title: Selumetinib: a promising pharmacologic approach for KRAS-mutant advanced non-small-cell lung cancer.
abstract: Selumetinib is a potent and selective inhibitor of MEK1 and 2 that is currently being clinically developed for the treatment of several human malignancies. Initially administered as free-base suspension, a more convenient Hyd-sulfate capsule formulation has recently been developed. Phase I studies revealed that acneiform dermatitis was the dose-limiting toxicity of both the free-base and capsule formulation given two-times a day at the maximum tolerated doses of 100 and 75 mg, respectively, with the capsule formulation resulting into a significantly higher drug bioavailability. Importantly, as a MEK inhibitor, selumetinib could be particularly effective in tumors with a hyperactivated Ras/Raf/MEK/ERK pathway, which might be the case of KRAS-mutant non-small-cell lung cancers (NSCLCs). Accordingly, a recent randomized Phase II study evaluating docetaxel plus selumetinib or placebo in KRAS-mutant pretreated advanced NSCLC patients has demonstrated a significant improvement in terms of response rate, progression-free survival and patient-reported outcomes in favor of the combination arm. These positive results support further clinical evaluation of selumetinib in NSCLC, and confirmatory ongoing and future trials will assess its role according to KRAS-mutation status and in combination regimens with other targeted agents.
authors: Division of Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, via Dottori 1, 06156 Perugia, Italy.
authors: Giulio
authors: G
authors: Metro
authors: Rita
authors: R
authors: Chiari
authors: Alice
authors: A
authors: Baldi
authors: Verena
authors: V
authors: De Angelis
authors: Vincenzo
authors: V
authors: Minotti
authors: Lucio
authors: L
authors: Crinò
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004353:Drug Evaluation, Preclinical; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors