髙原 健

BACKGROUND: Enfortumab vedotin plus pembrolizumab (EVP) has emerged as a standard first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). However, large-scale real-world data in Japanese patients remain limited. METHODS: We retrospectively analyzed consecutive patients with la/mUC who received first-line EVP across multiple Japanese centers. Oncologic outcomes including tumor response, progression-free survival (PFS), cancer-specific survival (CSS), overall survival (OS), and adverse events (AEs) were assessed. Survival was estimated using the Kaplan-Meier method, and exploratory analyses were performed to identify factors associated with OS, PFS and objective response rate (ORR). RESULTS: A total of 212 patients were included. The median age was 75 years, and 23 patients (10.8%) had ECOG performance status (PS) ≥2. Among 201 evaluable patients, ORR was 63% including 12.5% of complete response. Subgroup analysis of ORRs showed broadly consistent efficacy across diverse patient or cancer characteristics. The median PFS, CSS, and OS was 12.0, 15.0, and 12.9 months, respectively. Liver metastasis was associated with poor PFS (HR 2.35, P = 0.012), ECOG PS ≥ 2 was associated with poor OS (HR 2.84, P = 0.002), and variant histology was associated with poorer PFS (HR 3.19, P < 0.001) and OS (HR 2.6, P = 0.001). Any-grade AEs occurred in 87% of patients, and severe AEs occurred in 34%. Skin-related AEs were the most frequent toxicity, occurring in 59% of patients, with grade ≥3 skin-related AEs in 11%. Median time to onset of skin-related AEs was 15.5 days. CONCLUSIONS: In this multicenter Japanese real-world cohort, first-line EVP demonstrated favorable antitumor activity with manageable but frequent toxicities, particularly early skin AEs. These findings support the effectiveness of EVP in routine practice while underscoring the importance of proactive AE management and careful risk stratification, including histologic subtype.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based combination therapy (ICI plus ICI [IO-IO] or ICI plus tyrosine kinase inhibitor [IO-TKI]) is the standard first-line treatment for metastatic renal cell carcinoma (mRCC), but its impact in patients undergoing maintenance hemodialysis (HD) relative to non-HD patients remains unclear. METHODS: We retrospectively compared patients with mRCC who received first-line IO-IO or IO-TKI therapy (2018-2025) according to HD status at treatment initiation. Oncologic outcomes (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) and safety were assessed in the crude cohort and after inverse probability of treatment weighting (IPTW) based on propensity scores. IO-IO and IO-TKI regimens were also compared within the HD cohort. RESULTS: Among 601 patients, 37 were receiving HD. In the crude cohort, HD patients had significantly worse PFS, OS, and ORR (37% vs. 57%) than non-HD patients. After IPTW, PFS remained significantly shorter in the HD group (hazard ratios [HR] 1.76, 95% confidence interval [CI] 1.21-2.57; P = 0.003), whereas OS (HR 1.49, 95% CI 0.89-2.50; P = 0.1) and ORR (odds ratios 0.58, 95% CI 0.22-1.54; P = 0.3) were no longer significant. Safety, including Grade ≥3 adverse events, was comparable. Among HD patients, PFS and OS did not differ between IO-IO and IO-TKI regimens. CONCLUSIONS: In mRCC patients undergoing HD, first-line ICI-based combination therapy was associated with significantly shorter PFS, whereas the worse crude OS and ORR were attenuated after adjustment, largely reflecting baseline prognostic differences rather than reduced efficacy. With a comparable safety profile, it may be a reasonable option in selected patients undergoing HD.

BACKGROUND/AIM: Oncological outcomes for metastatic castration-sensitive prostate cancer (mCSPC) have improved with upfront androgen receptor signaling inhibitor (ARSI) doublet therapy. However, the prognostic value of prostate-specific antigen (PSA) kinetics in real-world settings remains unclear. This study aimed to evaluate the clinical significance of PSA kinetics in patients with high-risk mCSPC. PATIENTS AND METHODS: We retrospectively analyzed 352 patients with high-risk mCSPC from the ULTRA-J database who received upfront ARSI doublet therapy between 2018 and 2023. PSA kinetics, including PSA nadir, PSA response rate, and time to PSA nadir (TTN), were assessed. Associations with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS) were evaluated using Kaplan-Meier analysis and Cox proportional hazards models. RESULTS: A PSA nadir ≤0.02 ng/ml and PSA response rate ≥99% were significantly associated with prolonged CRPC-FS and OS (p<0.05). Conversely, TTN ≤3 months was associated with poorer outcomes. Multivariate analysis identified PSA nadir >0.02 ng/ml, PSA response rate <99%, and TTN ≤3 months as independent predictors of shorter CRPC-FS and OS. These trends were generally consistent across ARSI agents, although some differences were observed in subgroup analyses. CONCLUSION: PSA kinetics are strong independent prognostic factors in patients with high-risk mCSPC treated with upfront ARSI doublet therapy. These readily available biomarkers may help identify patients who require treatment intensification or closer monitoring in clinical practice.

