Multicenter phase 2 trial of ctDNA-guided immunotherapy following radical cystectomy for muscle-invasive bladder cancer

Standard treatment of localized muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), but approximately 50% of patients relapse within 2 years. The multicenter phase 2 TOMBOLA trial in Denmark evaluated serial circulating tumor DNA (ctDNA) testing to guide postoperative immunotherapy after NAC and RC. ctDNA-positive (ctDNA+) patients initiated atezolizumab for up to 1 year, irrespective of imaging; whereas ctDNA- patients received immunotherapy only upon radiographic detection of metastases. The primary endpoint was molecular and radiographic complete response. Among 178 evaluable patients with a median follow-up of 34 monts, 104 (58%) were ctDNA+ within 2 years after RC (63% within 4 months). The median lead-time from ctDNA detection to imaging-confirmed recurrence was 90 days (range -61 to + 961). Of the ctDNA+ patients, 84 completere atezolizumab and had scanning and ctDNA analyses available for primary endpoint assessment. Fifty of 84 patients (60%) achieved the primary endpoint of complete response. One-year recurrence-free survival rate was 97% in ctDNA- patients and 70% in ctDNA+ patients. Treatment was well tolerated with no new safety concerns. The authors conclude that tumor-informed ctDNA testing after NAC and RC predict recurrence risk and enables personalized postoperative management in MIBC. TOMBOLA demonstrates that ctDNA+, low-risk patients may benefit from early immunotherapy, while ctDNA-, high-risk patients may safely avoid adjuvant treatment (visual abstract).