CONTEXT: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens. OBJECTIVE: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials. EVIDENCE ACQUISITION: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features. EVIDENCE SYNTHESIS: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival. CONCLUSIONS: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.

• MeSH
• adjuvantní chemoterapie metody   MeSH
• inhibitory kontrolních bodů * terapeutické užití   farmakologie   MeSH
• invazivní růst nádoru MeSH
• karcinom z přechodných buněk farmakoterapie   patologie   MeSH
• lidé MeSH
• nádory močového měchýře farmakoterapie   patologie   MeSH
• síťová metaanalýza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH

BACKGROUND: Recently, a plethora of novel systemic agents have been incorporated into the therapeutic armamentarium of advanced urothelial carcinoma (aUC). The antibody-drug conjugate (ADC), enfortumab vedotin (EV), has demonstrated relevant clinical benefit in patients with aUC refractory to platinum and immune-checkpoint inhibitor (ICI) therapy. Our study provides a retrospective, international, real-world analysis comparing the effectiveness of EV to chemotherapy in this setting. METHODS: The data were extracted from the medical records of patients treated with EV or chemotherapy following pembrolizumab for recurrent or progressive aUC after platinum-based chemotherapy. Patients were assessed for overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and duration of response (DoR). RESULTS: Our analysis included 247 patients treated with EV (88, 36%) or chemotherapy (159, 64%). Median OS was 9.1 months (95%CI 7.2-10.7) in the overall study population, 13.6 months (95%CI 10.0-31.0) in patients receiving EV and 6.8 months (95%CI 6.0-8.9) in patients receiving chemotherapy (p < 0.001). The OS benefit of EV was not affected by primary tumour site and histology, metastatic sites, type of first platinum-based chemotherapy or response to pembrolizumab. In the EV cohort, the median PFS was significantly longer (8.8 months [95%CI 6.5-17.0] vs. 3.0 months [95%CI 2.6-3.7]) and the ORR was significantly higher (56% vs. 23%) than in the chemotherapy cohort. CONCLUSIONS: The results of our international analysis of real-world data confirm the effectiveness of EV in the sequential strategy of aUC patients who have received prior platinum-based chemotherapy and anti-PD-1 pembrolizumab, regardless of commonly considered prognostic factors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05290038.

• MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * terapeutické užití   aplikace a dávkování   MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• karcinom z přechodných buněk farmakoterapie   mortalita   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• monoklonální protilátky terapeutické užití   aplikace a dávkování   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• urologické nádory farmakoterapie   patologie   mortalita   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

Souhrn: Autoři prezentují případ pacienta s metastatickým uroteliálním karcinomem, disku tují výborný efekt imunoterapie pembrolizumabem v souvislosti s výsledky komplexního genomického profilování nádorové tkáně.

Summary: The authors present a case report of a patient suffered from metastatic urothelial carcinoma and discuss the role and efficacy of pembrolizumab in the context of comprehensive genomic profiling of tumor tissue.

• Klíčová slova
• pembrolizumab,
• MeSH
• humanizované monoklonální protilátky aplikace a dávkování   terapeutické užití   MeSH
• inhibitory kontrolních bodů aplikace a dávkování   terapeutické užití   MeSH
• karcinom z přechodných buněk * diagnóza   farmakoterapie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• protinádorové látky imunologicky aktivní aplikace a dávkování   terapeutické užití   MeSH
• protokoly protinádorové léčby MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Renální karcinom je histologicky diverzní onemocnění s variabilním a často nepředvídatelným chováním. Profilování genové exprese se jeví jako slibná technika k upřesnění diagnózy a stagingu renálního karcinomu a též k přesnějšímu zacílení léčby (1).

Renal cell carcinoma (RCC) is a histologically diverse disease, with variable and often unpredictable clinical behavior. Gene expression profiling is a promising technique for refining the diagnosis and staging of RCC, as well as for highlighting potential therapeutic targets (1).

