Patients with muscle-invasive urothelial cancer and postsurgical circulating tumor DNA (ctDNA) positivity have high risk of disease recurrence following cystectomy and experienced improved clinical outcomes with adjuvant atezolizumab as compared to patients undergoing observation. These translational research findings from the IMvigor010 study were presented by Thomas Powles, MD, at the European Society for Medical Oncology (ESMO) Immuno-Oncology Virtual Congress 2020 (Abstract 10).
Dr. Powles, of the Oncology Department, Barts Cancer Institute, Queen Mary University of London, St. Bartholomew’s Hospital, noted that muscle-invasive urothelial cancer carries a substantial risk of recurrence and/or death, with nearly 50% of patients with muscle-invasive urothelial cancer developing recurrence within 2 years of cystectomy. This underscores the need to identify these high-risk patients who may benefit from adjuvant therapy.
Thomas Powles, MD
IMvigor010
Dr. Powles and colleagues used ctDNA data from patients in the global phase III IMvigor010 study, which evaluated atezolizumab as adjuvant treatment compared with observation in patients with muscle-invasive urothelial cancer. They conducted this study to determine whether ctDNA-positive patients would benefit from adjuvant atezolizumab therapy; they included a prospective ctDNA exploratory analysis to determine whether atezolizumab provided clinical benefit compared to observation in these patients and if ctDNA clearance occurred at a higher rate with atezolizumab vs observation.
The investigators performed whole-exome sequencing and ctDNA analysis by Natera’s Signatera assay using C1D1 plasma obtained at a median 11 weeks postcystectomy in 581 biomarker-evaluable patients with evaluable samples, comprising 72% of the intent-to-treat population of the IMvigor010 study. Tumor mutational burden status was determined by whole-exome sequencing, and PD-L1 status was established by immunohistochemistry using the Ventana SP142 antibody.
Baseline characteristics were similar between the intent-to-treat and biomarker-evaluable populations.
Results
In the biomarker-evaluable population, 214 (37%) patients were ctDNA-positive. The baseline characteristics that associated with positivity included nodal status (P < .001) and tumor stage (P = .09). Although the primary endpoint of disease-free survival in the intent-to-treat population was not met in IMvigor010, translational study found an association between ctDNA-positive patients and disease-free survival benefit with atezolizumab compared to observation (stratified hazard ratio [HR] = 0.57, 95% confidence interval [CI] = 0.41–0.79, P < .001).
The interim overall survival analysis also favored atezolizumab in ctDNA-positive patients (stratified HR = 0.58, 95% CI = 0.39–0.85, P = .005); the cohort of ctDNA-positive patients demonstrated a median overall survival of 25.8 months with atezolizumab compared to 15.8 months with observation.
Analysis according to PD-L1 expression levels and tumor mutational burden in the ctDNA-positive patients revealed a greater disease-free survival benefit in PD-L1–high patients (stratified HR = 0.50, 95% CI = 0.31–0.80, P = .0034), as well as in tumor mutational burden–high patients (stratified HR = 0.32, 95% CI = 0.16-0.64, P < .001).
With ctDNA positivity, the rate of ctDNA clearance from C1D1 to C3D1 was significantly higher with atezolizumab vs observation; 18.2% vs 3.8%, respectively (P = .0048).
No benefit was seen with atezolizumab over observation in patients who were ctDNA-negative.
The authors concluded that these findings demonstrated that postsurgical ctDNA positivity, which is associated with high risk for recurrence and death, could identify patients with muscle-invasive urothelial cancer that are likely to benefit from adjuvant atezolizumab.
They further advised that detection of minimal residual disease in an adjuvant setting will allow personalized treatment selection for patients. With further data, data may change approaches to adjuvant therapy in a spectrum of cancers.
Disclosure: This study was funded by F. Hoffmann-La Roche, Ltd. For full disclosures of the study authors, visit oncologypro.esmo.org.
