Nivolumab plus chemotherapy in first-line metastatic non-small-cell lung cancer: results of the phase III CheckMate 227 Part 2 trial.

Background: In CheckMate 227 Part 1, first-line nivolumab plus ipilimumab prolonged overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% versus chemotherapy. We report results from CheckMate 227 Part 2, which evaluated nivolumab plus chemotherapy versus chemotherapy in patients with metastatic NSCLC regardless of tumor PD-L1 expression.

Patients And Methods: Seven hundred and fifty-five patients with systemic therapy-naive, stage IV/recurrent NSCLC without EGFR mutations or ALK alterations were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus chemotherapy or chemotherapy.

Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.

Background: In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC.

Methods: In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy.

Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.

Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3.

Deletions within the 3' non-translated region of Alfalfa mosaic virus RNA4 do not affect replication but significantly reduce long-distance movement of chimeric Tobacco mosaic virus.

Alfalfa mosaic virus (AlMV) RNAs 1 and 2 with deletions in their 3' non‑translated regions (NTRs) have been previously shown to be encapsidated into virions by coat protein (CP) expressed from RNA3, indicating that the 3' NTRs of RNAs 1 and 2 are not required for virion assembly. Here, we constructed various mutants by deleting sequences within the 3' NTR of AlMV subgenomic (sg) RNA4 (same as of RNA3) and examined the effect of these deletions on replication and translation of chimeric Tobacco mosaic virus (TMV) expressing AlMV sgRNA4 from the TMV CP sg promoter (Av/A4) in tobacco protoplasts and Nicotiana benthamiana plants. While the Av/A4 mutants were as competent as the wild-type Av/A4 in RNA replication in protoplasts, their encapsidation, long-distance movement and virus accumulation varied significantly in N.

Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK).

Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor.