689 Background: Enfortumab vedotin (EV) and pembrolizumab have emerged as first-line combination therapy for locally advanced or metastatic urothelial carcinoma (UC). In retrospective studies of EV monotherapy, higher relative dose intensities (RDI) in the initial treatment cycles have been associated with improved response rates and prolonged progression-free survival (PFS), whereas cumulative RDI across the entire treatment course has not shown a consistent relationship with outcomes. The impact of EV RDI on outcomes in combination therapy treated patients remains unclear. Our single-center, retrospective study aims to assess the relationship between RDI within the first 3 and 6 cycles and PFS and overall survival (OS). Methods: We conducted a retrospective analysis of patients treated with EV + pembrolizumab. Only patients who received >1 cycle of EV were included. Data on PFS, OS, and dosing were collected from the EMR. For each patient, cumulative RDI was calculated through cycle 3 (RDI-3) and cycle 6 (RDI-6) as: (delivered EV dose) / (standard EV dose during that timeframe) x 100%. The primary analysis evaluated RDI as a continuous variable in Cox regression models using 63-day and 126-day landmark analyses, corresponding to the completion of 3 and 6 cycles, respectively. Models were adjusted for ECOG status and assessed PFS and OS as endpoints. RDI-3 and RDI-6 were selected to capture early versus later effects of RDI and to align with institutional restaging practices. The Kaplan-Meier method was used to analyze survival by RDI group (RDI >80% and < 80%). The 80% threshold was selected as it represents the typical first EV dose reduction from 1.25 mg/kg to 1.00 mg/kg, consistent with prior EV monotherapy studies. These analyses were exploratory and supplemental to the primary analysis. Results: 104 patients met inclusion criteria. Of these, 90 and 99 were evaluable for RDI-3 PFS and OS landmark analyses, and 78 and 89 for RDI-6, respectively. The median follow-up time was 17.2 months. In adjusted landmark Cox models, higher RDI-3 and RDI-6 showed no significant difference in PFS (RDI-3: HR 0.903, p = 0.152; RDI-6: HR 0.987, p = 0.859) or OS (RDI-3: HR 0.891, p = 0.155; RDI-6: HR 0.895, p = 0.218). Unadjusted Kaplan–Meier analyses similarly showed no association between RDI and PFS or OS (RDI-3: PFS p = 0.61, OS p = 0.23; RDI-6: PFS p = 1, OS p = 0.48). Conclusions: In adjusted analyses, RDI over the first 3 and 6 cycles did not significantly correlate with PFS or OS. These findings contrast with prior EV monotherapy data, suggesting that, within the EV + pembrolizumab paradigm, early EV dose intensity may be less critical, allowing flexibility in dosing without compromising efficacy, potentially reflecting a compensatory effect from immunotherapy combination. HR (95% CI) p-value RDI-3 PFS 0.903 (0.79-1.04) 0.152 OS 0.891 (0.76-1.04) 0.155 RDI-6 PFS 0.987 (0.86-1.14) 0.859 OS 0.895 (0.75-1.07) 0.218
Viti-Guzman et al. (Sun,) studied this question.