Sacituzumab Govitecan Demonstrates Efficacy across Tumor Trop-2 Expression Levels in Patients with Advanced Urothelial Cancer.

PURPOSE: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4×). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated. RESULTS: In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels. CONCLUSIONS: Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels.

Immunotherapy-Based Combinations in First-Line Urothelial Cancer: A Systematic Review and Individual Patient Data (IPD) Meta-Analysis.

INTRODUCTION: Platinum-based chemotherapy represents the standard of care (SoC) for the first-line treatment of advanced urothelial carcinoma (mUC). The benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy was recently investigated. We performed an individual patient data (IPD) meta-analysis of phase 3 clinical trials comparing ICI-based treatments. METHODS: A systematic literature search was conducted on the MEDLINE and CENTRAL databases. The results were filtered by including only reports on clinical trials or randomized clinical trials from 2018 to 2023, including 3047 patients from four clinical trials (EV302, CHECKMATE-901, IMVIGOR130, KEYNOTE-361). An IPD meta-analysis was performed by reconstructing IPD from Kaplan-Meier curves. The primary endpoints were overall survival (OS) and progression-free survival (PFS) of Pembrolizumab + EV compared to experimental arms of the other trials of immunotherapy + chemotherapy. RESULTS: The OS analysis showed an advantage of IPD from EV302 vs. all the other trials. For EV302 vs. KEYNOTE-361, the HR was 0.51; for EV302 vs. IMVIGOR130, the HR was 0.47; and for EV302 vs. CHECKMATE-901, the HR was 0.66 (CI 95% 0.51-0.85). In the PFS analysis, the EV302 arm showed a statistically significant advantage compared to CHECKMATE-901 (HR 0.66) and versus IMVIGOR130 (HR 0.51). LIMITATIONS: By using reconstructed IPD curves, it was not possible to adjust patient-level covariates, and the heterogeneity of the included population may have affected the pooled results. CONCLUSIONS: The EV302 experimental arm showed better OS and PFS when compared to the other immunochemotherapy combinations. An immunochemotherapy combination strategy at the beginning of treatment in mUC seems to be superior in terms of OS and PFS compared to platinum-based chemotherapy alone. EV-Pembrolizumab resulted to have better outcomes compared to avelumab, rather than other immunochemotherapy combinations. However, given the heterogeneity of these studies, a longer follow up and prospective trials are needed to confirm these data.

[Antibody-Drug Conjugates against Urothelial Carcinoma-Current Issues and Future Development].

Most recently, the antibody-drug conjugate, enfortumab vedotin, has been covered by insurance for the treatment of unresectable or metastatic urothelial carcinoma after chemotherapy and immune checkpoint inhibitors, and has significantly changed the pharmacotherapy for urothelial carcinoma in clinical practice. Recently, several reports demonstarated the efficacy and safety of enfortumab vedotin in real-world clinical practice, highlighting its current status and challenges. In addition, the combination of enfortumab vedotin and pembrolizumab for the treatment of untreated unresectable or metastatic urothelial carcinoma has received expedited approval by the FDA and is expected to become a key drug in urothelial carcinoma.

Radiotherapy plus pembrolizumab for advanced urothelial carcinoma: results from the ARON-2 real-world study.

The addition of metastasis-directed radiotherapy (MDRT) to immunotherapy in patients with advanced urothelial carcinoma (aUC) has shown promising results. We report the real-world data from the ARON-2 study (NCT05290038) on the impact of conventional (CRT) or stereotactic body radiotherapy (SBRT) on the outcome of aUC patients receiving pembrolizumab after platinum-based-chemotherapy. Medical records of 837 patients were reviewed from 60 institutions in 20 countries. Two hundred and sixty-two patients (31%) received radiotherapy (cohort A), of whom 193 (23%) received CRT and 69 (8%) received SBRT. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. With a median follow-up of 22.7 months, the median OS was 10.2 months, 6.8 months and 16.0 months in no RT, CRT and SBRT subgroups (p = 0.005), with an 1y-OS rates of 47%, 34% and 61%, respectively (p < 0.001). The 1y-OS rate in the SBRT subgroup were significantly higher for both lower (63%) and upper tract UC (68%), for pure urothelial histology (63%) and variant histologies (58%), and for patients with bone (40%) and lymph-node metastases (61%). Median PFS was 4.8 months, 9.6 months and 5.8 months in the CRT, SBRT and no RT subgroups, respectively (p = 0.060). The 1y-PFS rate was significantly higher (48%) in the SBRT population and was confirmed in all patient subsets. The difference in terms of ORR was in favour of SBRT. Our real-world analysis showed that the use of SBRT/pembrolizumab combination may play a role in a subset of aUC patients to increase disease control and possibly overall survival.

