Lung cancer

KRAS mutation targetable for better outcomes in smokers with NSCLC


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 KRASWT. Of the remaining patients with KRAS mutations, 45% had a KRASG12C and 55% had one of nine other KRAS mutations or codon 13.

The study, led by Dr Wanda Cui, found all patients with KRASG12C 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 KRASG12C is an important target in smokers.”

The study also found that patients with KRASG12C mutations had a higher frequency of brain metastases at diagnosis (28%) compared to KRASWT (17 %) and KRASother (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 KRASmut and KRASWT patients, or KRASG12C versus KRASother patients.

Dr Cui said the KRASG12C 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 KRASG12C 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%).”

“KRASG12C 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 KRASG12C targeting therapies needed to occur early in patients’ treatment.

“If KRASG12C covalent inhibitors will be shown to be beneficial, upfront use in first or second line should be considered,” the study said.

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