• MeSH
• faktor 1 indukovatelný hypoxií analýza   MeSH
• genetické testování * metody   MeSH
• hepatocytární růstový faktor analýza   MeSH
• imunoterapie metody   MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• karboanhydrasa IX analýza   MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   genetika   imunologie   MeSH
• prediktivní hodnota testů MeSH
• tkáňový inhibitor metaloproteinasy 1 analýza   MeSH
• Check Tag
• lidé MeSH

Gender- and sex-based disparities in response to immune-checkpoint inhibitors (ICI) has been reported in a variety of tumor types. Women have different anatomy with recurrent urinary tract infections, a different sex hormonal profile, and intrinsic differences in local and systemic immune systems and urobiome composition. Existing literature data in a pan-cancer context reveal contradictory results, and real-world evidence in urothelial carcinoma (UC) is lacking. This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic urothelial carcinoma (mUC) patients progressing or recurring after platinum-based therapy and treated with pembrolizumab as a part of routine clinical care. A total of 1039 patients, treated from January 1st, 2016 to December 31st, 2023 in 68 cancer centers were included. Our data showed that women with metastatic urothelial carcinoma treated with pembrolizumab had shorter OS than men, with a 13% advantage in the 5-year OS rate for male patients. A deeper understanding of these results may inform sex-stratification in future prospective clinical trials and help develop strategies to reduce the magnitude of the sex disparities observed in urothelial cancer outcomes.

• MeSH
• humanizované monoklonální protilátky * terapeutické užití   MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• karcinom z přechodných buněk farmakoterapie   mortalita   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory močového měchýře farmakoterapie   mortalita   patologie   MeSH
• protinádorové látky imunologicky aktivní terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sexuální faktory MeSH
• urologické nádory farmakoterapie   mortalita   patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH

• Klíčová slova
• trastuzumab deruxtecan,
• MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• mutace MeSH
• nemalobuněčný karcinom plic * farmakoterapie   patologie   MeSH
• protinádorové látky aplikace a dávkování   MeSH
• senioři MeSH
• trastuzumab * aplikace a dávkování   škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• klinická studie MeSH
• klinické zkoušky, fáze II MeSH
• randomizované kontrolované studie MeSH

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.

• MeSH
• antigeny CD274 * antagonisté a inhibitory   metabolismus   imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• imunoterapie metody   MeSH
• inhibitory kontrolních bodů * farmakologie   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádory imunologie   radioterapie   terapie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• střeva patologie   účinky záření   MeSH
• střevní mikroflóra MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Nanrilkefusp alfa (nanril; SOT101) is an interleukin (IL)-15 receptor βγ superagonist that stimulates natural killer (NK) and CD8+ T cells, thereby promoting an innate and adaptive anti-tumor inflammatory microenvironment in mouse tumor models either in monotherapy or combined with an anti-programmed cell death protein 1 (PD-1) antibody. In cynomolgus monkeys, a clinical schedule was identified, which translated into the design of a phase 1/1b clinical trial, AURELIO-03 (NCT04234113). In 51 patients with advanced/metastatic solid tumors, nanril increased the proportions of CD8+ T cells and NK cells in peripheral blood and tumors. It had a favorable safety profile when administered subcutaneously on days 1, 2, 8, and 9 of each 21-day cycle as monotherapy (0.25-15 μg/kg) or combined (1.5-12 μg/kg) with the anti-PD-1 pembrolizumab (200 mg). The most frequent treatment-emergent adverse events were pyrexia, injection site reactions, and chills. Furthermore, early clinical efficacy was observed, including in immune checkpoint blockade-resistant/refractory patients.

