Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.

BACKGROUND: A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma. METHODS: In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821. FINDINGS: Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation. INTERPRETATION: Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma. FUNDING: F Hoffmann-La Roche Ltd and Genentech Inc.

Discovery of {4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetic acid (GSK726701A), a novel EP4 receptor partial agonist for the treatment of pain.

A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.

Erlotinib Plus Bevacizumab Phase ll Study in Patients with Advanced Non-small-Cell Lung Cancer (JO25567): Updated Safety Results.

INTRODUCTION: The phase II JO25567 study compared the efficacy and safety of erlotinib plus bevacizumab vs. erlotinib alone as first-line therapy for advanced epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). OBJECTIVE: Our objective is to provide updated analyses of safety and the assessment of manageability of specific adverse events. METHODS: Patients with stage IIIB/IV or recurrent, non-squamous, EGFR mutation-positive NSCLC were randomized to receive erlotinib plus bevacizumab or erlotinib. The primary endpoint was progression-free survival. Adverse event frequency rates, predictability and manageability, reasons for discontinuation, time to onset, and outcomes of specific adverse events were analyzed. RESULTS: The safety analysis population comprised 152 randomized patients (75 erlotinib plus bevacizumab; 77 erlotinib) who received at least one dose of study drug between February 2011 and March 2012. There was no difference in overall incidence of serious adverse events between arms, but more grade 3 or higher adverse events were reported with erlotinib plus bevacizumab (90.7%) than with erlotinib (53.2%), primarily due to grade 3 hypertension. Hypertension was controllable with antihypertensive medications in most cases. Proteinuria and bleeding were also more frequently reported with erlotinib plus bevacizumab than with erlotinib but were manageable and did not lead to early discontinuations. CONCLUSIONS: The addition of bevacizumab to erlotinib prolonged progression-free survival in EGFR mutation-positive NSCLC. Follow-up safety data were consistent with the known safety profiles of both erlotinib and bevacizumab in NSCLC; this combination appeared to be manageable, and treatment was well tolerated. JapicCTI-111390.