ESMO 2024: Identification of Bladder Cancer Patients That Could Benefit from Early Post-Cystectomy Immunotherapy Based on Serial Circulating Tumour DNA Testing: Preliminary Results from the TOMBOLA Trial

(UroToday.com) The 2024 European Society for Medical Oncology (ESMO) Annual Congress held in Barcelona, Spain between September 13^th and 16^th, 2024 was host to a proffered paper session for non-prostate genitourinary malignancies. Dr. Jørgen Bjerggaard Jensen presented the preliminary results from the TOMBOLA trial, which evaluated whether serial circulating tumour DNA (ctDNA) testing could be used to identify bladder cancer patients that could benefit from early post-cystectomy immunotherapy.

A current standard of care management option for muscle-invasive bladder cancer (MIBC) patients includes neoadjuvant chemotherapy followed by radical cystectomy, with high-risk patients receiving adjuvant immunotherapy based on high-risk pathologic features and low-risk patients undergoing serial surveillance using cross-sectional imaging, with systemic therapy reserved for recurrence.
While there is evidence from phase III trials that adjuvant immunotherapy improves survival outcomes,¹ Dr. Jensen argued that this absolute benefit is not clinically meaningful. Furthermore, as illustrated using the red arrow below, adjuvant therapy may represent overtreatment of the subset of patients that never recur. As such, he argued that we must do better by avoiding overtreatment of ‘high-risk’ patients.
Furthermore, many patients with ‘low-risk’ disease cannot be salvaged with systemic immunotherapy at the time of clinical (i.e., imaging) recurrence, as demonstrated below, with 80% of metastatic patients experiencing progression while on atezolizumab in the IMvigor211 trial, and only a 3% complete response rate achieved.²

Accordingly, the study investigators asked the following question: Can we avoid overtreatment of ‘high-risk’ patients and avoid delay of treatment in ‘low-risk’ MIBC patients by incorporating the use of ctDNA?
The study investigators have previously demonstrated that patients with a negative ctDNA status after radical cystectomy had a superior recurrence-free survival, compared to those with a positive ctDNA status. Furthermore, in patients who convert from a ctDNA negative to positive status, ctDNA had a three-month positive lead time, compared to cross-sectional imaging.³
TOMBOLA was a national, non-randomized ctDNA-based intervention study conducted at 5 centers in Denmark. Eligible patients were those with cT2-4aN0-1M0, cisplatin, and immunotherapy-eligible MIBC who underwent NAC followed by radical cystectomy. Patients underwent serial ctDNA testing post-operatively. Upon ctDNA detection, patients were recommended for one year of atezolizumab therapy.
The primary objective was complete response after treatment with the investigational agent initiated by ctDNA positive status after radical cystectomy. A complete response was defined by both a negative ctDNA status and no visible metastasis on CT. The secondary objectives were:

• Duration of freedom from clinical relapse
• Overall survival
• Cancer-specific survival

The patient characteristics are summarized below. 39% and 61% of patients had clinical high- and low-risk disease. Notably, among the clinical high-risk patients, 65% had a positive ctDNA status post-radical cystectomy. Conversely, almost half (49%) of the ‘low-risk’ patients were also ctDNA+ post-operatively.
56% of patients were ctDNA+ post-radical cystectomy. 75% were detected <4 months post-cystectomy. Of the ctDNA- patients, only 2 (3%) developed metastases on CT scan during follow-up.
In the ctDNA- patients, both recurrence-free and overall survivals were excellent, as demonstrated in the Kaplan-Meier curves below:
With regards to the primary endpoint, 55% of the 44 patients with a ctDNA+ status converted to ctDNA- with no evidence of disease on CT scanning.
Dr. Jensen concluded that serial measurements of ctDNA following NAC and radical cystectomy is a highly specific method to identify patients who might benefit from early immunotherapy at a time of minimal metastatic disease.

Presented by: Jørgen Bjerggaard Jensen, MD, Professor and Chair, Department of Urology, Aarhus University, Aarhus, Denmark

Written by: Rashid Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Meeting, Barcelona, Spain, Fri, Sept 13 – Tues, Sept 17, 2024. 

1. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114.
2. Powles T, Duran I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomized controlled trial. Lancet 2018;391:748-757.
3. Christensen E, Birkenkamp-Demtroder K, Sethi H, et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J Clin Oncol. 2019; 37(18):1547-57.