• MeSH
• antigeny CD279 * antagonisté a inhibitory   imunologie   MeSH
• buňky NK imunologie   účinky léků   MeSH
• CD8-pozitivní T-lymfocyty imunologie   účinky léků   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky terapeutické užití   farmakologie   MeSH
• inhibitory kontrolních bodů farmakologie   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• Macaca fascicularis MeSH
• nádory * farmakoterapie   patologie   imunologie   MeSH
• senioři MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH

The KEYNOTE-564 trial showed that adjuvant immune checkpoint inhibitor (ICI) therapy with pembrolizumab, a PD-1 antibody, significantly improved disease-free survival (DFS) and overall (OS) survival in localised clear-cell renal cell carcinoma (RCC) with a high risk of relapse. The TiNivo and CONTACT-03 trials have reported results for subsequent therapy after progression on ICI therapy in the metastatic setting. The European Association of Urology (EAU) RCC guidelines panel reassessed the new trial results to update recommendations for adjuvant therapy and post-adjuvant therapy. Adjuvant pembrolizumab significantly improved OS (hazard ratio 0.62, 95% confidence interval 0.44-0.87; p = 0.005). Recent trials of subsequent ICI after recurrence on ICI in the metastatic setting do not support ICI monotherapy or combination therapy in patients with recurrence on or after adjuvant ICI therapy. There are no prospective trial results for treatment after adjuvant pembrolizumab failure. On the basis of the recent results, the EAU RCC guidelines panel has updated the recommendation for adjuvant therapy and now issues a strong recommendation for adjuvant pembrolizumab. ICI monotherapy or combination therapy is not recommended in patients with recurrence during or shortly after adjuvant pembrolizumab. PATIENT SUMMARY: Treatment with an immunotherapy drug called pembrolizumab after surgery in patients with intermediate-risk or high-risk kidney cancer delays the time to recurrence of cancer and prolongs survival. Therefore, pembrolizumab after surgery is strongly recommended for these patients. However, a significant proportion of patients have life-changing or serious side effects and these must be discussed.

• MeSH
• adjuvantní chemoterapie MeSH
• humanizované monoklonální protilátky MeSH
• inhibitory kontrolních bodů * terapeutické užití   škodlivé účinky   MeSH
• karcinom z renálních buněk * farmakoterapie   MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   patologie   MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• urologie normy   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• směrnice pro lékařskou praxi MeSH
• úvodníky MeSH
• Geografické názvy
• Evropa MeSH

Recent phase 3 randomized controlled trials (RCTs) demonstrate the promising impact of immune checkpoint inhibitor (ICI)-based combination therapies on locally advanced or metastatic urothelial carcinoma (UC). However, comparative data on the efficacy and toxicity of different ICI-based combinations are lacking. This study aims to compare the efficacy of first-line ICI-based combination therapies for locally advanced or metastatic UC using phase 3 RCT data. In November 2023, three databases were searched for RCTs evaluating oncological outcomes in patients with locally advanced or metastatic UC who were treated with first-line ICI-based combination therapies. Network meta-analysis (NMA) was conducted to compare outcomes, including overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), and treatment-related adverse events (TRAEs). Subgroup analyses were based on PD-L1 status and cisplatin eligibility. The NMA included five RCTs. Enfortumab vedotin (EV) + pembrolizumab ranked the highest for improving OS (100%), PFS (100%), ORR (96%), and CRR (96%), followed by nivolumab + chemotherapy. EV + pembrolizumab combination superiority held across PD-L1 status and cisplatin eligibility. In patients who are cisplatin-eligible, EV + pembrolizumab significantly improved OS (HR: 0.68, 95%CI 0.47-0.99) and PFS (HR: 0.67, 95%CI 0.49-0.92) compared to nivolumab + chemotherapy. Durvalumab + tremelimumab was the safest combination for severe TRAEs, and EV + pembrolizumab ranked second. Our analyses support EV + pembrolizumab combination as a first-line treatment for locally advanced or metastatic UC. Thus, EV + pembrolizumab may become a guideline-changing standard treatment.

• MeSH
• humanizované monoklonální protilátky terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory kontrolních bodů * terapeutické užití   MeSH
• karcinom z přechodných buněk farmakoterapie   mortalita   patologie   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• monoklonální protilátky MeSH
• nádory močového měchýře farmakoterapie   patologie   mortalita   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• randomizované kontrolované studie jako téma MeSH
• síťová metaanalýza * MeSH
• urologické nádory farmakoterapie   mortalita   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• přehledy MeSH
• systematický přehled MeSH