Atezolizumab More Likely to Benefit Urothelial Cancer With Detectable ctDNA

Adjuvant atezolizumab (Tecentriq) in patients with high-risk muscle-invasive urothelial cancer (MIUC) with detectable circulating tumor DNA (ctDNA) demonstrated more benefit compared with those with MIUC and undetectable ctDNA, according to data from the IMvigor010 trial (NCT02450331) presented at the 2020 European Society for Medical Oncology Immuno-Oncology Virtual Congress.¹

In the original evaluation of this global, open-label, phase 3 randomized trial, 809 patients were given atezolizumab at 1200 mg intravenously every 3 weeks or observation for 16 cycles of 1 year.² Of the 581 in the biomarker evaluable population, 214 patients had detectable ctDNA and 367 did not.

The patients with ctDNA-positive disease exhibited a disease-free survival (DFS) benefit with atezolizumab with a median DFS of 5.9 months versus 4.4 months with observation (HR, 0.58; 95% CI, 0.43-0.79). The median overall survival (OS) from an interim analysis was 25.8 months versus 15.8 months with atezolizumab in patients with ctDNA and observation, respectively (HR, 0.59; 95% CI, 0.41-0.86). These prespecified analyses were not formally tested according to the statistical plan in the study, but the data will inform a new phase 3 trial specifically for patients with MIUC and detectable ctDNA.

“Bladder cancer is a complex and often difficult disease to treat, but as we continue to understand its biology, we are gaining greater clarity around new therapeutic avenues,” Levi Garraway, MD, PhD, Roche’s chief medical officer and head of global product development, said in a statement. “By using ctDNA and other biomarkers, we hope to gain insights that enable a more personalized approach to treatment. We are applying these findings to our clinical development program.”

For patients in this setting, investigators are trying to provide early intervention to reduce the risk of disease recurrence or spread. The ctDNA, which comes from dying cells being replaced by new cells and releasing tumor DNA into the bloodstream, is a strong prognostic marker for recurrence in patients with MIUC. More treatment options are needed for this population post-surgery since almost half of these patients will recur within 2 years. Investigators are using ctDNA to identify patients who may benefit from adjuvant therapy in other disease settings, and this may be the case in MIUC as well since there are currently no predictive or prognostic biomarkers with this disease.

Initially, IMvigor010 missed its primary end point of DFS benefit for the intent-to-treat patients with high-risk MIUC using atezolizumab compared with observation, which was announced at the 2020 American Society of Clinical Oncology Virtual Meeting.2 The median DFS between these 2 groups of 19.4 months versus 16.6 months (HR, 0.89; 95% CI, 0.74-1.08; P =.2446). At this point, the OS had not been reached in either arm (HR, 0.85). The atezolizumab monotherapy toxicity was consistent with known safety profiles and no new safety concerns were identified.

In the exploratory analyses, patients with PD-L1 expression and high tumor mutational burden (TMB) were also evaluated. There were 102 patients with ctDNA-positive and PD-L1–positive disease, and their DFS hazard ratio was 0.52 (95% CI, 0.33-0.82). The 69 patients with ctDNA and TMB-high disease had a DFS hazard ratio of 0.34 (95% CI, 0.19-0.60).

Patients enrolled on the IMvigor010 trial 14 weeks or less after radical cystectomy or nephroureterectomy with lymph node dissections and had an ECOG performance status of 0 to 2 and resected tissue for PD-L1 testing on immune cells. Those with postsurgical radiation or adjuvant chemotherapy were not allowed on the trial. Once on trial, patients were stratified by the number of lymph nodes resected, pathologic nodal status, pathologic tumor stage, PD-L1 status, and prior neoadjuvant chemotherapy.

_Reference:

_{1. Roche presents exploratory data from the Phase III IMvigor010 study in early bladder cancer at the ESMO Immuno-Oncology Virtual Congress 2020. New release. Roche. Published December 10, 2020. Accessed December 11, 2020. https://bit.ly/3ncESWF}

_{2. Hussain MHA, Powles T, Albers P, et al. IMvigor010: Primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma (MIUC). J Clin Oncol. 2020;38(suppl 15):5000. doi:10.1200/JCO.2020.38.15_suppl.5000}