Impact of LAG-3/FGL1 pathway on immune evasive contexture and clinical outcomes in advanced urothelial carcinoma.

BACKGROUND: Anti-programmed death-1 (PD-1)/anti-PD-ligand-1 (PD-L1) pathway inhibition is a standard regimen for advanced urothelial carcinoma (UC); however, its limited efficacy has been reflected in reported medium response rates. This study explored the role of next-generation coinhibitory receptors (IRs; lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain 3 (TIM-3), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT)) and their ligands (LGs) in the response to PD-(L)1 blockade therapy and the oncological outcomes in patients with UC. METHODS: We investigated metastatic UC cases who underwent PD-(L)1 therapy (cohort 1: n=348, cohort 2: n=89, and cohort 4: n=29) or advanced UC cases involving surgery (cohort 3: n=293 and cohort 5: n=90). We assessed the mRNA expression profiles and corresponding clinical information regarding IRs and LGs using cohorts 1, 2, and 3. Additionally, we elucidated the spatial features of these targeted markers using multiplex immunohistochemistry (mIHC) on formalin-fixed paraffin-embedded samples from cohorts 4 and 5. Survival, differential expressed gene, and Gene Set Enrichment analyses were performed. For mIHC, quantitative analyses were also performed to correlate immune and tumor cell densities with patient survival. RESULTS: LAG-3 expression was strongly associated with the responsiveness of PD-(L)1 blockade compared with the expression of TIM-3 and TIGIT. In tumors with high LAG-3 levels, the increased expression of fibrinogen-like protein 1 (FGL1) had a significantly negative effect on the response to PD-(L)1 blockade and overall survival. Moreover, high FGL1 levels were associated with elevated CD4+ regulatory T-cell gene signatures and the upregulation of CD39 and neuropilin-1, with both indicating CD8+ T-cell exhaustion. mIHC analyses revealed that patients with stromal CD8+LAG-3+cellshigh-tumor FGL1+cellshigh exhibited a significant negative correlation with survival rates compared with those with stromal CD8+LAG-3+cellshigh-tumor FGL1+cellslow. CONCLUSIONS: LAG-3 expression and high FGL1 coexpression are important predictive factors of adverse oncological outcomes related to the presence of immunosuppressive contextures. These findings are hypothesis-generating, warranting further mechanistic and clinical studies aimed to evaluate LAG-3/FGL1 blockade in UC.

A Podcast on Platinum Eligibility and Treatment Sequencing in Platinum-Eligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma.

The treatment landscape for patients with advanced urothelial carcinoma continues to evolve. Enfortumab vedotin plus pembrolizumab has received Food and Drug Administration approval based on recent phase 3 trial data showing superior efficacy compared with first-line platinum-based chemotherapy; however, its distinct toxicity profile may make it less suitable for some patients, and availability in some countries may be limited by cost considerations. Consequently, platinum-based chemotherapy is expected to remain an important first-line treatment option. Choice of platinum regimen (cisplatin- or carboplatin-based) is informed by assessment of clinical characteristics, including performance status, kidney function, and presence of peripheral neuropathy or heart failure. For patients without disease progression after completing platinum-based chemotherapy, avelumab first-line maintenance treatment is recommended by international guidelines. For patients who have disease progression, pembrolizumab is the preferred approach. Additionally, following results from a recent phase 3 trial, nivolumab plus cisplatin-based chemotherapy has also received Food and Drug Administration approval and is an additional first-line treatment option for cisplatin-eligible patients. Later-line options for patients with advanced urothelial carcinoma, depending on prior treatment, may include enfortumab vedotin, erdafitinib (for patients with FGFR2/3 mutations or fusions/rearrangements), sacituzumab govitecan, and platinum rechallenge. For the small proportion of patients ineligible for any platinum-based chemotherapy (i.e., unsuitable for cisplatin or carboplatin), immune checkpoint inhibitor monotherapy with pembrolizumab or atezolizumab is a first-line treatment option, although approved agents vary between countries. In summary, this podcast discusses recent developments in the treatment landscape for advanced urothelial carcinoma, eligibility for platinum-based chemotherapy, potential first-line treatment options, and treatment sequencing. Supplementary file1 (MP4 246907 KB).

