Metastasis of gastric carcinoma simulating a urothelial tumor. Case report and review of the literature.

OBJECTIVE: To review two cases with the diagnostic suspicion of urinary tract tumor by clinical picture and imaging tests in which pathology of the surgical specimen revealed metastasis of gastric adenocarcinoma. METHODS: 82 and 68 year-old patients with past history of gastric adenocarcinoma that had undergone surgical treatment 6 months and 6 years before urology consultation,respectively. They were diagnosed upper urinary tract tumors by CT scan. RESULTS: Definitive pathologic diagnosis of urinary tract metastasis of gastric adenocarcinoma was obtained after radical surgery in both cases. CONCLUSIONS: Clinical and radiologic presentation of urothelial metastases of gastric adenocarcinoma may simulate de novo urothelial tumors. Evolution in these patients is usually bad although we currently don't have enough information to issue a therapeutic guide to follow.

Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma.

BACKGROUND: Cisplatin-based chemotherapy is a standard treatment of metastatic urothelial carcinoma (UC), though carboplatin-based chemotherapy is frequently substituted due to improved tolerability. Because comparative effectiveness in clinical outcomes of cisplatin- versus carboplatin-based chemotherapy is lacking, a meta-analysis was carried out. METHODS: PubMed was searched for articles published from 1966 to 2010. Eligible studies included prospective randomized trials evaluating cisplatin- versus carboplatin-based regimens in patients with metastatic UC. Individual patient data were not available and survival data were inconsistently reported. Therefore, the analysis focused on overall response (OR) and complete response (CR) rates. The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios (RRs). RESULTS: A total of 286 patients with metastatic UC from four randomized trials were included. Cisplatin-based chemotherapy was associated with a significantly higher likelihood of achieving a CR [RR = 3.54; 95% confidence interval (CI) 1.48-8.49; P = 0.005] and OR (RR = 1.34; 95% CI 1.04-1.71; P = 0.02). Survival end points could not be adequately assessed due to inconsistent reporting among trials. CONCLUSIONS: Cisplatin-based, as compared with carboplatin-based, chemotherapy significantly increases the likelihood of both OR and CR in patients with metastatic UC. The impact of improved response proportions on survival end points could not be assessed.

[Treatment of patients of local colorectal cancer with involvement of the urinary organs: participation of the urologist].

We treated 314 patients with local colorectal cancer (LCRC). Of them, 189 (60.2%) were males, 125 (39.8%)--females, age from 31 to 79 years (mean age 59.6 +/- 5.7 years). Combined surgery with resection of the affected urinary system components en bloc was made in 277 (88.2%) patients. Palliative urological care for obstructive lesions of the urinary system was delivered to 37 (11.8%) patients. Surgical intervention was performed by a surgical team consisting of coloproctologists and urologist. Treatment of most of the patients was multimodal. As a result, it became clear that involvement of the urinary system in tumor process in LCRC patients must not entail rejection of combined surgery. Subtotal resection of the urinary bladder affected by a tumor in LCRC patients is functionally valid and oncologically radical. Efficacy of this intervention is confirmed by a satisfactory social adaptation--18 (51.4%) of 35 followed up patients resumed their jobs. Resection of different parts of the urinary system has insignificant impact on postoperative lethality. Palliative urological care in urinary obstruction in LCRC patients improves quality of life and efficacy of conventional treatment. Treatment of such severe patients should be conducted with participation of the urologist who decides on optimal methods of urinary derivation, performs surgical reconstruction and follow-up of the patients after the operation.

Third-line gemcitabine monotherapy for platinum-resistant advanced urothelial cancer.

