A Phase III, Open-Label, Multicenter, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Versus Observation as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Urothelial Carcinoma After Surgical Resection.

Hoffmann-La Roche
Study Design: 
This is a phase III, multicenter open-label trial that randomly assigned patients with muscle-invasive urothelial cancer after surgical resection with high risk features for recurrence to either observation or adjuvant atezolizumab treatment in a 1:1 fashion. Patients randomized to intravenous atezolizumab received therapy with 1200 mg every 3 weeks for up to 16 cycles. Patients with pT2-T4 disease after neoadjuvant chemotherapy, or pT3-4 disease without neoadjuvant chemotherapy, or any node positive disease after radical cystectomy were considered high risk for recurrence and eligible for the trial. Assessment of tumor status was performed by radiographic imaging prior to initiation of treatment.
Patients with high-risk muscle invasive urothelial cancer after surgical resection have limited options for treatment. Historically, they have been observed only to later develop local or systemic recurrences and to eventually succumb to urothelial cancer. However, with the absence of a proven benefit of adjuvant therapy and dearth of treatments except for chemotherapy, there has been little progress in this disease space of urothelial cancer. This trial, also known as the IMvigor010 trial, aimed to evaluate the impact of adjuvant atezolizumab, a PD-L1 inhibitor, in patients randomized to receiving such therapy after radical cystectomy with high risk features seen on pathology.
Primary outcome was disease-free survival (DFS) from the time of randomization and included pelvic (local) recurrence, extravesical urinary tract recurrence, distant metastases, or death from any cause. Secondary outcomes included overall survival, disease-specific survival, disease metastasis-free survival, and non-urinary tract recurrence-free survival.
This trial unfortunately did not demonstrate a difference in DFS with the use of adjuvant atezolizumab. One of the criticisms is that this trial may have excluded patients likely to benefit and included patients unlikely to benefit with atezolizumab. Patients with positive surgical margins are most likely to recur with local (pelvic) recurrence and may benefit most from adjuvant therapy but were excluded from this trial. Another potential issue is potentially that there may be a difference in efficacy between PD-1 and PD-L1 inhibitors as PD-1 inhibitors have demonstrated slightly better survival results in some studies although no studies have directly compared these two different types of inhibitors.
In this trial, Atezolizumab failed to meet the primary end point, disease-free survival (DFS), as adjuvant monotherapy in patients with muscle-invasive urothelial cancer (MIUC) compared with observation in the phase III IMvigor010 clinical trial, according to a press release from Roche, developer of the drug on January 24, 2020 (https://bit.ly/38zdRoE)