BACKGROUND/AIM: Existing prognostic models for metastatic renal cell carcinoma (mRCC) were developed using all-age cohorts, and their validity in non-elderly patients remains unclear. We aimed to develop and validate our prognostic model for patients aged ≤65 years with mRCC, including non-clear cell histologies, and to establish a practical risk stratification system. PATIENTS AND METHODS: We retrospectively analyzed 210 patients with mRCC from multiple Japanese institutions. The primary endpoint was overall survival (OS). Independent prognostic factors were identified using a multivariable Cox regression analysis. A simplified scoring system was constructed to stratify patients into risk groups. Model discrimination was evaluated using the concordance index (C-index), with internal validation by bootstrap resampling. Clinical utility was assessed by a decision curve analysis (DCA). A nomogram was constructed based on the identified independent prognostic factors. RESULTS: During a median follow-up of 57 months, 77 OS events occurred; median OS was 65.7 months. Histopathological type, liver metastasis, C-reactive protein, serum-corrected calcium, and time to systemic therapy were independently associated with worse OS. Our prognostic model stratified patients into favorable- (n=89), intermediate- (n=76), and poor- (n=45) risk groups, with median OS of 95.1, 37.7, and 9.6 months, respectively (p<0.001). The 5-year C-index was 0.74, exceeding that of the International Metastatic RCC Database Consortium (IMDC) model (0.70). In DCA, our prognostic model showed higher net benefit across threshold of 0.3-0.6, corresponding to an average reduction of 3.26 unnecessary treatment escalations per 100 patients. The nomogram showed time-dependent C-indices of 0.83, 0.84, and 0.87 at 1, 3, and 5 years. CONCLUSION: Our prognostic model provides superior discrimination to and higher clinical utility than the IMDC model for predicting OS in non-elderly patients with mRCC, supporting age-specific risk stratification in this population.

OBJECTIVES: Sarcomatoid renal cell carcinoma (sRCC) is an aggressive histological variant associated with a poor prognosis. While immune checkpoint inhibitor (ICI)-based combinations have become the standard of care, the optimal first-line regimen, specifically dual immunotherapy (IO-IO) vs. IO plus tyrosine kinase inhibitor (IO-TKI), remains controversial. We herein examined the real-world clinical outcomes of Japanese patients with sRCC. METHODS: We conducted a retrospective multicenter study on 46 patients with advanced or metastatic sRCC receiving first-line ICI-based combination therapy between January 2018 and December 2024 (IO-IO: n = 18; IO-TKI: n = 28). In a comparative survival analysis, three favorable-risk patients in the IO-TKI group were excluded to align risk profiles, focusing on intermediate/poor-risk groups (n = 43). The primary endpoint was overall survival (OS). RESULTS: In the entire cohort (n = 46), the objective response rate was numerically higher in the IO-TKI group (64.3%) than in the IO-IO group (50.0%) (p = 0.37). In the comparative analysis of intermediate/poor-risk patients (n = 43), progression-free survival (PFS) was slightly longer (p = 0.071), and OS was significantly longer (p = 0.016) in the IO-TKI group than in the IO-IO group. A multivariable analysis adjusted for IMDC risk categories showed favorable survival with the IO-TKI regimen (HR 0.37, p = 0.061). CONCLUSIONS: The present study indicates that first-line IO-TKI combination therapy represents a promising treatment option with a potential survival advantage over IO-IO therapy for Japanese patients with sRCC. However, due to the retrospective design and small sample size, reliably determining the comparative efficacy of these regimens remains challenging, and further validation is warranted.