OBJECTIVE: To evaluate the efficacy and toxicity of third-line gemcitabine monotherapy (Gem) in patients with platinum-resistant advanced urothelial cancer (UC). PATIENTS AND METHODS: From July 2005 to March 2009, 13 patients were enrolled. All patients had previously received methotrexate, vinblastine, doxorubicin, and cisplatin as first-line therapy. Second-line therapy consisted of paclitaxel/carboplatin (Pca) therapy: paclitaxel (175 mg/m(2)) followed by carboplatin (area under the curve = 5) was intravenously infused on day 1 of each 21-day cycle. Following Pca failure, Gem was given as third-line treatment: gemcitabine (1,000 mg/m(2)) was intravenously administered on days 1, 8, and 15 of each 28-day cycle. All patients were eligible for toxicity assessment. Survival curves were produced using the Kaplan-Meier method. RESULTS: An average of 3.2 Gem cycles (range, 1-8 cycles) were given. Following Gem treatment, overall response rates were 0% CR, 7.7% PR (n = 1), 53.8% SD (n = 7), and 38.5% PD (n = 5). Grade 3-4 toxicities included anemia (31%), neutropenia (31%), and thrombocytopenia (31%). One case experienced grade 3-4 hepatic dysfunction during treatment with Gem. Low-grade alopecia was observed in all 13 patients (100%). Median time to progression and overall survival was 2 and 7.3 months, respectively, following Gem. The 1- and 2-year overall survival rate was 30.8% and 15.3%, respectively, for Gem. CONCLUSION: Gem as third-line therapy was performed safely with good tolerability in platinum-resistant advanced UC, even though the efficacy was very limited.

[An analysis of upper urinary tract recurrence following radical cystectomy for bladder cancer].

Transitional cell carcinoma of the urothelium is often multifocal, and subsequent tumors may occur anywhere in the urinary tract afer treating the initial carcinoma. The risk of an upper urinary tract recurrence following a radical cystectomy has been reported to be approximately 2 to 8%, but there are few reports with regard to the pattern and predictive factors of upper tract recurrence. We report here the incidence and pattern of upper tract recurrence following a radical cystectomy. Of the 166 patients 5 (3%) had upper tract recurrence. The prognosis of upper urinary tract recurrence is significantly better than other site of recurrence.

The Role of Metastasectomy in Urothelial Carcinoma: Where Are We in 2020?

Systemic therapy is the mainstay of treatment for metastatic urothelial carcinoma (UC). Responses to first-line platinum-based therapy tend to be short-lived with potential toxicity. Despite the approval of checkpoint inhibitors, the long-term prognosis for patients with metastatic UC remains dismal. Herein we report the case of a patient with a solitary pulmonary metastatic lesion of urothelial origin as the only site of metastatic disease who remained free of disease for more than 2 years without systemic therapy after metastasectomy. We review the literature discussing the role of combined surgical and medical management of oligometastatic UC. As our case illustrates, a growing body of evidence suggests a potential role for a multimodal approach in patients with oligometastatic UC.

68Ga-PSMA PET/CT Uptake in the Ureter Caused by Ligand Expression in Urothelial Cancer.

Ga-PSMA PET/CT has become a well-established imaging modality to detect prostate cancer (PCa) metastases in biochemical recurrence. Despite its claimed specificity for PCa, Ga-PSMA uptake in tissues unrelated to PCa, particularly in the neovascular tissue of other cancers, has been reported in numerous studies. A 73-year-old man underwent Ga-PSMA PET/CT for biochemical recurrence of PCa 7 years after radical prostatectomy. The Ga-PSMA PET/CT showed 1 lesion with PSMA uptake in the distal left ureter. Histology revealed a low-grade noninvasive papillary urothelial carcinoma. By immunohistochemistry, PSMA expression was observed in the neoplastic urothelial cells and in the vessels of the papillary structures.

Secondary neoplasms of the urinary system and male genital organs.

