Abstract CT101: ctDNA-guided immunotherapy following cystectomy in patients with urothelial carcinoma: Preliminary results from the TOMBOLA Trial

Abstract Introduction& objectives: The gold standard treatment for non-metastatic muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). Despite this aggressive treatment, approximately 50% of patients develop metastases within the first 2 years of follow-up. Adjuvant immunotherapy is recommended for patients at high risk of recurrence after cystectomy, while the remaining patients typically receive treatment only after visible recurrence is detected. In this study, we investigated the use of circulating tumor DNA (ctDNA) to guide immunotherapy after cystectomy (TOMBOLA trial; NCT04138628). Materials & Methods: The TOMBOLA trial is an ongoing national, multicenter, non-randomized, interventional study in Denmark, where patients undergoing NAC and RC due to non-metastatic MIBC (cT2-4aN0-1M0) are monitored with serial tumor-informed ctDNA testing in the postoperative period. Exome sequencing of tumor and germline DNA is used to design patient-specific ddPCR assays for monitoring plasma ctDNA status. If a patient tests positive for ctDNA at any time point, an additional CT scan is performed, and treatment with Atezolizumab is initiated regardless of the imaging results. ctDNA-negative patients receive immunotherapy only upon detection of metastases on imaging, irrespective of conventional risk groups. Ethical Committee approval has been obtained. Results: Patient recruitment was terminated in April 2024 (n=193). In total, 101 (56%, 101/179) patients were ctDNA-positive after RC, with 65% detected within 4 months after RC. Of the consistently ctDNA-negative patients, only 2 (3%) developed metastases on CT scans during follow-up. Primary endpoint data (response to immunotherapy measured by ctDNA clearance and CT scans) showed that 55% of 51 patients cleared ctDNA and exhibited no evidence of disease following immunotherapy. Secondary endpoint data showed a 96% recurrence-free survival (RFS) at 1 year for ctDNA-negative patients and 76% RFS for ctDNA-positive patients. The median lead time for ctDNA detection prior to metastases identified by CT scans was 90 days (-54 to 824). Exploratory biomarker analyses for PD-L1, tumor mutational burden (TMB), ctDNA levels/dynamics, and TGF-β are currently ongoing and will be presented. Conclusions: Tumor-informed serial ctDNA measurements after NAC and RC provide a highly specific method to identify patients who may benefit from early immunotherapy at a time of minimal metastatic disease. Overall, ctDNA testing shows promise for treatment de-escalation (in ctDNA-negative patients) and patient selection for adjuvant therapy (in ctDNA-positive patients). Citation Format: Lars Dyrskjøt, Karin Birkenkamp-Demtröder, Iver Nordentoft, Sia V. Lindskrog, Trine Strandgaard, Rikke V. Milling, Stefanie Körner, Simone B. Brandt, Michael Knudsen, Tine Andreasen, Gitte Lam, Line H. Dohn, Knud Fabrin, Andreas Carus, Astrid Petersen, Ulla N. Joensen, Helle Pappot, Per Holt, Niels V. Jensen, Mads Agerbaek, Jørgen B. Jensen. ctDNA-guided immunotherapy following cystectomy in patients with urothelial carcinoma: Preliminary results from the TOMBOLA Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT101.