Introduction:

Poor clinical outcomes are common in patients with muscle-invasive bladder cancer (MIBC) after cystectomy. Distinguishing patients who will relapse after surgery and may benefit from additional treatment from patients who were successfully cured by bladder removal is a significant challenge. Non-invasive circulating tumor DNA (ctDNA) monitoring has potential as a prognostic and predictive tool to detect and manage residual disease after surgery. Landmark testing after cystectomy has shown promise in identifying ctDNA+ patients at higher risk of relapse and ctDNA– patients with a better prognosis; however, some ctDNA– patients still experience relapse. Serial testing may have greater clinical utility as a risk stratification tool, as repeated sampling may enable the detection of patients initially ctDNA– who later convert to ctDNA+ status. This analysis evaluated clinical outcomes in patients with high-risk MIBC and persistent ctDNA– status based on serial ctDNA monitoring from the IMvigor011 surveillance cohort.

Methods:

IMvigor011 (NCT04660344) is a randomized Phase III study assessing atezolizumab versus placebo in patients with high-risk MIBC who are ctDNA+ post-cystectomy based on a personalized (tumor-informed) assay (NateraSignatera^TM). Patients are enrolled into a surveillance run-in phase 6–24 weeks post-cystectomy and undergo serial ctDNA testing (q6w for 6 months, then q12w up to 12 months) and imaging (q12w up to 12 months). Patients remaining ctDNA– after 12 months continued imaging and follow-up for disease-free survival (DFS) and overall survival (OS). Eligible patients who became ctDNA+ were randomized to receive atezolizumab or placebo (treatment phase). This exploratory analysis focused on clinical outcomes in persistently ctDNA– patients in the surveillance cohort, defined as patients who had no ctDNA+ result, ≥1 ctDNA– result, ≥1 post-baseline disease assessment, were disease free at baseline and completed ≥12 months of surveillance post-cystectomy or discontinued surveillance within <12 months without a ctDNA+ result.

Results:

Among the 286 patients enrolled in the IMvigor011 surveillance cohort who were ctDNA– post-cystectomy, 171 patients met the criteria to be included in the analysis. The median age of the surveillance arm population was 69 years (range, 40–90). Most patients were White (56.1%), male (78.9%), and had an ECOG performance status of 0 (67.3%). Tumor stage distribution was 10.7% <T2, 34.9% T2, 43.8% T3 and 10.7% T4. Slightly more than half of patients (51.5%) did not receive neoadjuvant chemotherapy. At a median follow-up duration of 16.3 months (IQR, 11.6-19.3), 9.9% of patients (17/171) experienced a DFS event (Figure 1). The 12- and 18-month DFS rates were 92% and 88%, respectively. DFS outcomes were similar regardless of PD-L1 status and tumor stage at cystectomy. With an OS event rate of 1.2% (2/171 patients), the 12- and 18-month OS rates were 100% and 98%, respectively.

Conclusion:

This exploratory analysis of the phase III IMvigor011 surveillance cohort demonstrated that serial ctDNA testing may have greater clinical utility as a risk stratification tool than landmark ctDNA testing in patients with high-risk MIBC post-cystectomy. Furthermore, the data lend increasing confidence that patients with high-risk MIBC who have persistent ctDNA– status after cystectomy may not require adjuvant treatment. A follow-up analysis will be completed as part of the primary IMvigor011 analysis.

Funding: F. Hoffmann-La Roche Ltd