Lung Cancer: Assessment, Treatment

KRAS: Kirsten RAT Sarcoma Viral Oncogenic Homolog

Background: KRAS is the most frequently mutated oncogene in human cancers and is often associated with resistance to targeted therapies and poor outcomes. KRAS acts like a switch to activate downstream signaling pathways, including MAPK and PI3K, involved in cell proliferation, cell cycle regulation, metabolic changes, cell survival and cell differentiation. Dysregulated KRAS has been associated with tumor growth, cancer cell survival, invasion and migration. Alterations in KRAS account for approximately 25% of mutations in NSCLC and are found exclusive of EGFR and ALK mutations in treatment-naive patients.

Clinical Features Associated: Caucasian or African ancestry, males, smoking history, history of exposure asbestos, adenocarcinoma histology

Most Common Alterations:

Point Mutations: The most common point mutations are identified in codons 12 and 13 and include G12C, G12V, and G12D. Conflicting data exists in the literature regarding the prognostic value of mutational subtypes, with some finding worse prognosis associated with G12C and G12V and others finding no differences.
- The most common point mutation is KRAS G12C, accounting for around 39% of KRAS mutations and 12% to 13% of all mutations identified in NSCLC. G12C is often associated with smokers, while G12D is more common in nonsmokers.

Distribution and frequency of KRAS mutations in NSCLC

Figure 5. Distribution and frequency of KRAS mutations in Non-Small Cell Lung Cancer.

Adapted from: Reck M, et al. Ann Oncol. 2021;doi:10.1016/j.annonc.2021.06.001.

Co-mutational Partners: The most common mutational partners include TP53 (40%), STK11/LKB1 (32%), and CDKN2A (19.8%). The presence of these co-mutational partners has been associated with altered response rates to therapy. STK11/LKB1 has been linked to greater resistance to immune checkpoint inhibitors in NSCLC. TP53/KRAS co-mutation is associated with enhanced PD-L1 expression; therefore, patients have seen clinical benefit from PD-1 inhibitors. Of note: STK11/LKB1 and CDKN2A have been associated with worse prognosis compared with TP53

FDA-Approved Targeted Therapies:

Sotorasib (Lumakras, Amgen):
- Irreversible RAS GTPase inhibitor received accelerated approval by the FDA in 2021 for adult patients withKRAS G12C mutated locally advanced or metastatic NSCLC and at least one prior line of systemic therapy. Approval was based on the CodeBreak 100, multicenter clinical trial of patients with locally advanced or metastatic KRAS G12C mutated NSCLC. An ORR of 36% was found with a median duration of response at time of approval of 10 months
- Most common adverse events: diarrhea, joint and muscle pain, nausea, fatigue, liver damage, cough
Adagrasib (MRTX849, Mirati Therapeutics Inc.):
- Highly selective inhibitor ofKRAS G12C received breakthrough designation by the FDA in 2021 for patients with KRAS G12C-mutated locally advanced or metastatic NSCLC and at least one prior line of systemic therapy. This designation was based on the preliminary results from the phase 1/2 KRYSTAL-01 clinical trial of patients with advanced NSCLC who harbor the KRAS G12C mutation and progressed on prior systemic therapy. An ORR of 64% with 45% of patients experiencing a partial response was found at time of designation.
- Most common adverse events: diarrhea, joint and muscle pain, nausea, fatigue, liver damage, cough

Previous Section Next Section

KRAS: Kirsten RAT Sarcoma Viral Oncogenic Homolog

Notice