The European Medicines Agency review of the initial application of atezolizumab and the role of PD-L1 expression as biomarker for checkpoint inhibitors.

Immune checkpoint inhibitors have revolutionised cancer therapeutics. Translational research evaluating the role of biomarkers is essential to identify the ideal target population for these drugs. From a regulatory perspective, the identification of biomarkers and diagnostic assays is strongly encouraged by the European Medicines Agency (EMA). The aim of this article is to analyse the role of programmed death-ligand 1 (PD-L1) expression as a predictive biomarker in relation to the data submitted for the initial assessment of atezolizumab, a monoclonal antibody targeting human PD-L1. On 20 July 2017, atezolizumab was granted a marketing authorisation valid throughout the European Union (EU) for adult patients with (i) locally advanced or metastatic non-small-cell lung cancer (NSCLC) after chemotherapy and (ii) locally advanced or metastatic urothelial carcinoma (UC) after chemotherapy or cisplatin-ineligibility. Initially, these indications were not restricted by the level of PD-L1 expression, but preliminary data from an ongoing phase III trial in patients with UC led to a restriction in the UC indication to cisplatin-ineligible patients whose tumours have ≥5% PD-L1 expression. Still, the role of PD-L1 expression as predictive biomarker for atezolizumab therapy remains inconclusive and further research is needed. Data in this paper came from the scientific review leading to the initial regulatory approval of atezolizumab in the EU and its complementary application for indication (EMEA/H/C/004143/II/0010). The full scientific assessment report and product information are available on the EMA website (www.ema.europa.eu).

A new Q/QS pattern on the resting electrocardiogram is associated with impaired insulin secretion and a poor prognosis in elderly men independently of history of myocardial infarction.

OBJECTIVES: To evaluate risk factors and prognosis of subjects who had developed a new Q/QS pattern on the resting electrocardiogram (ECG) in relation to history of myocardial infarction (MI). DESIGN: Cross-sectional and prospective population-based cohort study. SETTING: Uppsala, Sweden. SUBJECTS: In 1970-73, all 50-year-old men in Uppsala, were invited to participate in a health survey aimed at identifying risk factors for cardiovascular disease. The present study included the 1221 subjects who also were re-examined at age 70. RESULTS: Subjects with a new Q/QS pattern on the resting ECG at age 70 were characterized by impaired insulin secretion compared with those without Q/QS, and a higher prevalence of diabetes compared with the control group. In Cox proportional hazard analysis a new Q/QS pattern at age 70 was a significant predictor of cardiovascular mortality (hazard ratio : 1.67, 95% CI: 1.22-2.26) and total mortality (hazard ratio: 1.31, 95% CI: 1.04-1.62) (after age 70) during 9.4 years follow-up, also when adjusted for other risk factors and MI diagnosis. CONCLUSION: The finding of a new Q/QS pattern on the resting ECG, regardless of history of MI was associated with impaired insulin secretion and was an independent predictor of total and cardiovascular mortality. Therefore, these subjects must be given a high priority to preventive measures against both coronary heart disease and diabetes.