Induction ipilimumab plus nivolumab followed by consolidating chemoradiotherapy as bladder-sparing treatment in stage II/III urothelial carcinoma of the bladder: The phase 2 Indi-Blade trial.

Abstract

LBA637 Background: Radical cystectomy remains the most commonly used curative treatment for muscle-invasive bladder cancer (MIBC). Bladder-sparing options are typically for patients (pts) with limited tumors, or those unfit for cystectomy. Effective systemic induction therapy could broaden the population eligible for bladder-sparing treatment. The NABUCCO trial showed promising pathological complete responses (43-46%) and a 5-year overall survival (OS) of 70% using neoadjuvant ipilimumab (ipi) + nivolumab (nivo) in stage III MIBC pts. We hypothesize that induction immune checkpoint inhibition (ICI) followed by chemoradiotherapy (CRT) is an effective bladder-sparing approach in MIBC pts. Methods: Indi-Blade is a multicenter, single-arm, phase-II trial, enrolling cT2-4aN0-2 MIBC pts. Treatment consists of ipi 3mg/kg (day 1), ipi 3mg/kg + nivo 1mg/kg (day 22) and nivo 3mg/kg (day 43), followed by standard-of-care CRT using mitomycin C and fluoropyrimidines (5FU or capecitabine. The primary endpoint is two-year bladder-intact event-free survival (BI-EFS), estimated by Kaplan-Meier analysis. Events are defined as muscle-invasive, nodal or distant recurrence; cystectomy; switch to chemotherapy or death by any cause. With a two-sided alpha of 0.05, a sample size of n = 50 has 81.3% power to exclude an estimated BI-EFS of 50% (median 24 months), with a target two-year BI-EFS of 70% (median 46.6 months). Secondary endpoints include OS, toxicity and circulating tumor DNA (ctDNA) analysis. Results: 50 pts were enrolled between February 2022 and February 2024. Pts had cT2N0 (22; 44%), cT3N0 (21; 42%) and cN+ (7; 14%) MIBC. 45/50 pts (90%) proceeded to CRT following induction ICI. After a median follow-up of 28.7 months (interquartile range 22.6 – 34.7), the primary endpoint of estimated two-year BI-EFS was met at 76% (95%CI 0.65-0.89; p < 0.001). Estimated two-year OS was 96% (95%CI 0.9-1.0). Grade ≥3 immunotherapy-related AEs occurred in 24% of pts; grade ≥3 CRT related AEs occurred in 6%. ctDNA positive status was associated with significantly shorter BI-EFS compared to ctDNA negatives at both baseline (HR = 4.5, p = 0.02) and after induction ICI (HR = 6.1, p = 0.02). Pts who were ctDNA negative at baseline or post-ICI had an 88.6% and 88.4% two-year BI-EFS, respectively. ctDNA clearance in baseline ctDNA positive pts occurred in 76.9% (10/13 evaluable pts) post-ICI and 91.7% (11/12) post-CRT. Conclusions: Induction ipi + nivo followed by CRT provided encouraging two-year BI-EFS and OS in MIBC pts. ctDNA negative pts at either baseline or post-ICI had high rates of BI-EFS. Potent systemic induction ICI followed by CRT is an effective bladder-sparing treatment strategy for a broad population of MIBC pts. Clinical trial information: NCT05200988 .