The most common of the KRAS mutations in non-small cell lung cancer (NSCLC) has been flagged as potentially targetable and may therefore help improve patient outcomes.

A real-world study from the Thoracic Malignancies Cohort at Peter MacCallum Cancer Centre comprised 346 patients with metastatic or recurrent non-squamous NSCLC who had available KRAS mutation test results and did not have an EGFR, ALK, or ROS1 gene aberration.

The study found 58% of patients were KRAS^WT. Of the remaining patients with KRAS mutations, 45% had a KRAS^G12C and 55% had one of nine other KRAS mutations or codon 13.

The study, led by Dr Wanda Cui, found all patients with KRAS^G12C mutant NSCLC were current or former smokers.

“We usually associate oncogenic driven NSCLC (eg EGFR, ALK and ROS1) with never or light ex smokers,” Dr Cui told the limbic.

“Therefore this finding is important as we need to comprehensively sequence all NSCLC, not just non smokers, given KRAS^G12C is an important target in smokers.”

The study also found that patients with KRAS^G12C mutations had a higher frequency of brain metastases at diagnosis (28%) compared to KRAS^WT (17 %) and KRAS^other (19 % ) although this difference was not statistically significant.

“Brain mets are common and thus current / future drug development should focus on improved intracranial activity as seen with 2nd/3rd generation EGFR and ALK inhibitors,” Dr Cui said.

There were no other significant differences in clinicopathologic characteristics or in survival between KRAS^mut and KRAS^WT patients, or KRAS^G12C versus KRAS^other patients.

Dr Cui said the KRAS^G12C mutation was important given it was found in 10%-15% of all NSCLC.

“KRAS mutations are the most common oncogenic driver found in NSCLC (approx 25%) and KRAS^G12C is the most common KRAS variant (approx 40%-50% of all KRAS mutations).”

“This is not a small proportion, given 1 in 10 patients of a common cancer will have this mutation, and it is more prevalent than some of the other current standard druggable oncogenes in NSCLC such as ROS1 fusions (1-2%) and ALK fusions (5%).”

“KRAS^G12C is common. It is now potentially targetable. It should be looked for in NSCLC,” she said.

She added that the small molecule covalent inhibitors were currently in phase 3 trials.

The study noted that mutation testing and consideration of KRAS^G12C targeting therapies needed to occur early in patients’ treatment.

“If KRAS^G12C covalent inhibitors will be shown to be beneficial, upfront use in first or second line should be considered,” the study said.