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Survival According Circulating Tumour DNA Status in the Study of Adjuvant Atezolizumab for High-Risk Muscle Invasive Urothelial Cancer

Post-surgical ctDNA-positivity in patients with MIUC associates with higher risk of disease recurrence and identifies patients that may benefit from adjuvant atezolizumab therapy
10 Dec 2020
Cancer Immunology and Immunotherapy;  Genitourinary cancers;  Translational research

Patients with muscle invasive urothelial cancer (MIUC) and post-surgical circulating tumour 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, according to translational research findings from the IMvigor010 study presented at the ESMO Immuno-Oncology Virtual Congress 2020, held from 9 to 12 December 2020.

Thomas Powles of the Oncology Department, Barts Cancer Institute, Queen Mary University of London, St. Bartholomew’s Hospital in London, UK noted that MIUC carries a substantial risk of recurrence and/or death with nearly 50% of MIUC patients developing recurrence within two years of cystectomy, which underscores the need to identify these high-risk patients who may benefit from adjuvant therapy.

Professor Powles and colleagues used ctDNA data from patients in the global phase III IMvigor010 (NCT02450331) study, which evaluated atezolizumab as adjuvant treatment compared with observation in patients with MIUC. They conducted this study to determine whether ctDNA-positive patients would benefit from adjuvant atezolizumab therapy and 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 versus observation.

The investigators performed whole exome sequencing (WES) and ctDNA analysis by Natera’s Signatera assay using C1D1 plasma obtained at a median 11 weeks post-cystectomy in 581 biomarker evaluable patients (BEP) with evaluable samples, comprising 72% of the intent-to-treat population (ITT) of the IMvigor010 study. Tumour mutational burden (TMB) status was determined by WES and PD-L1 status was established by immunohistochemistry using the Ventana SP142 antibody.

Baseline characteristics were similar between the ITT and BEP populations.

The ctDNA-positive patients demonstrated a survival benefit with atezolizumab

In the BEP, 214 (37%) patients were ctDNA-positive. The baseline characteristics that associated with positivity included nodal status (p < 0.001) and tumour stage (p = 0.09). Although the primary endpoint of disease-free survival (DFS) in the ITT population was not met in IMvigor010, translational study found an association between ctDNA-positive patients and DFS benefit with atezolizumab compared to observation (stratified hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.41–0.79; p < 0.001).

The interim overall survival (OS) analysis also favoured atezolizumab in ctDNA-positive patients (stratified HR 0.58; 95% CI, 0.39–0.85; p = 0.005); the cohort of ctDNA-positive patients demonstrated median OS of 25.8 months with atezolizumab compared to 15.8 months with observation.

ctDNA clearance rates were higher with atezolizumab

Analysis according to PD-L1 expression levels and TMB in the ctDNA-positive patients revealed a greater DFS benefit in PD-L1-high patients (stratified HR 0.50; 95% CI, 0.31-0.80; p = 0.0034), as well as in TMB-high patients (stratified HR 0.32; 95% CI, 0.16-0.64; p < 0.001).

With ctDNA positivity, the rate of ctDNA clearance from C1D1 to C3D1 was significantly higher with atezolizumab versus observation; the ctDNA clearance rates with were 18.2% versus 3.8%, respectively (p = 0.0048).

No benefit was seen with atezolizumab over observation in patients who were ctDNA-negative.

Conclusions

The authors concluded that these findings demonstrated that post-surgical ctDNA positivity, which is associated with high risk for recurrence and death, could identify patients with MIUC that are likely to benefit from adjuvant atezolizumab.

They further advised that detection of minimal residual disease in an adjuvant setting will allow personalised treatment selection for patients. With further data, data may change approaches to adjuvant therapy in a spectrum of cancers. 

This study was funded by F. Hoffmann-La Roche, Ltd.

Reference

1O – Powles T, Assaf ZJ, Davarpanah N, et al. Clinical outcomes in post-operative ctDNA-positive muscle-invasive urothelial carcinoma (MIUC) patients after atezolizumab adjuvant therapy. ESMO Immuno-Oncology Virtual Congress 2020 (9-12 December).

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