Circulating tumour DNA (ctDNA) testing after neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) may inform patients with muscle-invasive bladder cancer (MIBC) of their risk for recurrence and allows personalized postoperative management in MIBC, results of the TOMBOLA trial have shown.
“TOMBOLA demonstrates that ctDNA-positive, low-risk patients may benefit from early immunotherapy, while ctDNA-negative, high-risk patients may safely avoid adjuvant treatment without compromising outcomes,” the investigators said.
“By integrating ctDNA-guided escalation and de-escalation across both low- and high-risk patients, TOMBOLA demonstrates the feasibility of tailoring adjuvant immunotherapy based on molecular residual disease,” they added.
This multicentre, open-label, single-arm phase II trial evaluated serial ctDNA testing to guide immunotherapy after RC. The investigators postoperatively monitored both low- and high-risk MIBC patients (cT1-4aN0-1M0) treated with NAC and RC with tumour-informed ctDNA assays.
Participants who tested positive on ctDNA testing initiated atezolizumab for up to 1 year, regardless of imaging, where those with ctDNA negative results received immunotherapy only upon radiographic detection of metastases. Molecular and radiographic complete response was the primary endpoint, while recurrence-free survival (RFS) and overall survival (OS) were secondary.
A total of 192 patients were enrolled, of whom 178 were assessable in the intention-to-treat population (median follow-up 34 months). Of the 178 patients, 104 (58 percent) were ctDNA-positive within 2 years after RC, 63 percent within 4 months. The median lead time from ctDNA detection to imaging-confirmed recurrence was 90 days. [Ann Oncol 2026;37:712-724]
Predictors
Among patients with ctDNA positive results, 84 completed treatment with atezolizumab and had scanning and ctDNA analyses available for the assessment of the primary endpoint. Of these, 50 (60 percent) achieved complete response.
At 1 year, RFS was 97 percent in ctDNA-negative patients and 76 percent in those with ctDNA-positive findings. In prespecified biomarker analysis, ctDNA status and levels, risk stratification, and immune-related gene expression signatures predicted both recurrence risk and response to immunotherapy.
Moreover, no new safety concerns were found, and treatment was well tolerated.
“This biomarker-driven approach has the potential to reduce overtreatment, improve patient quality of life, and optimize healthcare resources,” the investigators said.
“As ongoing randomized trials such as IMvigor011 and MODERN continue to define the role of adjuvant immunotherapy, TOMBOLA provides complementary real-world evidence supporting ctDNA-guided precision strategies for future clinical implementation,” they added.
Molecular relapse
Early treatment of molecular relapse could eliminate micrometastatic disease, prevent immune escape, and potentially improve long-term outcomes, as shown by the high ctDNA clearance rate seen in TOMBOLA, along with similar trends found in IMvigor011. [Curr Oncol 2011;18:e150-e157; Mol Biol Rep 2021;48:8075-8095]
“These observations reinforce that ctDNA status refines recurrence risk beyond conventional pathological staging,” the investigators said.
Furthermore, the wide range of lead times noted between ctDNA detection and radiographic recurrence (up to 961 days) suggests biological heterogeneity in tumour growth kinetics and metastatic progression. Some patients with very low ctDNA tumour fractions may have indolent micrometastatic disease that remains below the detection threshold of imaging for prolonged periods, according to the investigators.
“Together, these results support a biology-driven rather than pathology-driven framework for selecting patients for adjuvant therapy,” they said.