A phase 2 study of gemcitabine plus carboplatin as second-line therapy after prior enfortumab vedotin and pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma.

Abstract

TPS901 Background: Urothelial carcinoma (UC) is a common malignancy of older adults, associated with poor survival once metastatic. Enfortumab vedotin plus pembrolizumab (EVP) is now the first-line standard of care for locally advanced and metastatic UC based on the landmark EV-302 trial, supplanting platinum-based chemotherapy. However, the optimal treatment following EVP progression remains critically undefined. Gemcitabine plus carboplatin (GC) is an active and well-tolerated regimen in cisplatin-ineligible patients. We hypothesize GC will become the de facto second-line therapy in this setting and propose a phase 2 study to prospectively evaluate its efficacy and establish a benchmark for future later line trials. Methods: This is a non-randomized, single-arm, open-label phase 2 study using a Simon two-stage design to assess GC efficacy and safety following EVP progression. Eligible patients have locally advanced or metastatic UC, prior EVP exposure, ECOG PS 0-2, and adequate organ function. Treatment consists of gemcitabine 1,000 mg/m² IV on days 1 and 8 plus carboplatin AUC 5 on day 1 every 3 weeks for up to 6 cycles or until progression or unacceptable toxicity. Tumor response will be assessed every 9 weeks per RECIST v1.1. The primary objective is overall response rate (ORR), including confirmed complete and partial responses. A Simon two-stage design will be utilized. If 3 (16%) or fewer of 19 patients enrolled in the first stage have a CR or PR, enrollment will stop for futility. The second stage will enroll an additional 36 patients. We will test the alternative hypothesis that ORR ≥ 0.3 against the null hypothesis that ORR ≤ 0.15 with 80% power and one-sided type-I error of 4.8%. Secondary objectives include progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. Key exploratory objectives will focus on unique factors affecting the older subpopulation of adults (≥65 years) receiving GC. Multifaceted geriatric assessments (GA) and a novel battery of biomarkers of molecular aging—including telomere length and epigenetic clocks, will be collected at specific timepoints and correlated to risk of treatment related toxicity and clinical outcomes. A predictive model, based on a composite of these variables, will be built for future validation studies and to optimize care delivery for older patients with cancer. Clinical trial information: NCT07043972 .