IMvigor010: Primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma (MIUC).

Abstract

5000 Background: Radical surgery ± cisplatin-based neoadjuvant chemo (NAC) is the mainstay treatment (tx) for MIUC, with no conclusive level 1 evidence for adjuvant chemo (AC). Here we present the primary analysis from IMvigor010, a global, open-label, multicenter, randomized trial of adjuvant atezo (anti–PD-L1; approved in metastatic UC [mUC] settings) in pts with MIUC at high risk of recurrence following primary resection. Methods: Pts with MIUC (bladder, upper tract [UT]), ECOG PS 0-2 and resected tissue for PD-L1 testing on immune cells (IC; VENTANA SP142 assay) were enrolled ≤ 14 wks after radical cystectomy/nephroureterectomy with lymph node (LN) dissection. Pathologic stage: 1) ypT2-4a or ypN+ if pts had NAC or 2) pT3-4a or pN+ if pts did not have NAC. No postsurgical radiation or AC was allowed; if no NAC was given, pts must have been ineligible for or declined cisplatin-based AC. Pts were randomized 1:1 to atezo 1200 mg IV q3w or obs for 16 cycles or 1 y (stratification factors: no. of LNs resected, pathologic nodal status, pathologic tumor stage, PD-L1 status, prior NAC). Disease-free survival (DFS) was the primary endpoint (EP). Final DFS, first interim overall survival (OS; secondary EP) and safety are reported. Results: The ITT population included 809 pts (median follow-up, 21.9 mo). In the atezo and obs arms, respectively, 48% and 47% had NAC; 7% and 6% had UTUC as primary disease; 48% each had LN+ disease. DFS and OS are in Table. Baseline prognostic/clinical factors did not influence DFS tx benefit; stratified HR was 0.81 (95% CI: 0.63, 1.05) in IC0/1 pts (PD-L1 < 5%; n = 417) and 1.01 (0.75, 1.35) in IC2/3 pts (PD-L1 ≥ 5%; n = 392). 16% of atezo-treated pts had a tx-related G3-4 AE. Skin and gastrointestinal toxicities most commonly led to tx discontinuation. Conclusions: IMvigor010, the first phase 3 adjuvant study of a checkpoint inhibitor in MIUC, did not meet its primary EP of DFS. More tx discontinuation due to AEs was seen vs mUC studies. Safety was generally consistent with previous studies. Clinical trial information: NCT02450331 . [Table: see text]

Prognostic Value of Programmed Death Ligand-1 Expression on Tumor-Infiltrating Immune Cells in Patients Treated with Cisplatin-Based Combination Adjuvant Chemotherapy Following Radical Cystectomy for Muscle-Invasive Bladder Cancer: A Retrospective Cohort Study

“…In a Phase III IMvigor010 trial, adjuvant atezolizumab in patients with high-risk muscle invasive BCa did not improve DFS (HR = 0.89; P = 0.2446). 32 However, in a phase III CheckMate-274 trial, adjuvant nivolumab in patients with high-risk muscle invasive BCa improved DFS in both all randomized patients and in patients whose tumor cells express PD-L1 ≥1%. 33 In addition, in a phase III JAVELIN Bladder 100 trial, the addition of maintenance avelumab to best supportive care significantly prolonged OS (HR = 0.56; P < 0.001) in PD-L1 positive patients with unresectable locally advanced or metastatic BCa who had not progressed with first-line chemotherapy.…”

Moving towards Personalized Medicine in Muscle-Invasive Bladder Cancer: Where Are We Now and Where Are We Going?

“…Finally, evidence suggests that neoadjuvant is more effective than adjuvant treatment, based on the greater tumor antigen exposition before tumor resection [ 49 ]. The recent results of the IMvigor 010 phase III trial showed that adjuvant atezolizumab did not demonstrate a significant benefit in high-risk MIBC patients treated with cystectomy [ 57 ].…”

Considerations in prescribing pharmacotherapy for localized and metastatic urothelial carcinoma

“…In the localized disease setting, there are data emerging for the use of neoadjuvant PD-(L)1 inhibition, with or without chemotherapy [17], and phase 3 trials evaluating this strategy are underway. In contrast, there was no benefit seen with adjuvant atezolizumab in patients who underwent surgery for high muscle-invasive urothelial carcinoma, with or without neoadjuvant chemotherapy [18]. Nevertheless, we await data from other adjuvant immunotherapy trials and the ongoing PROOF-302 phase 3 trial that is evaluating adjuvant infigratinib, an FGFR inhibitor, in patients with FGFR3 alterations.…”