BACKGROUND AND AIMS: In this review we discuss those secondary tumours involving the urinary system and male genital organs that can pose differential diagnostic difficulties with primary lesions, and highlight morphological and ancillary features that could be helpful in reaching a proper assignment of primary origin. MATERIALS AND METHODS: Based on MEDLINE database searches all reports of secondary tumours involving the urinary system (kidney and bladder) and male genital organs (prostate, testis and penis) were examined. RESULTS AND DISCUSSION: Involvement by a secondary tumour occurs either as a metastasis or by direct extension. Among non-genitourinary primary sites, colorectal, pulmonary, skin (melanoma) and breast are the most common contributors. Secondary spread from a genitourinary site primary tumour to another genitourinary organ occurs most frequently between the prostate and urinary bladder, given the intimate topographic proximity of the two. The prognosis is very poor, as the secondary tumour usually occurs in patients with carcinoma in the late stages. Few secondary tumours have distinctive histological and immunohistochemical features, making it difficult to make the appropriate diagnosis. Hence, knowledge of the history and clinical setting are particularly important in these cases. CONCLUSION: The urinary system and male genital organs are not common sites for secondary tumours. They often go either undiagnosed or misdiagnosed in the clinical follow-up of patients with cancer. Accurate diagnosis is essential because of differing therapeutic approaches compared with a primary neoplasm.

Metastatic involvement of the urinary tract in patients with advanced ovarian carcinoma: lessons from the autopsy for an interdisciplinary treatment approach.

PURPOSE OF INVESTIGATION: Frequency and extent of metastases in urologic organs found at autopsy of ovarian carcinoma patients were evaluated. METHODS: Autopsy reports from 170 patients who died of advanced ovarian carcinoma between 1975 and 2005 were studied. The distribution of abdominal metastatic sites with particular attention to the involvement of the urologic organs, and hydronephrosis was analyzed. RESULTS: The distribution of metastatic sites was as follows: kidney (n = 6, 3.5%), urinary bladder (n = 38, 22.4%), and ureter (n = 20, 11.8%). In 36 patients, hydronephrosis was observed (21.2%); of these patients, 20 (55.6%) also had ureteral involvement. All patients with ureteral involvement had hydronephrosis. CONCLUSION: Hydronephrosis in late stages of ovarian carcinoma, usually attributed to extrinsic compression of the ureter by an abdominal tumor, may also be explained by ureteral metastases. This fact must be considered in the clinical management of these patients, particularly in the restoration of luminal patency through an endoscopically placed internal ureteral stent.

[Results of treatment for recurrent cancer of the uterine cervix].

The investigation involved 285 patients suffering from recurrences and distant metastases of uterine carcinoma cases of 24% of all (primary tumor). All recurrences generally occurred 12-20 months after the beginning of specialized therapy in 3.3-40%, with 78.3% detected within the first 24 months. Relapse was reported mostly in groups in which a single modality was used: surgery (32.4%) or radiotherapy (24.7%). Local recurrence rate for primary squamous cell tumor was 53.6%, adenocarcinoma - 6.3% and poorly-differentiated cell carcinoma - 4.9%. Complete regression of relapse following combined treatment was reported in 19% versus 14% and 4% after radiotherapy and chemotherapy, respectively. Moreover, more apparent responses were registered as a result of combinations of modalities (69%) as compared with 26% and 20% for radio- and chemotherapy, respectively.

Can circulated lung cancer cells pass to the urine without apparent urine tract metastases? A single centre series.

Urine cytology has been a useful tool for the diagnosis of urinary tract malignancies. However, the presence of tumor cells in the urine sediment without an obvious urothelial metastatic deposit is a rare phenomenon and in patients with lung cancer has never been reported. We present five cases with metastatic lung cancer and positive urine cytology. The possible mechanisms underlining this phenomenon and its implications are discussed.

The role of lymph-node dissection in the treatment of upper urinary tract cancer: a multi-institutional study.

OBJECTIVES: To determine the role of lymph-node (LN) dissection in patients undergoing surgery for upper urinary tract (UUT) cancer. PATIENTS AND METHODS: We reviewed the clinicopathological data from 312 patients with UUT cancer treated predominantly by nephroureterectomy. The relationship between clinical characteristics and cancer-specific survival (CSS) was analysed, focusing on node-related information. RESULTS: In all, 166 patients had LN dissection while 146 did not (pNx). Multivariate analysis showed that T stage, grade and pN status were significant variables for CSS. The difference in survival between the pN0 and pNx groups remained significant in a multivariate analysis. The median (range) number of LNs removed was 6 (1-65). There was no significant difference in CSS between the 72 patients with fewer than six LNs removed and the 78 with six or more removed. CONCLUSIONS: LN dissection is important for postoperative stratification of patients with UUT cancer because node-positive disease was one of the variables with a significant adverse effect on survival. In addition, the significant difference in survival between the pN0 and pNx groups might indicate a therapeutic benefit of LN dissection, although removing more LNs did not uniformly increase the probability of CSS.

