Targeting KRAS in NSCLC: Old Failures and New Options for “Non-G12c” Patients

SIMPLE SUMMARY: Non-small cell lung cancer (NSCLC) with Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) mutation comprises a specific subgroup of patients who are particular in terms of several clinical and molecular aspects. Indeed, there is a clear medical need to find specific and effective treatments for these patients, since KRAS mutation positive NSCLC has demonstrated to be—in some cases—less responsive to standard therapies. For many years, targeting KRAS mutations has been considered an impossible challenge. The scenario is further complicated by the possible role of co-mutations that could influence both tumour microenvironment and drug response. However, some promising preclinical and clinical data are expected to change the treatment landscape of this hard-to-treat disease. Indeed, tumors harbouring G12C mutations could now be effectively targeted with specific inhibitors based on clinical trial results. This review aims to provide a clinical update on potential therapies for advanced NSCLC with KRAS mutations other than the more common G12C, for which good results have already been achieved, particularly focusing on clinical trials, molecules and mechanisms currently under investigation. ABSTRACT: Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene mutations are among the most common driver alterations in non-small cell lung cancer (NSCLC). Despite their high frequency, valid treatment options are still lacking, mainly due to an intrinsic complexity of both the protein structure and the downstream pathway. The increasing knowledge about different mutation subtypes and co-mutations has paved the way to several promising therapeutic strategies. Despite the best results so far having been obtained in patients harbouring KRAS exon 2 p.G12C mutation, even the treatment landscape of non-p.G12C KRAS mutation positive patients is predicted to change soon. This review provides a comprehensive and critical overview of ongoing studies into NSCLC patients with KRAS mutations other than p.G12C and discusses future scenarios that will hopefully change the story of this disease.