Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein1. One approach to addressing this challenge is to define frequently co-occurring mutations with KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function (LOF) mutations in Kelch-like ECH-associated protein 1 (KEAP1)2-4, a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response5-10. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR/Cas9-based approach in a mouse model of Kras-driven LUAD we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyper-activates Nrf2 and promotes Kras-driven LUAD. Combining CRISPR/Cas9-based genetic screening and metabolomic analyses, we show that Keap1/Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for sub-stratification of human lung cancer patients with KRAS-KEAP1 or -NRF2-mutant tumors as likely to respond to glutaminase inhibition.

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Summary. Background: The incidence of venous thromboembolism (VTE) by lung cancer histology and stage is unknown. Objectives: To determine the incidence of VTE and the risk factors associated with development of VTE in a large population-based study of patients with non-small cell and small cell lung cancer. Methods: The California Cancer Registry was merged with the Patient Discharge Data Set to determine the incidence of VTE among lung cancer cases diagnosed between 1993 and 1999. Results: Among 91 933 patients with newly diagnosed lung cancer, the 1-year and 2-year cumulative VTE incidences were 3.0% and 3.4%, respectively, with a person-time rate of 7.2 events/100 patientyears during the first 6 months. The 1-year incidence of VTE was significantly increased in comparison to the general population [standardized incidence ratio = 21.2, 95% confidence interval (CI) = 20.4-22.0]. In a multivariate model, significant predictors of developing VTE within 1 year of nonsmall cell lung cancer (NSCLC) diagnosis were: younger age, the number of chronic medical comorbidities [hazard ratio (HR) = 2.8 if 3 vs. 0, 95% CI = 2.5-3.1], advancing cancer stage (HR = 4.0 for metastatic vs. local disease, 95% CI = 3.4-4.6) and adenocarcinoma histology (HR = 1.9 vs. squamous cell, 95% CI = 1.7-2.1). In multivariate models, VTE was a significant predictor of death within 2 years for both NSCLC and small cell lung cancer (SCLC), HR = 2.3, 95% CI = 2.2-2.4, and HR = 1.5, 95% CI = 1.3-1.7, respectively. Conclusions: Approximately 3% of lung cancer patients developed VTE within 2 years. The diagnosis of VTE was associated with a higher risk of death within 2 years for NSCLC and SCLC.

Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.