Circulating tumour DNA-guided treatment for high-risk, post-cystectomy muscle-invasive bladder cancer

Adjuvant atezolizumab for muscle-invasive bladder cancer using a minimally invasive biomarker approach

an unselected label in the United States but requires tumour cell PD-L1 expression ≥1% in Europe.[2,3]

While progress has been made against bladder cancer as a whole, there are still large subsets of patients with high unmet needs and a lack of clear guidance on how to treat them. For example, some patients with muscle-invasive bladder cancer (MIBC) who are at high risk for disease recurrence following cystectomy (pT3/T4 or N+), including those unable to receive neoadjuvant cisplatin-based chemotherapy, may benefit from adjuvant treatment. However, no data demonstrating overall survival (OS) benefit exist to guide patient selection and treatment.

To address this ongoing dilemma, biomarker-based personalised approaches have been pursued in urothelial carcinoma since the adoption of immune checkpoint inhibitors and other targeted agents.

PD-L1 is one consideration in selecting patients who may derive benefit from checkpoint inhibitors in some treatment settings; however, challenges exist in its applicability, including diagnostic assay choice, and are reflected by differences in recommendations between global health authorities.[1] For example, in the adjuvant setting, the checkpoint inhibitor nivolumab is approved with

The use of blood levels of circulating tumour DNA (ctDNA) as a biomarker for disease detection and recurrence has been demonstrated in multiple cancer types.[4] ctDNA is highly prognostic in MIBC[5] and may aid in risk stratification to inform post-surgical disease management, including determining which patients with ctDNA-negative status may be spared adjuvant therapy. It also represents a less invasive alternative to follow-up tissue biopsies, allowing for earlier detection of recurrence and potentially removing barriers to frequent testing of mutation status. An exploratory analysis from the phase III IMvigor010 study used ctDNA positivity as a surrogate for molecular residual disease to enrich for patients who may derive disease-free survival (DFS) or OS benefit with the checkpoint inhibitor atezolizumab compared with observation as well as to identify patients who could be spared adjuvant treatment [6,7]. These hypothesis-generating data provided rationale for further investigation of the role of ctDNA in MIBC management in the ongoing phase III IMvigor011 study.

IMvigor011 (Figure 1) is enrolling patients with high-risk MIBC to undergo serial ctDNA surveillance after cystectomy; patients with ctDNA(+) status, as determined using a personalised panel (tumour-informed) assay (Natera Signatera) will be randomised to adjuvant atezolizumab vs placebo (2:1). Patients who are ctDNA(–) will undergo surveillance for ctDNA relapse. Serial ctDNA surveillance after cystectomy allows an intervention window before radiographic recurrence occurs. The primary endpoint is investigator-assessed DFS in patients who are ctDNA(+) within 24 weeks of cystectomy. Key secondary endpoints include OS in this population, investigator-assessed DFS in all randomised patients, and centrally reviewed DFS. Notwithstanding the importance of selecting the appropriate patient subset for adjuvant therapy, preventing overtreatment of patients who may not relapse is another key piece. Given the promise of ctDNA, we are excited to enrol patients in the IMvigor011 study evaluating adjuvant immunotherapy in patients with MIBC to prospectively test ctDNA as a biomarker, while we await results from other ongoing studies evaluating serial ctDNA testing for relapse detection (e.g., TOMBOLA, a phase II adjuvant atezolizumab study).[8]

Reference

1. Powles T. Adjuvant immuno-oncological treatment (next steps in immunotherapy for GU malignancies session). EAU 2023. Milan, Italy. 12 March 2023.

2. Opdivo (nivolumab). Prescribing information. Bristol Myers Squibb; 2023.

3. Opdivo (nivolumab). Summary of product characteristics. Bristol Myers Squibb; 2023.

4. Stadler JC, et al. Cancer Res 2022;82:349-358.

5. Szabados B, et al. Eur Urol. 2022;82:212-222.

6. Gschwend JE, et al. Overall survival by circulating tumor DNA status in patients with post-operative muscleinvasive urothelial carcinoma treated with atezolizumab: update from IMvigor010 (session GS5). EAU 2022. Amsterdam, the Netherlands. 4 July 2022.

7. Powles T, et al. Nature. 2021;595:432-437.

8. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/ NCT04138628. Accessed 29 March 2023.