International journal of clinical oncology · 2026
Timing-dependent skin toxicity phenotypes during enfortumab vedotin plus pembrolizumab therapy for advanced urothelial carcinoma.
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Hashimoto Mamoru, Inoki Lan, Yamamoto Yutaka, Fukuokaya Wataru, Yanagisawa Takafumi, Mori Keiichiro, Maenosono Ryoichi, Yoshikawa Yuki, Tsujino Takuya, Saruta Masanobu, Nukaya Takuhisa, Oishi Yuya, Tamura Keita, Sugiyama Seitetsu, Morinaka Hirofumi, Komura Kazumasa, Takahara Kiyoshi, Inamoto Teruo, Fujita Kazutoshi, ULTRA-J group
Аннотация
BACKGROUND: Enfortumab vedotin plus pembrolizumab (EV/Pem) has improved the survival of patients with advanced urothelial carcinoma; however, many patients suffer treatment-related adverse events, particularly skin toxicity. This study aimed to clarify the clinical impact of skin-toxicity timing on treatment outcomes.
METHODS: We retrospectively analyzed patients with advanced urothelial carcinoma treated with EV/Pem. Patients were categorized into three groups according to skin-toxicity timing: no rash, early-onset rash (< 1 month), and late-onset rash (≥ 1 month). Baseline clinical and laboratory characteristics were compared among groups and incorporated into multivariable Cox proportional hazards analyses. Kaplan-Meier analyses with pairwise log-rank tests were performed to evaluate progression-free survival (PFS) and overall survival (OS). The 1-month cutoff was selected for clinical interpretability.
RESULTS: The three-group analysis included 210 patients: no rash (n = 87), early-onset rash (n = 84), and late-onset rash (n = 39). Late-onset rash was associated with significantly prolonged PFS and OS in conventional analyses. In multivariable analysis, late-onset rash was significantly associated with prolonged PFS (HR 0.34, 95% CI 0.15-0.74, p = 0.007) and OS (HR 0.25, 95% CI 0.07-0.81, p = 0.02). Because late-onset rash could only be assigned after continued observation, these associations should be interpreted as exploratory and potentially affected by immortal time bias. In the 3-month landmark analysis, PFS remained significantly longer in the late-onset than early-onset rash group, whereas OS did not differ significantly.
CONCLUSIONS: Skin toxicity during EV/Pem therapy appears to have timing-dependent prognostic implications. Late-onset rash showed favorable outcomes in conventional analyses, but these findings should be considered hypothesis-generating.
METHODS: We retrospectively analyzed patients with advanced urothelial carcinoma treated with EV/Pem. Patients were categorized into three groups according to skin-toxicity timing: no rash, early-onset rash (< 1 month), and late-onset rash (≥ 1 month). Baseline clinical and laboratory characteristics were compared among groups and incorporated into multivariable Cox proportional hazards analyses. Kaplan-Meier analyses with pairwise log-rank tests were performed to evaluate progression-free survival (PFS) and overall survival (OS). The 1-month cutoff was selected for clinical interpretability.
RESULTS: The three-group analysis included 210 patients: no rash (n = 87), early-onset rash (n = 84), and late-onset rash (n = 39). Late-onset rash was associated with significantly prolonged PFS and OS in conventional analyses. In multivariable analysis, late-onset rash was significantly associated with prolonged PFS (HR 0.34, 95% CI 0.15-0.74, p = 0.007) and OS (HR 0.25, 95% CI 0.07-0.81, p = 0.02). Because late-onset rash could only be assigned after continued observation, these associations should be interpreted as exploratory and potentially affected by immortal time bias. In the 3-month landmark analysis, PFS remained significantly longer in the late-onset than early-onset rash group, whereas OS did not differ significantly.
CONCLUSIONS: Skin toxicity during EV/Pem therapy appears to have timing-dependent prognostic implications. Late-onset rash showed favorable outcomes in conventional analyses, but these findings should be considered hypothesis-generating.