Postoperative disseminated intravascular coagulation in a patient with ureteral metastasis from gastric cancer.

A 66-year-old man, with a history of gastric signet ring cell carcinoma, was admitted due to intermittent dull pain in the left lower abdomen for 3 months. Left ureteral obstruction with suspicious tumor encasement and hydronephrosis was found on imaging studies. Endoscopic ureteral biopsy revealed infiltrating high-grade urothelial carcinoma. As a result, he underwent left nephroureterectomy and bladder cuff excision. Unexpectedly, metastatic carcinoma of the left ureter from the stomach was the final diagnosis after comparison of the permanent sections of the two specimens. Unfortunately, acute disseminated intravascular coagulation developed and the patient died of disease complications 16 days after the operation, even with intensive care. The details of this rare condition are reported herein with a review of the medical literature.

Evolution of randomized controlled trials and surrogacy of progression-free survival in advanced/metastatic urothelial cancer.

BACKGROUND: Clinical trials in advanced/metastatic urothelial cancer have been difficult to perform. We review the current characteristics of randomized controlled trials (RCTs) and evaluate whether PFS could be a potential surrogate endpoint for overall survival (OS) in advanced/metastatic urothelial cancer. METHODS: We identified trials by a systematic review of Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to April 2017. We included RCTs of patients with locally advanced/metastatic urothelial cancer that involved systemic therapy as an intervention, and those with reported hazards ratios (HRs) and corresponding 95% confidence intervals (CIs) for both OS and PFS, or provided Kaplan-Meier curves from which HRs and 95% CI could be calculated. The correlation coefficient between log of HRs for OS and PFS was calculated using linear regression weighted by sample size. RESULTS: Forty eight trials that enrolled 7019 patients were included in the review and 24 RCTs were included in the surrogacy analysis. 27(56.3%) of identified 48 RCTs were phase II trials, and the median sample size was 107(range, 30-626) for all RCTs. The correlation coefficient between log HR for PFS and log HR for OS was 0.79 (95% CI, 0.58-0.91). The correlation coefficient increased to 0.87 (95% CI, 0.72-0.94) after excluding the only trial with immune checkpoint inhibitor. Multiple sensitivity analyses did not change the results..aph."/> CONCLUSIONS: PFS is strongly correlated with OS in trials of advanced/metastatic urothelial cancer assessing the treatment benefit of new drugs And PFS warrants further exploration as a surrogate endpoint in clinical trial datasets.

Immune-checkpoint inhibitors in previously treated patients with advanced or metastatic urothelial carcinoma: A systematic review and meta-analysis.

Immunotherapy represents a new hope for patients with advanced urothelial carcinoma (UC). However, to date, only one of two randomized studies showed a clear survival advantage with these treatments. Aimed to investigate the role of immune-checkpoint inhibitors in patients with platinum progressed metastatic UC we performed a systematic review and meta-analysis of clinical trials to evaluate the efficacy and activity, in terms of Overall Survival (OS) and Objective Response Rate (ORR). Immune checkpoint inhibitors have showed to improve OS compared to chemotherapy in unselected patients (HR 0.80, 95% CI 0.69-0.93, p = 0.003), while the difference was not significant in patients selected for PD-L1 expression (HR 0.72, 95% CI 0.48-1.09, p = 0.12). Pooled probability of response was 0.18 (95% CI 0.16-0.20) in unselected patients and 0.27 (95% CI 0.25-0.32) in PD-L1 selected patients. Immunotherapy results in a significant survival advantage in PD-L1 unselected patients suggesting that PD-L1 expression may not be a reliable marker in previously platinum treated patients.