Targeting KRAS mutated non-small cell lung cancer: A history of failures and a future of hope for a diverse entity

•KRAS mutations are the most common genetic event in lung adenocarcinoma.•The prognostic and predictive value of KRAS mutations is unclear.•Previous attempts to directly target KRAS have been unsuccessful.•A large number of novel agents and combinations are being currently evaluated.

Lung cancer remains the leading cause of cancer-related deaths in both men and women. However, the discovery of several oncogenic driver mutations and the development of immune checkpoint inhibitors resulted in improved clinical outcomes for most patients. Although activating KRAS mutations are the most common recurring molecular events in lung adenocarcinoma, little progress has been made during the past decades with no new agents being approved for this indication. The elucidation of the underlying biology of this diverse patient subgroup offers great potential and renewed hope regarding the rational development, rigorous evaluation and subsequent approval of novel targeted agents and combinations which will effectively suppress compensatory escape routes and the emergence of resistance, issues that have plagued previous attempts. Here, we review in a structured manner all aspects of KRAS positive non-small cell lung cancer, including the molecular biology, clinicopathologic characteristics, the prognostic and predictive value of KRAS mutations, as well as previous and contemporary approaches towards the treatment of this elusive target.