Although immune checkpoint inhibitors have shown benefit for advanced urothelial carcinoma (aUC) patients, prognostication of treatment efficacy and response duration remains a clinical challenge. We evaluated the expression of immune markers in the tumor microenvironment and assessed their associations with response to and survival after pembrolizumab treatment in 26 aUC patients. High levels of CD8⁺ tumor-infiltrating lymphocytes (TILs) were associated with favorable objective responses (23.0% vs. 15.3%, p = 0.0425), progression-free survival (median, 8.8 vs 2.1 months; hazard ratio (HR), 0.24; 95% confidence interval (CI), 0.07–0.66, p = 0.0060), and overall survival (median, >24.0 vs. 5.3 months; HR, 0.17; 95% CI, 0.04–0.56, p = 0.0034) compared with low levels. High interferon-gamma (IFNγ) expression levels were associated with longer post-progression survival (median, 4.9 vs. 1.0 months; HR, 0.18; 95% CI, 0.04–0.59, p = 0.0027) compared with low expression. Multivariate analysis incorporating clinical prognosticators demonstrated that the coincidence of low CD8⁺ T cells/IFNγ was an independent factor for unfavorable overall survival after pembrolizumab treatment (HR, 4.07; 95% CI, 1.36–12.73; p = 0.0125). The combination of low CD8⁺ TILs and IFNγ expression was an independent prognostic factor with predictive ability equivalent to previously reported clinical prognosticators.

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⁺cells^high–tumor FGL1⁺cells^high exhibited a significant negative correlation with survival rates compared with those with stromal CD8⁺LAG-3⁺cells^high–tumor FGL1⁺cells^low. 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.

Objectives: The JAVELIN Bladder 100 phase 3 trial showed that avelumab first‐line maintenance + best supportive care significantly prolonged overall survival and progression‐free survival versus best supportive care alone in patients with advanced urothelial carcinoma who were progression‐free following first‐line platinum‐based chemotherapy. We report findings from J‐AVENUE (NCT05431777), a real‐world study of avelumab first‐line maintenance therapy in Japan.Methods: Medical charts of patients with advanced urothelial carcinoma without disease progression following first‐line platinum‐based chemotherapy, who received avelumab maintenance between February and November 2021, were reviewed. Patients were followed until June 2022. The primary endpoint was patient characteristics; secondary endpoints included time to treatment failure and progression‐free survival.Results: In 79 patients analyzed, median age was 72 years (range, 44–86). Primary tumor site was upper tract in 45.6% and bladder in 54.4%. The most common first‐line chemotherapy regimen was cisplatin + gemcitabine (63.3%). Median number of chemotherapy cycles received was four. Best response to chemotherapy was complete response in 10.1%, partial response in 58.2%, and stable disease in 31.6%. Median treatment‐free interval before avelumab was 4.9 weeks. With avelumab first‐line maintenance therapy, the disease control rate was 58.2%, median time to treatment failure was 4.6 months (95% CI, 3.3–6.4), and median progression‐free survival was 6.1 months (95% CI, 3.6–9.7).Conclusions: Findings from J‐AVENUE show the effectiveness of avelumab first‐line maintenance in patients with advanced urothelial carcinoma in Japan in clinical practice, with similar progression‐free survival to JAVELIN Bladder 100 and previous real‐world studies, supporting its use as a standard of care.

