Phase III IMmotion151 Study Met Its Co-Primary Endpoint of Investigator-Assessed PFS

Atezolizumab and bevacizumab doublet in first-line treatment for patients with advanced or metastatic RCC whose disease express the PD-L1

The findings from IMmotion151 study presented at ASCO 2018 Genitourinary Cancers Symposium (8-10 February, San Francisco, US) show improvement in investigator-assessed progression-free survival (PFS) compared with sunitinib alone for patients with inoperable, locally advanced or metastatic renal cell carcinoma (RCC) who have not received prior systemic treatment and whose disease expressed PD-L1. IMmotion151 is the second phase III study to show positive PFS results for a treatment regimen including atezolizumab plus bevacizumab

IMmotion151 is a phase III multicentre, randomised, open-label study to evaluate the efficacy and safety of atezolizumab and bevacizumab versus sunitinib alone; it enrolled 915 patients globally. Patients in the atezolizumab and bevacizumab arm received atezolizumab at a fixed dose of 1200 mg and bevacizumab at a dose of 15 mg/kg as i.v. infusion every 3 weeks until loss of clinical benefit or unacceptable toxicity. Patients in the sunitinib arm received sunitinib 50 mg orally, once daily for 4 weeks followed by 2 weeks rest until loss of clinical benefit or unacceptable toxicity. 

The co-primary endpoints were PFS, as determined by the investigator using RECIST v1.1 in patients whose tumours expressed PD-L1 (expression ≥1% on immune cells), and overall survival (OS) in the intention-to-treat (ITT) population. 

PD-L1 expression was prospectively assessed using an immunohistochemistry test (SP142) developed by Roche Tissue Diagnostics. 

Secondary endpoints included OS in patients whose tumours expressed PD-L1, PFS as determined by an Independent Review Facility according to RECIST v1.1, investigator-assessed objective response rate (ORR) and median duration of response (mDOR), change from baseline in symptom interference and symptom severity as determined by MD Anderson Symptom Inventory (MDASI), and change from baseline in health-related quality of life as determined by European Quality of Life 5-Dimension (EQ-5D) Scores. 

Stratification factors included the Memorial Sloan-Kettering Cancer Center (Motzer) prognostic scoring system, which predicts for OS based upon an individual's baseline clinical and laboratory characteristics. 

The study met its co-primary endpoint of investigator-assessed PFS in patients whose disease expressed the PD-L1 protein. Those who received atezolizumab plus bevacizumab had median PFS of 11.2 vs. 7.7 months in patients treated with sunitinib (HR 0.74; 95% CI 0.57, 0.96; p = 0.02). 

Initial observations from the co-primary endpoint of OS in the ITT population were encouraging, but are still immature. 

Safety for the atezolizumab and bevacizumab combination appeared consistent with the known safety profile of the individual medicines and what was previously reported in the phase II IMmotion150 study. No new safety signals were identified with the combination. The rate of treatment-related grade 3-4 adverse events was lower with the atezolizumab and bevacizumab combination (40%) than with sunitinib alone (54%) in all treated patients. 

Observations of a pre-specified subgroup analysis of the atezolizumab and bevacizumab combination indicated that, in patients whose disease expressed PD-L1, a numerical difference in PFS favouring atezolizumab was seen across all patient risk factor groups (favourable, intermediate and poor) compared to sunitinib. 

In addition, a pre-defined analysis of patient-reported outcomes (PRO) revealed that the combination of atezolizumab and bevacizumab markedly delayed the time to a worsening of disease symptoms that interfere with day-to-day life compared to sunitinib, (median time to deterioration: 11.3 vs 4.3 months; HR 0.56; 95% CI: 0.46, 0.68) in the ITT population. Due to the study design, pre-defined subgroup analyses and pre-defined PRO analyses were not assessed for statistical significance and are descriptive only. 

This is the second positive phase III study that includes atezolizumab and bevacizumab as part of a treatment regimen. Roche announced on 6 February 2018 that the data will be discussed with global health authorities, including the US Food and Drug Administration and European Medicines Agency. 

Reference

Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). Abstract 578. Presented on 10 February 2018, Genitourinary Cancers Symposium, San Francisco, US.