What is the significance of a KRAS (Kirsten Rat Sarcoma virus) mutation?

From the Guidelines

KRAS mutations, particularly the G12C mutation, can be effectively targeted with small molecule inhibitors such as sotorasib and adagrasib, which have shown significant clinical benefit in patients with advanced non-small cell lung cancer (NSCLC) harboring this mutation. These mutations occur in approximately 25% of all cancers, with high frequencies in pancreatic, colorectal, and lung adenocarcinomas 1. KRAS mutations lead to constitutive activation of the RAS/MAPK signaling pathway, promoting uncontrolled cell growth and survival. The most common mutations occur at codons 12,13, and 61, with G12C being especially important in non-small cell lung cancer.

Key Points

• KRAS mutations are prognostic of poor survival when compared to patients with tumors without KRAS mutation 1
• Mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy 1
• Sotorasib and adagrasib have been shown to have activity in patients with KRAS G12C mutations, with sotorasib demonstrating a 34% reduction in the risk of disease progression or death compared to docetaxel in the phase III CodeBreaK 200 study 1
• KRAS mutation status should be determined through molecular testing of tumor tissue or liquid biopsy before initiating treatment, as it significantly impacts prognosis and therapeutic options

Treatment Options

• Sotorasib (Lumakras) and adagrasib are oral medications that target the G12C mutation specifically, and are typically administered at doses determined by a patient's oncologist based on cancer type and stage 1
• These medications have received FDA approval for clinical use following first-line standard chemotherapy and/or immunotherapy in advanced NSCLC, offering another effective option for this group of patients who often have an especially poor prognosis 1

From the FDA Drug Label

The treatment effect in the all-randomized population for PFS was driven by treatment effects limited to patients who have K-Ras wild-type tumors. There is no evidence of effectiveness in the subgroup of patients with K-Ras mutant tumors

• K-Ras mutation status is a factor in the effectiveness of cetuximab.
• Patients with K-Ras wild-type tumors may benefit from cetuximab treatment.
• There is no evidence of effectiveness in patients with K-Ras mutant tumors.
• The presence of a K-Ras mutation may indicate a lack of response to cetuximab treatment 2

From the Research

Kras Mutation Overview

• The KRAS gene is one of the most common mutated oncogenes in solid tumors 3, 4, 5.
• KRAS mutations are complex, with various subtypes, and the development of inhibitors targeting non-G12C subtypes is still at an early stage 3, 4.
• The monotherapy of KRAS inhibitors has accumulated possible resistance, acquiring the exploration of combination therapies or next-generation KRAS inhibitors 3, 5, 6.

Therapeutic Strategies

• Chemotherapy was the initial recommended therapy for KRAS-mutant cancer patients, which was then replaced by or combined with immunotherapy 3.
• KRAS G12C inhibitors, such as Sotorasib, have been approved by the Food and Drug Administration (FDA) and have shown significant efficacy in multiple clinical studies 3, 5, 7, 6.
• Sotorasib is currently recognized as the newest clinically targeted agent with apparent clinical efficacy in NSCLC patients with KRAS G12C mutations 7, 6.

Clinical Advances and Challenges

• The efficacy of the first-generation KRAS inhibitor is modest, but with scientific advancement, KRAS G12C inhibitors with higher potency are on the horizon 4.
• Novel therapeutic approaches targeting other KRAS subvariants are also being explored in clinical trials with encouraging early data 4, 5.
• Clinical data suggests that sotorasib monotherapy has significant efficacy in NSCLC patients with the KRAS G12C mutation and tolerable toxicity 6.