ctDNA-Guided Atezolizumab Extends Survival After Cystectomy

Key Takeaways

• In the randomized ctDNA-positive cohort, atezolizumab was associated with a lower risk of recurrence or death than placebo.
• Patients who remained persistently ctDNA-negative were observed without study drug and had disease-free survival of 95% at the end of the 1-year monitoring period and 88% at 2 years.
• Grade 3 or 4 and fatal adverse events occurred in both groups, and treatment-related fatal adverse events were reported only with atezolizumab.

In the phase 3 IMvigor011 trial, ctDNA-positive patients had median disease-free survival of 9.9 months with adjuvant atezolizumab and 4.8 months with placebo after cystectomy. The trial enrolled patients with muscle-invasive bladder cancer, no radiographic evidence of disease after surgery, and serial ctDNA surveillance for molecular residual disease. Among those who became ctDNA-positive during monitoring, atezolizumab was associated with longer disease-free survival than placebo, with a P value of 0.005. Overall survival, outcomes in the persistently ctDNA-negative cohort, and adverse events were also reported.

The study was a phase 3, double-blind trial conducted after surgery in patients with muscle-invasive bladder cancer and no radiographic evidence of disease. Serial ctDNA testing continued for up to 1 year to detect molecular residual disease during postoperative surveillance. Overall, 761 patients enrolled, and 250 who became ctDNA-positive were randomized in a 2:1 ratio, with 167 assigned to atezolizumab and 83 to placebo. In IMvigor011, atezolizumab or placebo was given every 4 weeks for up to 1 year, while persistently ctDNA-negative patients received no study drug.

In the randomized ctDNA-positive cohort, the hazard ratio for recurrence or death was 0.64, with a 95% confidence interval of 0.47 to 0.87. The NEJM report noted that overall survival was assessed hierarchically to control alpha. Median overall survival was 32.8 months with atezolizumab and 21.1 months with placebo. The hazard ratio for death was 0.59, with a 95% confidence interval of 0.39 to 0.90 and a P value of 0.01. Atezolizumab was associated with longer disease-free and overall survival than placebo in patients who became ctDNA-positive during surveillance.

A separate cohort remained persistently ctDNA-negative throughout serial surveillance after surgery. This group included 357 patients and did not receive atezolizumab or placebo during the study period. Disease-free survival remained high through the end of the monitoring period and at the later 2-year assessment. These outcomes were observed during surveillance in a nonrandomized cohort.

Grade 3 or 4 adverse events occurred in 28% of atezolizumab-treated patients and 22% of placebo recipients. Treatment-related adverse events occurred in 7% of the atezolizumab group and 4% of the placebo group. Fatal adverse events occurred in 3% and 2%, respectively, while treatment-related fatal adverse events occurred in 2% and none.