Prolonged Response to Osimertinib in EGFR-Mutated Metastatic Urothelial Carcinoma, a Case Report.

A 48-year-old woman without obvious environmental risk factors was diagnosed with metastatic urothelial carcinoma harboring a mutation in EGFR typical of driver mutations for non-small cell lung cancer. Within a year, her cancer progressed on four standard therapies for urothelial cancer, including cancer in lungs, liver, bone, and brain. As fifth-line therapy, she received osimertinib, leading to a complete response in the brain and improvement elsewhere, and the cancer remained controlled for six months. Targeted therapy for rare driver mutations can be effective in urothelial cancer and should be considered prior to exhausting standard therapies.

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab for advanced urothelial carcinoma: results from the randomized phase III ECHO-303/KEYNOTE-698 study.

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%. METHODS: ECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Target enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35-48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67-29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent. CONCLUSIONS: Epacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03374488. Registered 12/15/2017.

Pembrolizumab plus either epacadostat or placebo for cisplatin-ineligible urothelial carcinoma: results from the ECHO-307/KEYNOTE-672 study.

BACKGROUND: Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC. METHODS: ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1). RESULTS: A total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%). CONCLUSIONS: Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.

Enfortumab Vedotin for Elderly Advanced Urothelial Carcinoma Patients or Those With a Poor Performance Status.

BACKGROUND/AIM: The efficacy, safety, and liver toxicity of enfortumab vedotin (EV) for elderly advanced urothelial carcinoma (UC) patients and patients with a poor performance status (PS) are unclear. PATIENTS AND METHODS: We retrospectively analyzed the efficacy, safety, and liver toxicity of EV in elderly patients and patients with a poor PS between December 2021 and August 2023. RESULTS: Sixty-two patients (≥75 years old, n=22; PS≥2, n=10) were enrolled. Patients with PS≥2 had significantly lower albumin levels than those with PS<2 (p=0.023). The objective response and disease control rates did not differ significantly between patients <75 and ≥75 years old (p=0.598 and p=0.769, respectively) or between those with PS<2 and PS≥2 (p>0.99 and p=0.178, respectively). Progression-free survival (PFS) and overall survival (OS) were not significantly different in patients <75 years and ≥75 years (p=0984, 0.368). A significant difference in PFS (p=0.047) but not OS (p=0.086) was observed between the PS<2 and PS≥2 groups. The rates of any-grade and severe (grade ≥3) adverse events did not differ significantly between patients <75 and ≥75 years (p=0.471, p=0.136) or between PS<2 and PS≥2 groups (p>0.99, 0.99). Aspartate aminotransferase (AST) levels significantly increased, but alanine aminotransferase levels did not, following EV treatment (p<0.001). Multivariate analyses revealed that the albumin level was an independent prognostic factor (hazard ratio=0.159; p<0.001). CONCLUSION: EV demonstrated similar efficacy and safety in elderly and younger patients with advanced UC. In patients with a poor PS, although the safety was similar, survival was significantly worse in terms of PFS, while the AST levels were significantly elevated.

Clinical Outcomes of Enfortumab Vedotin in Advanced Urothelial Carcinoma With Prior Avelumab Versus Pembrolizumab Therapy.

