KRASG12C-Mutant NSCLC Likely Smoking-Related, Targetable by Brain Metastasis Therapies

By Marilynn Larkin

July 09, 2020

NEW YORK (Reuters Health) - KRASG12C-mutant non-small-cell lung cancer (NSCLC) appears to be smoking-related and is likely targetable by inhibitors that can delay or prevent brain metastasis, according to an analysis of real-world outcomes.

"Currently, the majority of druggable oncogene-driven NSCLCs occur in non-smokers/light ex-smokers," Dr. Wanyuan Cui of the Peter MacCallum Cancer Centre in Melbourne told Reuters Health by email. "However, as promising covalent KRASG12C inhibitors continue to develop, it is crucial for all patients with NSCLC to undergo early comprehensive genomic profiling, regardless of smoking history, to look for this important targetable mutation."

Dr. Cui and colleagues analyzed data from patients enrolled in the Thoracic Malignancies Cohort between 2012 to 2019 with recurrent/metastatic non-squamous NSCLC, available KRAS results, and without EGFR/ALK/ROS1 gene aberrations. They compared clinicopathologic features, treatment and overall survival for KRAS G12C, KRAS wildtype (KRASwt), KRAS-mutated (KRASmut); and other KRAS (KRASother) mutations.

As reported in Lung Cancer, among 1,386 NSCLC patients, 1,040 were excluded due to non-metastatic/recurrent; unknown KRAS status; ALK/EGFR/ROS1-positive status; or duplicates.

Overall, 346 patients were analyzed: 144 (42%) were KRASmut, of whom 65 (45%) were KRAS G12C. All patients with KRASG12C were active or ex-smokers, versus 92% of KRASother and 83% of KRASWT.

The prevalence of brain metastases during follow-up was similar between KRASmut and KRASwt (33% vs. 40%), and KRASG12C and KRASother (40% vs. 41%).

The proportion of patients receiving one or multiple lines of systemic therapy was comparable and overall survival was similar between KRASmut and KRASWT, and KRASG12C and KRASother.

The authors conclude, "40% of patients with KRASG12C NSCLC developed brain metastasis during follow up. Therefore, in this group of patients, treatments with good intracranial penetration have important implications for long-term disease control. While we did not observe any prognostic impact of KRASG12C mutations, the development of KRASG12C targeted therapies, which have shown promising early efficacy in KRASG12C NSCLC, are expected to improve outcomes in the population."

Dr. Cui said, "Parallel to the lessons learned from EGFR- and ALK-aberrant NSCLC, agents that are effective for existing brain metastases, and that prevent or delay new brain metastases will be valuable for targeting KRASG12C."

"We did not find differences in overall survival between KRASG12C and KRASother NSCLC, similar to a previous U.S. study, but different to a prior European study," she added. "Patients in our study were predominantly Caucasian (88%), and therefore our findings may not be generalizable to patients of different ethnicities globally."

Dr. Joshua Sabari, an oncologist at NYU Langone Perlmutter Cancer Center in New York City who is involved in studies of KRASG12C mutation inhibitors, told Reuters Health, "In the era of novel, active, and highly-potent KRASG12C inhibitors such as MRTX849 and AMG510, data from this study support the development of targeted therapeutics in this population."

Specifically, he said by email, the study findings "solidify that KRASG12C is a common alteration worthy of targeting. All patients identified to have KRASG12C mutations were current or former smokers, in line with what I see in my clinical practice."

"The activity of the KRAS G12C inhibitors in the central nervous system remains unknown," he added. "Intracranial response rate will be critical for the successful development of these agents, as over one quarter of patients in this study presented with brain metastases at initial diagnosis."

Like Dr. Cui, he said, "These data solidify the importance of novel KRASG12C inhibitors currently being investigated in the clinic."

SOURCE Lung Cancer, online June 26, 2020.