Sotorasib: A Review in KRAS G12C Mutation-Positive Non-small Cell Lung Cancer

Target Oncol. 2022 Nov;17(6):727-733. doi: 10.1007/s11523-022-00922-w. Epub 2022 Oct 31.

Abstract

Sotorasib (LUMAKRAS™ in the USA and LUMYKRAS™ in the EU) is an orally active, first-in-class G12C-mutant KRAS (KRASG12C) inhibitor. By binding irreversibly to KRASG12C, sotorasib inhibits downstream signalling pathways which are associated with cell growth and differentiation. Sotorasib is indicated for the treatment of adults with advanced, previously treated, KRAS G12C mutation-positive non-small cell lung cancer (NSCLC) in multiple countries, including the countries of the EU and the USA. A clinically relevant objective response rate was observed in patients with KRAS G12C mutation-positive NSCLC during the primary analysis and in an updated analysis of the phase I/II CodeBreaK 100 trial. Furthermore, a clinically relevant response duration was reported in updated analyses of the trial. Sotorasib has a manageable tolerability profile, with permitted dose modifications to manage toxicity. In summary, sotorasib is a promising KRASG12C inhibitor that increases the available treatment options for patients with KRAS G12C mutation-positive NSCLC who were previously treated with platinum-based chemotherapy and/or immunotherapy.

Plain language summary

KRAS is a protein that is involved in cell signalling pathways, including those that are associated with cell growth and differentiation. KRAS mutations are detected in 23% of patients with non-small cell lung cancer (NSCLC), with the G12C mutation being the most common. G12C-mutant KRAS (KRASG12C) is kept in an activated state, which is associated with cancer. Sotorasib (LUMAKRAS™ in the USA and LUMYKRAS™ in the EU), which is taken orally once daily, is the first approved drug that inhibits KRASG12C; it permanently binds to KRASG12C and locks it in an inactivated state. Sotorasib is approved for adults who have advanced, previously treated, KRAS G12C mutation-positive NSCLC. In a clinical trial in patients with KRAS G12C mutation-positive NSCLC, a clinically relevant proportion of patients responded to sotorasib treatment. Furthermore, the duration of effectiveness with sotorasib was considered to be clinically relevant. Adverse reactions with sotorasib treatment were manageable; the dose may be decreased and/or sotorasib treatment may be temporarily stopped to manage adverse reactions. Overall, sotorasib is a promising treatment option for patients with KRAS G12C mutation-positive NSCLC who have received at least one prior systemic therapy.

Publication types

  • Review

MeSH terms

  • Adult
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Mutation
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism

Substances

  • sotorasib
  • Proto-Oncogene Proteins p21(ras)
  • KRAS protein, human

Associated data

  • figshare/10.6084/m9.figshare.21086737