BACKGROUND/AIM: This study retrospectively evaluated whether enfortumab vedotin (EV) monotherapy is effective as a late-line treatment according to prior treatment type in patients with advanced urothelial carcinoma (UC). PATIENTS AND METHODS: We assessed consecutive patients from the Uro-Oncology Group in the Kyushu study population with lower and upper urinary tract cancer treated with EV monotherapy after platinum-based chemotherapy and immune checkpoint inhibitor therapy failure between December 2021 and March 2024. In particular, patients receiving avelumab maintenance or pembrolizumab therapy before EV for advanced UC were analyzed and compared according to the response rate, progression-free survival (PFS), and overall survival (OS). RESULTS: Of the 80 enrolled patients, 31 and 49 received avelumab and pembrolizumab before EV therapy, respectively. The avelumab and pembrolizumab groups had comparable objective response rates (48.4% vs. 44.9%, p=0.820) and disease control rates (77.4% vs. 67.3%, p=0.448). These two groups showed no significant difference in PFS from the initiation of EV (median: 6.4 months vs. 4.2 months, p=0.184); meanwhile, the avelumab group had better OS from the initiation of EV than the pembrolizumab group (median: 16.0 months vs. 10.2 months, p=0.019). Moreover, the median OS after first-line chemotherapy initiation was longer in the avelumab group than in the pembrolizumab group (40.3 months vs. 24.7 months, p=0.054). On multivariate analysis, avelumab maintenance therapy before EV reduced the mortality risk by 47% (95% confidence interval=0.27-1.03; p=0.059). CONCLUSION: EV monotherapy after avelumab maintenance therapy provides favorable survival outcomes in patients with advanced UC.

Impact of baseline body composition on prognostic outcomes in urological malignancies treated with immunotherapy: a pooled analysis of 10 retrospective studies.

OBJECTIVE: Numerous epidemiological investigations have explored the impact of body composition on the effectiveness of immune checkpoint inhibitors (ICIs) in urological malignancies (UM) patients, yielding conflicting findings. As a result, our study aims to elucidate the influence of baseline body composition on the long-term prognosis of UM patients treated with ICIs. METHODS: We employed a rigorous systematic search across various databases, including PubMed, Embase, the Cochrane Library, and Google Scholar, to identify studies meeting our inclusion criteria. Our primary endpoints of interest encompassed overall survival (OS) and progression-free survival (PFS). RESULTS: This analysis included a total of 10 articles with a combined patient cohort of 707 individuals. Our findings revealed a noteworthy association between several body composition parameters and unfavorable OS outcomes, including low psoas muscle index (PMI; HR: 3.88, p < 0.001), low skeletal muscle index (SMI; HR: 1.63, p < 0.001), sarcopenia (HR: 1.88, p < 0.001), low visceral adipose index (VAI; HR: 1.38, p = 0.018) and low subcutaneous adipose index (SAI; HR: 1.37, p = 0.018). Furthermore, our analysis demonstrated that low PMI (HR: 2.05, p = 0.006), low SMI (HR: 1.89, p = 0.002), sarcopenia (HR: 1.80, p < 0.001), and low VAI (HR:1.59, p = 0.005) were significantly correlated with inferior PFS. Conversely, SAI did not manifest a pronounced association with PFS in UM patients treated with ICIs. CONCLUSION: Collectively, our study findings underscore a substantial relationship between baseline body composition and reduced clinical efficacy in UM patients undergoing ICI therapy.

A Podcast on Practical Considerations in Patients with Advanced Urothelial Cancer Receiving First-Line Cisplatin- or Carboplatin-Based Chemotherapy Followed by Avelumab Maintenance in a Changing Therapeutic Landscape.

Platinum-based chemotherapy has been the cornerstone of first-line treatment for advanced urothelial carcinoma for decades, based on its proven efficacy and well-characterized safety profile. Although enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy versus platinum-based chemotherapy in the EV-302 phase 3 trial, common and potentially cumulative toxicities associated with EV plus pembrolizumab may make this combination less suitable for some patients, such as those with pre-existing neuropathy, hyperglycemia, or hepatic impairment, or patients likely to have favorable outcomes with platinum-based chemotherapy. The availability of EV plus pembrolizumab in various countries may also be limited by financial considerations. Thus, platinum-based chemotherapy is likely to remain a valuable option for advanced urothelial carcinoma. Eligibility for cisplatin- or carboplatin-based regimens can be determined by assessing renal function, performance status, and specific comorbidities. In cisplatin-eligible and -ineligible patients without disease progression following platinum-based chemotherapy, avelumab first-line maintenance is standard of care based on findings from the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab first-line maintenance plus best supportive care prolonged overall survival and progression-free survival compared with best supportive care alone across clinically relevant subgroups. Adverse events associated with avelumab were generally consistent with those observed with other immune checkpoint inhibitors, and long-term follow-up showed no new safety concerns with prolonged treatment. Efficacy benefits and safety profiles were similar in patients who received avelumab first-line maintenance after cisplatin- or carboplatin-based chemotherapy. The effectiveness and safety of avelumab first-line maintenance have been confirmed in several real-world studies. Overall, these data support the use of avelumab first-line maintenance for all platinum-treated patients without disease progression. In this podcast, we discuss the evolving role of platinum-based chemotherapy in this disease setting in the context of EV-302 trial results and describe practical considerations in patients receiving first-line cisplatin- or carboplatin-based chemotherapy followed by avelumab maintenance therapy.

