Induction combination ICI followed by CRT shows promise for bladder preservation in MIBC

Induction immunotherapy with ipilimumab (Yervoy) plus nivolumab (Opdivo) followed by consolidative chemoradiotherapy produced encouraging bladder preservation outcomes in patients with muscle-invasive bladder cancer (MIBC), according to results from the phase 2 Indi-Blade trial (NCT05200988).

The findings were presented by Jan-Jaap J. Mellema, MD, PhD candidate, at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium¹ and published concurrently in Nature Medicine.²

According to Mellema, the Indi-Blade trial was borne out of prior findings from the NABUCCO trial (NCT03387761), which demonstrated promising pathologic response rates and progression-free survival (P = .06) with preoperative ipilimumab plus nivolumab in patients with locally advanced urothelial carcinoma.³ These findings provided the biological rationale for exploring the regimen in a bladder preservation setting. In the Indi-Blade trial, investigators evaluated whether incorporating immune checkpoint blockade before chemoradiotherapy could offer an effective bladder-sparing treatment for patients with MIBC.

Indi-Blade was an investigator-initiated, multicenter, single-arm phase 2 study enrolling 50 patients with clinical stage cT2–4aN0-2MO MIBC in which suspected lymph nodes needed to be amenable to radiation therapy. Patients first received 3 cycles of immune checkpoint inhibition (ICI): ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43.⁴ Induction ICI was followed by response assessment using imaging and cystoscopy. In the absence of disease progression, participants proceeded to consolidative chemoradiotherapy.

The study’s primary end point was 2-year bladder-intact event-free survival (BI-EFS), defined as the absence of death from any cause, muscle-invasive local recurrence, nodal or distant recurrence, salvage cystectomy, or switch to systemic chemotherapy. The null hypothesis assumed a 2-year BI-EFS of 50%, with 70% prespecified as the threshold supporting further clinical development. Secondary end points included overall survival (OS), safety, and circulating tumor (ctDNA) analyses.

The data cutoff was October 3, 2025, with a median follow-up of 28.7 months. At 24 months, the BI-EFS rate reached 78% (95% CI, 0.67-0.9; P < .001), exceeding the predefined target and allowing investigators to reject the null hypothesis. OS, although immature at the time of data report, was estimated at 96% (95% CI, 0.91-1) at 2 years.

Treatment was generally feasible, with most participants (58%) receiving all 3 cycles of induction immunotherapy. Five patients did not proceed to chemoradiotherapy due to disease progression (n = 4) or patient choice (n = 1).

No new safety signals were reported. Adverse events (AEs) related to chemoradiotherapy occurred in 71% of patients, with the most common being diarrhea (22%), fatigue (20%), and increased urinary frequency (13%). Grade 3 to 4 AEs related to chemoradiotherapy were reported in 7% of patients.

Immunotherapy-related AEs occurred in most patients (94%), and grade 3 to 4 immunotherapy-related AEs were reported in 24% of patients. The most common immunotherapy-related AEs of any grade were fatigue (42%), maculopapular rash (30%), diarrhea (26%), and pruritus (20%).

An exploratory biomarker analysis was also conducted to evaluate ctDNA dynamics during treatment. Plasma samples were collected longitudinally before each immunotherapy cycle, at response assessments, and during follow-up.

Investigators reported that patients who experienced an event (n = 9) had either persistent or newly detectable ctDNA throughout the course of treatment (HR, 3.59; 95% CI, 0.86-15.02; P = .0805). Conversely, the absence of ctDNA after induction immunotherapy was associated with BI-EFS (HR, 8.33; 95% CI, 1.38-50.36; P = .0209). According to the authors, this finding suggests that ctDNA status post immunotherapy could “aid clinical decision-making after systemic induction.”

Overall, Mellema concluded, “Potent induction combination immunotherapy followed by consolidated chemoradiotherapy is an effective bladder-sparing treatment for a broad population of [patients with MIBC].”

REFERENCES

1. Mellema JJ. 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. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 26-28, 2026; San Francisco, CA. Abstract LBA637. https://www.asco.org/abstracts-presentations/257348/abstract

2. Mellema JJ, Stockem CF, Herberts C, et al. Ipilimumab and nivolumab followed by chemoradiotherapy as bladder-sparing treatment in muscle-invasive bladder cancer: a phase 2 trial. Nat Med. Published online February 27, 2026. doi:10.1038/s41591-026-04271-3

3. van Dijk N, Gil-Jimenez A, Silina K, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020;26(12):1839-1844. doi:10.1038/s41591-020-1085-z

4. Checkpoint inhibition and chemoradiotherapy as bladder sparing treatment in UC (Indi-Blade). ClinicalTrials.gov. Updated March 18, 2024. Accessed March 5, 2026. https://clinicaltrials.gov/study/NCT05200988