KRASᴳ¹²ᶜ Mutation–Positive Advanced NSCLC

Lung cancer is the second most frequent cancer in both men and women, and the leading cause of cancer death on the globe.¹ Non–small-cell lung cancer (NSCLC) accounts for approximately 84% of lung cancer cases.¹ The majority of patients with NSCLC in the United States have advanced disease and a dismal prognosis.¹

NSCLC has a high prevalence of mutations in the RAS viral oncogene family of proto-oncogenes, with the KRAS homolog being the most often mutated isoform.¹ KRAS mutations are detected in 20% to 40% of NSCLC cases in Western cultures.² They are more common in Western populations than in Asian populations, and more prevalent in smokers than nonsmokers.²

Despite the fact that KRAS mutations in NSCLC tumors have been detected for more than 30 years, they have long been regarded as “untreatable,” and until recently no licensed targeted therapy existed.²

We now have a better understanding of the complex interactions involved in the RAS family of signaling proteins thanks to the discovery of the switch II pocket on the surface of active and inactive forms of KRAS, which has led to the development of a number of promising direct KRAS^G12C inhibitors, such as sotorasib and adagrasib (MRTX-849).³ Clinical activity has been demonstrated for sotorasib and adagrasib monotherapy in previously treated patients with KRAS^G12C mutation–positive NSCLC; these findings have led to the development of new targeted therapeutic options.³

Sotorasib is a covalent KRAS^G12C inhibitor that binds to the switch II pocket within mutant KRAS, trapping it in an inactive form irreversibly and selectively.³ In the CodeBreaK 100 study, sotorasib monotherapy was tested in patients with previously treated, locally progressed, or metastatic cancers carrying a KRAS^G12C mutation.³ Findings from this study led to its regulatory approval in the United States in 2021. Adagrasib is another KRAS^G12C inhibitor in development.³

Although sotorasib and adagrasib have shown to be effective in treating individuals with lung adenocarcinomas and KRAS^G12C mutations, numerous uncertainties remain. What are the mechanisms of inhibitor resistance, and how may a greater understanding of these mechanisms help with patient selection or combination strategies?³

References

1. Spira AI, Tu H, Aggarwal S, et al. A retrospective observational study of the natural history of advanced non-small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease. Lung Cancer. 2021;159:1-9.
2. Sebastian M, Eberhardt WEE, Hoffknecht P, et al; for the CRISP Registry Group. KRAS G12C-mutated advanced non-small cell lung cancer: a real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315). Lung Cancer. 2021;154:51-61.
3. Reck M, Carbone DP, Garassino M, Barlesi F. Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches. Ann Oncol. 2021;32:1101-1110.