- 1Dept of Medical Oncology, Virgen del Rocio Teaching Hospital, Instituto de Biomedicina de Sevilla - IBIS, Seville, Spain Dept of Medical Oncology, Pharmacology Unit, AP-HP, Henri Mondor Teaching Hospital, Créteil, France emma@kempf.pro.
- 2Dept of Medical Oncology, Pharmacology Unit, AP-HP, Henri Mondor Teaching Hospital, Créteil, France Université Paris-Est, VIC DHU, Inserm U 955, Team 18, UPEC, Créteil, France.
- 3Dept of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France Paris-Sud University, Inserm U981, Paris, France.
- 4Dept of Medical Oncology, Virgen del Rocio Teaching Hospital, Instituto de Biomedicina de Sevilla - IBIS, Seville, Spain.
Abstract
KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS-mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients' clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step in KRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens.
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