Adjuvant Atezolizumab Promotes Enhanced ctDNA Clearance Linked to Improved DFS in MIBC

Adjuvant atezolizumab (Tecentriq) encourages circulating tumor DNA (ctDNA) reduction and clearance, and these dynamics were linked with improved disease-free survival (DFS) in patients with muscle-invasive bladder cancer (MIBC), according to data from an exploratory analysis of the phase 3 IMvigor011 study (NCT04660344) presented during the 2026 Genitourinary Cancers Symposium.¹

When looking at the correlation between ctDNA concentration and time from cystectomy, it was reported that the highest incidence of recurrence was within the first 6 months; these patients were also found to have high ctDNA concentration. Moreover, late conversion to ctDNA-positive status was linked with lower ctDNA concentration.

Additional analysis showed that high-risk pathological stage correlated with earlier time to ctDNA positivity as well as higher concentration. “We see there is a variability within pathological risk groups, and that is greater than the variability between all of these groups,” Joaquim Bellmunt, MD, PhD, said in the presentation of the data. “And we cannot say that pathology alone is sufficient to predict ctDNA timing or concentration.” Bellmunt is a professor of medicine at Harvard Medical School and director of the Bladder Cancer Center, a Genitourinary Oncology Program of Dana-Farber Cancer Institute, in Boston, Massachusetts.

Investigators also assessed how the timing of ctDNA positivity (n = 212) correlated with outcome in untreated patients and found that early positivity was linked with inferior clinical outcomes. In those who were ctDNA negative (n = 357), the 6-, 12-, and 24-month DFS rates were 98.0%, 95.4%, and 88.4%, respectively; the overall survival (OS) rates at these respective time points were 100%, 100%, and 97.1%. In those with ctDNA positivity at the initial test, the 6-, 12-, and 24-month DFS rates were 49.9%, 19.2%, and 8.2%; the OS rates at these time points were 96.4%, 87.4%, and 48.5%. In those with ctDNA positivity at subsequent test, the DFS rates were 89.1%, 43.8%, and 22.3% at 6, 12, and 24 months, respectively; the OS rates were 98.8%, 98.8%, and 71.8%, respectively. “So, this is a prognostic indicator in patients that we are analyzing, the timing of the ctDNA [positivity],” Bellmunt said.

When analyzing how ctDNA concentration correlates with DFS and OS outcomes, it was found that patients with high ctDNA concentration had inferior clinical outcomes. “We see that patients who have some degree of concentration are doing much better, but in the end, all these patients recur,” he explained. “And this compares with the patients who do not have ctDNA presenting in the plasma.”

In those with ≤ 0.1 mean tumor molecules (MTM)/mL, the 6-month DFS rate was 82.1%, the 12-month DFS rate was 53.4%, and the 24-month DFS rate was 28.4%; the OS rates at these time points were 100%, 100%, and 67.4%. In those with > 0.1 MTM/mL to ≤ 3 MTM/mL, the DFS rates at 6, 12, and 24 months were 71.2%, 26.6%, and 13.2%, respectively; the respective OS rates were 97.2%, 95.0%, and 60.1%. In those with > 3 MTM/mL, the 6-month DFS rate was 44.0%, the 12-month DFS rate was 9.4%, and the 24-month DFS rate was 0%; the OS rates at 6, 12, and 24 months were 95.2%, 76.0%, and 42.6%, respectively.

Atezolizumab was also found to have comparable efficacy irrespective of the timing of ctDNA positivity or concentration. The median DFS with atezolizumab (n = 99) in those who had ctDNA positivity at initial test was 8.3 months vs 4.2 months with placebo (n = 49; HR, 0.62; 95% CI, 0.42-0.91). The median OS in the respective arms was 27.7 months and 18.2 months (HR, 0.71; 95% CI, 0.43-1.17). In those with ctDNA positivity at subsequent test, the median DFS with atezolizumab (n = 68) was 10.5 months vs 8.3 months with placebo (n = 34; HR, 0.67; 95% CI, 0.40-1.10). The median OS in the respective arms was not available (NA) vs 27.4 months (HR, 0.52; 95% CI, 0.24-1.12).

In those with a ctDNA concentration of ≤ 0.1 MTM/mL, the median DFS was 12.6 months with atezolizumab (n = 59) vs 10.5 months with placebo (n = 28; HR, 0.81; 95% CI, 0.46-1.42). The median OS with atezolizumab was 34.4 months vs NA with placebo (HR, 0.83; 95% CI, 0.38-1.85). In those with a concentration of > 0.1 MTM/mL to ≤ 3 MTM/mL, those given atezolizumab (n = 77) experienced a median DFS of 8.5 months vs 4.5 months with placebo (n = 39; HR, 0.59; 95% CI, 0.38-0.91). The median OS with atezolizumab or placebo was 35.9 months and 21.1 months, respectively (HR, 0.54; 95% CI, 0.29-1.01). In those with a concentration of >3 MTM/mL, the median DFS with atezolizumab (n = 31) or placebo (n = 16) was 8.1 months and 2.3 months, respectively (HR, 0.47; 95% CI, 0.24-0.94). The median OS with atezolizumab was 24.3 months vs 10.9 months with placebo (HR, 0.64; 95% CI, 0.29-1.40).

Investigators also evaluated the log two-fold change of ctDNA from starting treatment or when the patients achieved a response. “The distribution of the clearance, the two-fold decrease, the no change, or the more than two-fold increase in patients receiving atezolizumab, compares favorably to the patients receiving placebo,” Bellmunt reported. “One important message here is that we see that adjuvant atezolizumab promotes ctDNA clearance in a statistical way compared to placebo. Also, there is a deeper molecular response when we compare patients receiving atezolizumab or placebo.”

He added that ctDNA reduction or clearance was linked with improved DFS with atezolizumab, and many patients reduced or cleared ctDNA from high pretreatment concentration. “Atezolizumab is acting enormously well in these patients with high concentrations of ctDNA,” Bellmunt said. Some ctDNA clearance was also associated with placebo, and there was some DFS benefit; however, those who clear ctDNA represent a prognostically favorable subgroup with low pretreatment ctDNA concentration, he added.

What was the design of IMVigor011, and what data have previously been reported?

The global, randomized, phase 3 IMVigor011 study included patients with MIBC within 6 to 24 weeks of undergoing radical cystectomy. Patients had histologically confirmed (y)pT2-T4aN0M0 or (y)pT0-TaN+M0 urothelial cancer with no evidence of radiographic disease and an ECOG performance status ranging from 0 to 2. Patients were allowed to have previously received neoadjuvant chemotherapy.

Patients underwent surveillance ctDNA monitoring until 1 year after cystectomy. They underwent repeat testing if ctDNA negative. If ctDNA negative until 1 year, they received no treatment and entered into surveillance follow-up. If ctDNA positive at any time and were confirmed to have no evidence of radiographic disease, they were randomized 2:1 to receive atezolizumab at 1680 mg vs placebo every 4 weeks for up to 1 year. They subsequently entered into follow-up.

The primary end point of the study was DFS by investigator assessment and a key secondary end point was OS. The trial met these end points at the time of the first interim analysis.² The median DFS with atezolizumab (n = 167) was 9.9 months (95% CI, 7.2-12.7) vs 4.8 months (95% CI, 4.1-8.3) with placebo (n = 83), translating to a 36% reduction in the risk of disease progression or death (HR, 0.64; 95% CI, 0.47-0.87; P = .0047). The median OS with atezolizumab was 32.8 months (95% CI, 27.7-not evaluable [NE]) vs 21.1 months (95% CI, 14.7-NE) with placebo, translating to a 41% reduction in the risk of death (HR, 0.59; 95% CI, 0.39-0.90; P = .0131).

What were the methods leveraged for the current exploratory analyses?

Investigators performed ctDNA testing using the personalized, tumor-informed, 16-plex mPCR-NGS Signatera assay.¹ They sequenced tumor and normal DNA to identify a unique set of tumor variants, and the custom-designed multiplex assay targeted high-ranked variants. Blood samples that had at least 2 variants detected were determined to be ctDNA positive.

“We have been using the Signatera platform, and we know there are different ways to interpret the Signatera platform,” Bellmunt explained. “One is a binary yes or no, meaning that if the patients have 2 or more variants in the blood, the test is positive. But there is another way that is analyzing the MTM values, and this is the concentration. And this concentration has been studied for the analysis in this study.”

In the surveillance phase of the research, investigators sought to examine the natural history of ctDNA dynamics in untreated patients with MIBC (n = 761). After cystectomy, if they had ctDNA positivity at any time (n = 379), they went on to undergo randomization (n = 250) to atezolizumab (n = 167) or placebo (n = 83). In the treatment phase, investigators sought to evaluate the impact of adjuvant atezolizumab on ctDNA dynamics. Of those assigned to the atezolizumab arm, 151 had a post-baseline ctDNA result; of those assigned to the placebo arm, 77 had a post-baseline result.

The analysis focused on four populations: all patients with ctDNA positivity (n = 379), untreated patients with ctDNA positivity (screen failed or placebo treated; n = 212), those with ctDNA positivity randomized with at least 1 post-baseline ctDNA result (n = 228), and those with persistent ctDNA negativity (n = 357).

What should be taken away from this research?

“Serial ctDNA testing can differentiate patients with high vs low recurrence risk, which can help avoid unnecessary treatment,” Bellmunt concluded. “ctDNA timing and concentration conveyed additional prognostic information beyond binary ctDNA-positive or -negative status. Some patients treatment with placebo cleared ctDNA and had improved DFS; this represents a prognostically favorable subgroup with low baseline ctDNA concentration.”

Disclosures: Dr Bellmunt disclosed stock and other ownership interests in Rainier Therapeutics, receipt of honoraria from UpToDate, and serving in a consulting or advisory role for AstraZeneca/MedImmune, Bristol Myers Squibb, EMD Serono/Merck, Merck, Novartis, Pfizer, and Pierre Fabre. Research funding was provided by Pfizer/EMD Serono and Pfizer/Gilead. He also disclosed patents, royalties, and other intellectual property in UpToDate Bladder Cancer and travel, accommodations, and expenses support from Genentech/Roche and Ipsen.

References

1. 1.Powles T, Grindheim J, Yilmaz M, et al. Circulating tumor (ct)DNA-guided adjuvant atezolizumab (atezo) in muscle-invasive bladder cancer (MIBC): Exploratory analysis of ctDNA dynamics in the IMvigor011 trial. J Clin Oncol. 2026;44(suppl 7):633. doi:10.1200/JCO.2026.44.7_suppl.633
2. 2.Powles T, Kann AG, Castellano D, et al. ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med. 2025;393(24):2395-2408. doi:10.1056/NEJMoa2511885