Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs). While the use of targeted therapies and immune checkpoint inhibitors (CPIs) has drastically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC) in recent years, historic attempts to target KRAS (both direct and indirect approaches) have had little success, and no KRAS-specific targeted therapies have been approved to date for patients in this molecular subset of NSCLC. With the discovery by Ostrem, Shokat, and colleagues of the switch II pocket on the surface of the active and inactive forms of KRAS, we now have an improved understanding of the complex interactions involved in the RAS family of signaling proteins which has led to the development of a number of promising direct KRAS(G12C) inhibitors, such as sotorasib and adagrasib. In previously treated patients with KRAS(G12C)-mutant NSCLC, clinical activity has been shown for both sotorasib and adagrasib monotherapy; these data suggest promising new treatment options are on the horizon. With the stage now set for a new era in the treatment of KRAS(G12C)-mutated NSCLC, many questions remain to be answered in order to further elucidate the mechanisms of resistance, how best to use combination strategies, and if KRAS(G12C) inhibitors will have suitable activity in earlier lines of therapy for patients with advanced/metastatic NSCLC.
- Reck, M.
- Carbone, D. P.
- Garassino, M.
- Barlesi, F.
Keywords
- *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics
- Humans
- *Lung Neoplasms/drug therapy/genetics
- Mutation
- Piperazines
- Proto-Oncogene Proteins p21(ras)/genetics
- Pyridines
- Pyrimidines
- *g12c
- *kras
- *kras(g12c)
- *non-small-cell lung cancer
- Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Merck, Mirati Therapeutics, Inc.,
- Merck Sharp & Dohme, Novartis, Pfizer, Sanofi Aventis, and Roche, outside the
- submitted work. DPC has reported personal fees from GenePlus, Gloria Biosciences,
- Roche, GlaxoSmithKline, Bristol-Myers Squibb, Daiichi Sankyo, Boehringer Ingelheim,
- Seattle Genetics, Flame Biosciences, AstraZeneca, Pfizer/Eisai, Bristol-Myers Squibb
- K.K., Janssen, Novocure, and Piper Sandler and has received advisory board fees from
- GlaxoSmithKline, Pfizer, Janssen, EMD Serono/Merck, G1 Therapeutics (Intellisphere),
- Gritstone Oncology, Inivata, Roche China, Oncocyte, Loxo Oncology, Merck, and Merck
- Sharp & Dohme and has received advisory board fees from OncoHost™, outside the
- submitted work. MG has reported advisory boards and speaking engagements for
- Janssen, Daiichi Sankyo, Seattle Genetics Inc., Sanofi-Aventis, Merck Sharp & Dohme,
- GlaxoSmithKline, Bayer, Takeda, Inivata, Incyte, Celgene, Pfizer, Roche, and
- Bristol-Myers Squibb, and has received research funding from Exelixis, MedImmune,
- Ipsen, Bayer, Bristol-Myers Squibb, Roche, Pfizer, Incyte, Tiziana Life Sciences,
- Clovis Oncology, Merck-Serono, Merck Sharp & Dohme, Spectrum Pharmaceuticals, Inc.,
- and Blueprint Medicines, and has received nonfinancial support from Lilly and Merck
- Sharp & Dohme, outside the submitted work. FB has reported consultancy and honoraria
- received from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, F.
- Hoffmann–La Roche Ltd, Novartis, Merck, Merck Sharp & Dohme, Pierre Fabre, Pfizer,
- and Takeda, outside the submitted work.