To investigate the association between the onset, severity, and type of immune‐related adverse events (irAEs) and the efficacy of pembrolizumab in patients with platinum‐pretreated advanced urothelial carcinoma (UC), we retrospectively collected clinical datasets of 755 patients and conducted landmark analysis. Patients who survived for fewer than 3 months were excluded from the evaluation to reduce the immortal time bias. In total, 620 patients were evaluated, of whom 220 patients (35.5%) experienced grade ≥2 irAEs, including 134 patients with grade 2 irAEs and 86 with grade ≥3 irAEs. Propensity score matching extracted 198 patients with and without grade ≥2 irAEs. The onset of grade ≥2 irAEs was associated with longer median progression‐free survival (PFS) (8.3 months vs. 4.5 months, p = 0.003) and overall survival (OS) (20.4 months vs. 14.3 months, p = 0.031) and a higher objective response rate (ORR) (44.8% vs. 30.2%, p = 0.004). Patients with grade 2 irAEs had significantly better oncological outcomes (PFS, OS, and ORR) than grade ≤1 and ≥3 irAEs. Patients with grade ≥3 irAEs had worse outcomes than grade 2 irAEs. Endocrine and skin irAEs were related with better survival outcomes, and the rate of severities was lower in these categories. In conclusion, the occurrence of irAEs, particularly low‐grade irAEs, was predictive of pembrolizumab efficacy in patients with platinum‐pretreated advanced UC.

Objectives: Clinical guidelines recommend that patients with non‐muscle‐invasive bladder cancer (NMIBC) should be treated with appropriate adjuvant therapy. However, compliance with guideline recommendations is insufficient, and this may lead to unfavorable outcomes. We aimed to investigate the level of adherence to guideline recommendations in patients with NMIBC and evaluate the outcomes of those who did and did not receive guideline‐recommended therapies.Methods: We performed a retrospective analysis of patients with histologically diagnosed NMIBC. The percentage of patients with intermediate‐ and high‐risk tumors who received adjuvant intravesical therapy or second transurethral resection (TUR) was calculated. Recurrence‐free survival was assessed in patients who did and did not receive the therapies. We conducted a propensity score‐matched analysis to compare outcomes between patients with intermediate‐risk and T1 NMIBC who did and did not undergo guideline‐recommended therapies.Results: Overall, 1204 patients from the Tohoku Urological Evidence‐Based Medicine Study Group and Kyoto University Hospital were included. Of patients with intermediate‐ and high‐risk tumors, 91.0% and 74.0% did not receive maintenance bacillus Calmette–Guérin (BCG), respectively. In both groups, significantly better recurrence‐free survival was found for patients treated with maintenance BCG. Among patients with T1 NMIBC, only 16.7% underwent guideline‐recommended therapies, that is, a second TUR and maintenance BCG. Significantly greater recurrence‐free survival was observed in patients who received guideline‐recommended therapies compared with propensity‐matched patients who did not.Conclusions: Guideline‐recommended therapies may contribute to improvements in outcomes for patients with NMIBC, suggesting that improvements in adherence to clinical guidelines may lead to favorable outcomes.

Objective: To evaluate the effects of the number of neoadjuvant chemotherapy (NAC) cycles and the addition of adjuvant chemotherapy (AC) after NAC on overall survival (OS) of patients with muscle‐invasive bladder cancer (MIBC). Patients and Methods: We retrospectively evaluated 1687 patients with cT2‐4NxM0 MIBC who received radical cystectomy (RC) alone or RC plus perioperative chemotherapy at 36 institutions within the Japanese Urological Oncology Group. We evaluated the effect of the number of NAC cycles (2 vs. ≥ 3 cycles) and the addition of AC on OS. Results: Among the 1687 patients analyzed, 946 received a median of three NAC cycles. The pathologic complete response rate did not significantly differ between those who received 2 (22.9%) and ≥ 3 cycles (27.5%, p = 0.112). Moreover, no significant difference in OS was observed between the groups ( p = 0.559). Multivariable Cox regression analysis showed that pathologic high‐risk (ypT2–4, pT3–4, or pN+) or cisplatin ineligibility were significantly associated with poor OS but not the number of NAC cycles ( p = 0.238). We identified 942 pathologically high‐risk patients after RC who were eligible for AC. Notably, no significant OS improvement was observed with the addition of AC as intensive perioperative chemotherapy after NAC. The primary limitation was selection bias from confounding by clinical indication. Conclusions: Our findings showed that three or more NAC cycles and the addition of AC may have limited effects on OS in MIBC patients who received RC.