Ipilimumab/Nivolumab Induction Strategy May Spare Bladder in Urothelial Carcinoma

Results from the phase 2 INDIBLADE trial (NCT05200988), showed that induction immunotherapy with ipilimumab (Yervoy) and nivolumab (Opdivo) followed by consolidative chemoradiotherapy facilitated bladder preservation in patients with stage 2/3 urothelial carcinoma of the bladder.

Data from the trial presented at the 2026 ASCO Genitourinary Cancers Symposium showed that at a median follow-up of 28.7 months, the estimated 2-year bladder-intact event-free survival (BI-EFS) rate was 78% (95% CI, 0.67-0.90; P < .00). The 2-year overall survival (OS) rate reached 96% (95% CI, 0.91-1.00). Investigators also reported that post-induction circulating tumor DNA (ctDNA) positivity was associated with inferior BI-EFS (HR, 8.33; 95% CI, 1.38-50.36; P = .0209), supporting a potential role for ctDNA-guided treatment selection.

“Potent induction combination immunotherapy followed by consolidated chemoradiotherapy is an effective bladder-sparing treatment for a broad population of [patients] with muscle-invasive bladder cancer,” lead presenter Jan-Jaap J. Mellema, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, said during the meeting. “Absence of ctDNA post-immunotherapy was associated with BI-EFS and could aid clinical decision making after systemic induction.”

Eleven BI-EFS events were observed, yielding the 78% 2-year rate. OS data remain immature but favorable, with 3 deaths reported at the time of analysis.

Baseline ctDNA status was not significantly associated with BI-EFS (HR, 3.59; 95% CI, 0.86-15.02; P = .0805). However, patients who were ctDNA positive after induction experienced substantially higher event risk compared with those who were ctDNA negative.

Mellema noted that patients who experienced disease progression tended to remain ctDNA positive throughout treatment or convert to positivity at the time of recurrence. Conversely, those without events were typically ctDNA negative at baseline or achieved clearance during induction.

INDIBLADE Trial Design and Patient Population

INDIBLADE was an investigator-initiated, single-arm, multicenter phase 2 study conducted in the Netherlands. Eligible patients had clinical T2–T4aN0–2M0 muscle-invasive urothelial carcinoma with lymph nodes amenable to radiation and an ECOG performance status of 0 or 1. Prior pelvic radiotherapy, prior systemic therapy for muscle-invasive disease, extensive carcinoma in situ, upper tract urothelial carcinoma, and bilateral hydronephrosis were exclusion criteria.

Patients received induction ipilimumab at 3 mg/kg plus nivolumab at 1 mg/kg for 2 cycles, followed by nivolumab at 3 mg/kg for 1 cycle. Response assessment incorporated imaging and cystoscopy. In the absence of progression, patients proceeded to chemoradiotherapy consisting of radiotherapy with concurrent mitomycin C and fluorouracil or capecitabine.

The primary end point was 2-year BI-EFS. Secondary end points included OS, safety, and ctDNA analyses.

Baseline characteristics reflected a higher-risk population: 42% had clinical T3 disease and 14% had node-positive involvement. Median age was 65 years.

Most patients completed planned induction therapy, although a minority did not receive all cycles. Five patients did not proceed to chemoradiotherapy, including 4 due to disease progression and 1 by patient choice. Overall, 45 of 50 patients (90%) initiated chemoradiotherapy.

Safety Profile

No new safety signals were observed. Chemoradiotherapy-related adverse effects (AEs) occurred in 71% of patients, with grade 3/4 events in 7%. Immunotherapy-related AEs were reported in 94% of patients, with grade 34 events in 24%.

Common immune-related toxicities included fatigue (42%), maculopapular rash (30%), diarrhea (26%), pruritus (20%), colitis (16%), hypothyroidism (16%), pneumonitis (16%), hypophysitis (14%), and adrenal insufficiency (10%). A single colon perforation was reported. Chemoradiotherapy-related toxicities included urinary frequency, dysuria, anemia, and noninfectious cystitis, predominantly low grade.

ctDNA as a Potential Decision-Making Tool

Serial plasma ctDNA was collected before each induction cycle, at response assessments, and during follow-up. Of patients without BI-EFS events, 26 were ctDNA negative at baseline and remained undetectable throughout therapy.

Post-induction ctDNA status demonstrated prognostic separation. Patients who were ctDNA positive after immunotherapy experienced worse BI-EFS compared with those who were ctDNA negative, supporting ctDNA as a potential biomarker for selecting candidates for bladder preservation vs early cystectomy.

Clinical Implications

The investigators concluded that induction dual checkpoint blockade followed by chemoradiotherapy is a feasible and active bladder-sparing strategy in muscle-invasive disease, including patients with higher-risk features such as T3 tumors and nodal involvement amenable to radiation.

Longer follow-up will be needed to assess durability of bladder preservation and late toxicities.

REFERENCE

1. Mellema JJ, Stockem CF, Herberts C, et al. 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. J Clin Oncol. 2026;44(suppl 7):LBA637. doi:10.1200/JCO.2026.44.7_suppl.LBA637.