Enfortumab vedotin and pembrolizumab combination as a relevant game changer in urothelial carcinoma: What is left behind?

The EV-302 study1 marks a pivotal leap in the management of advanced urothelial carcinoma, setting a new benchmark for frontline therapy. Enfortumab vedotin plus pembrolizumab is the first combination therapy that has ever outperformed standard chemotherapy. The degree of benefit and the reported safety profile should make this combination a first-choice option for most patients with advanced-stage urothelial carcinoma.

Recent developments and future directions of first-line systemic therapy combined with immunotherapy for advanced or metastatic urothelial carcinoma: a historical perspective on treatment evolution.

Urothelial carcinoma presents significant treatment challenges, especially in advanced stages. Traditionally managed with platinum-based chemotherapy, the advent of immunotherapies, particularly immune checkpoint inhibitors, has revolutionized urothelial carcinoma treatment. This review explores the evolution of urothelial carcinoma management, focusing on the transition from immune checkpoint inhibitors monotherapy to innovative combination therapies. Pembrolizumab, following the KEYNOTE-045 trial, emerged as a pivotal ICI in pretreated metastatic urothelial carcinoma, outperforming traditional chemotherapy. However, limitations surfaced in untreated metastatic urothelial carcinoma patients, particularly in those with low PD-L1 expression, as evidenced by trials like IMvigor130 and KEYNOTE-361. These challenges led to the exploration of combination therapies, including immune checkpoint inhibitors with platinum-based chemotherapy, tyrosine kinase inhibitors, and antibody-drug conjugates. Notably, the CheckMate 901 trial demonstrated improved outcomes with a nivolumab-chemotherapy combination. A significant breakthrough was achieved with the combination of enfortumab vedotin, an antibody-drug conjugates, and pembrolizumab, setting a new standard in first-line treatment for locally advanced or metastatic urothelial carcinoma. Future directions involve further exploration of antibody-drug conjugates and immune checkpoint inhibitors, as seen in the TROPHY-U-01 and TROPiCS-4 trials. The review concludes that the locally advanced or metastatic urothelial carcinoma treatment landscape is rapidly evolving, with combination therapies offering promising avenues for improved patient outcomes, signaling a new era in urothelial carcinoma management.

Highlights from the 2024 ASCO Genitourinary Symposium: focus on urothelial and prostate cancer.

The 2024 ASCO Genitourinary Cancer Symposium, this year celebrating the 20th anniversary, delved into key advancements in urothelial carcinoma (UC) and prostate cancer (PC). For UC, insights emerged from adjuvant pembrolizumab for muscle-invasive urothelial carcinoma, and from the efficacy of the EV-302 study of enfortumab vedotin +pembrolizumab in the metastatic setting. In PC, adjuvant therapy with high-dose radiotherapy schedules plus long-t erm ADT was explored. In metastatic castration-resistant PC, highlights included a novel combo (cabozantinib+atezolizumab) for poor prognosis patients; confirmed benefits of ARSI+PARPi in BRCA-mutated patients; and safety considerations for ARSI treatments. The symposium continued its role as an indispensable platform for shaping specialized oncological care.

C-reactive Protein Is a Prognostic Factor for Survival in Metastatic Upper Tract Urothelial Carcinoma Patients Receiving Pembrolizumab.

