Purpose: We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods: This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight <50 kg) every 2 weeks plus oral apatinib 250 mg daily. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC) per RECIST v1.1. Results: Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred. Conclusions: Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients. See related commentary by Pinato et al., p. 908

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Objectives Our previous studies indicated that highly selective kappa opioid receptor (KOR) agonists could protect the brain, indicating an important role of KOR agonist in brain ischemia. In this study, we investigated the role and related mechanisms of KOR agonists in brain ischemia in a middle cerebral artery occlusion (MCAO) mouse model. Subjects and Interventions The MCAO model was established by 120 minutes of ischemia followed by 24 h reperfusion in male adult mice. Various doses of salvinorin A (SA), a highly selective and potent KOR agonist, were administered intranasally 10 min after initiation of reperfusion. Norbinaltorphimine (2.5 mg/kg, i.p.) as a KOR antagonist was administered in one group before administration of SA (50 µg/kg) to investigate the specific role of KOR. After 24 h reperfusion, neurobehavioral outcome was determined. Infarct volume, KOR expression, and Evans blue extravasation in the brain were determined. Immunohistochemistry and western blot were performed to detect the activated caspase-3, IL-10 and TNF-alpha levels to investigate the role of apoptosis and inflammation. Main Results KOR expression was elevated significantly in the ischemic penumbral area compared to that in the non-ischemic area. SA reduced infarct volume and improved neurological deficits dose-dependently. SA at the dose of 50 µg/kg reduced Evans blue extravasation, suggesting reduced impairment of the blood-brain barrier, and decreased the expression of cleaved casepase-3, IL-10 and TNF-alpha in the penumbral areas. All these changes were blocked or alleviated by norbinaltorphimine. Conclusions KORs were up-regulated and played a critical role in brain ischemia and reperfusion. KOR activation could potentially protect the brain and improve neurological outcome via blood brain barrier protection, apoptosis reduction and inflammation inhibition.