BACKGROUND/AIM: The number of available treatment options for urothelial carcinoma has increased recently. Upper tract urothelial carcinoma (UTUC) is relatively rare compared with bladder cancer. There are few reports on the efficacy of immune checkpoint inhibitors (ICIs) for metastatic UTUC, and ICIs may occasionally show less efficacy and cause severe side effects. Therefore, it is important to predict the treatment response and change the treatment strategy as appropriate. We investigated the prognostic factors for treatment response in patients with metastatic UTUC treated with pembrolizumab at our hospital. PATIENTS AND METHODS: Patients who received pembrolizumab for UTUC between January 2018 and June 2023 were analyzed. Patients who presented with bladder cancer complications at initial diagnosis were excluded. The primary endpoints assessed were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted using laboratory values obtained before and after pembrolizumab administration. The relationship between cancer and inflammation is important. Therefore, we analyzed this relationship using prognostic factors for urothelial carcinoma as previously reported. Specifically, pretreatment C-reactive protein (CRP) level, neutrophil-to-lymphocyte ratio (NLR), and NLR/albumin values were examined. RESULTS: Forty-seven patients were analyzed. The median PFS was 66 days (24-107 days), and the median OS was 164 days (13-314 days). A CRP level <1 before the first cycle was a useful factor in the multivariate analysis for both OS and PFS [OS: p=0.004, hazard ratio (HR)=3.244, 95% confidence interval (CI)=1.464-7.104; PFS: p=0.003, HR=2.998, 95%CI=1.444-6.225]. CONCLUSION: CRP level is a prognostic factor for pembrolizumab treatment response in patients with UTUC.

[Antibody-drug conjugates combined with immunotherapy: a potential game changer in the treatment of upper tract urothelial carcinoma].

Currently, treatment strategies for upper tract urothelial carcinoma (UTUC) are changing rapidly. However, there are many limitations in the implementation of new surgical methods and systemic treatment options, which cannot reverse the current status quo of UTUC treatment. In recent years, antibody-drug conjugates have shown great potential in the field of cancer treatment, which can activate the immune system and enhance the effect of immunotherapy while accurately killing targeted tumor cells. The results of multiple clinical trials, including the EV-302 study, have confirmed that combination therapy can improve the survival rate of patients with advanced urothelial cancer, and may replace chemotherapy as the first-line treatment for advanced urothelial cancer. However, there are still a series of challenges in the application of combination therapy in UTUC, such as low level of evidence, adverse reactions, and drug resistance. In the future, it is necessary to focus on clinical trials of UTUC combination therapy, further optimize antibody drug conjugates and immunotherapy drugs to adapt to the disease characteristics of UTUC, and further study the molecular biology characteristics of UTUC to meet this series of challenges.

Frontline immune checkpoint inhibitors in patients ≥ 90 years with advanced urothelial cancer: a single center experience.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are approved for advanced urothelial cancer alone and as first-line in combination with enfortumab vedotin. Platinum based chemotherapy which is another frontline choice is often not a treatment option for older patients due to comorbidities that increase with age. Despite ICIs being better tolerated compared to traditional chemotherapy little is known about their efficacy and toxicity in patients ≥ 90 years due to the rarity of this population in clinical trials. Our objective was to analyze the efficacy and toxicity of immune checkpoint inhibitors in patients ≥ 90 years. MATERIALS AND METHODS: We conducted a single center retrospective review of patients ≥ 90 years treated between July 2019 and September 2023 with standard of care ICIs for advanced urothelial cancer. RESULTS: Six patients treated with pembrolizumab were identified. Four (66.7%) were male and mean age was 93.5 years at the time of treatment initiation. Response rate was 66.7% (4 patients) with 3 complete responses, which were durable off therapy. Median follow up was 18.2 months. Median progression free survival (PFS) was 10.2 months [95%confidence interval (95%CI): 1.77, not reached (NR)] and median overall survival (OS) was 18.2 months (95%CI: 12.1, NR). Side effects presented in 4 (66.7%) patients and included hypothyroidism, diarrhea, anemia, thrombocytopenia, rash, and bullous dermatitis. One patient developed grade 3 anemia and no patients experienced grade 4 events or required hospitalization due to treatment side effects. CONCLUSIONS: Our experience in a small cohort of patients ≥ 90 years indicate that ICIs are well tolerated and effective for the treatment of advanced urothelial carcinoma in this patient population.