Asians bare unique genetic profile of KRAS-mutated NSCLC

Nonsmall cell lung cancer (NSCLC) with mutations in the KRAS gene show a unique genetic and clinical profile in Asian patients relative to Western counterparts, according to a recent study.

KRAS-mutated NSCLC appears common even among Asian never smokers and is predominated by the G12D subtype as opposed to G12C, the most commonly documented mutational subtype in Western cohorts.

“Although treatment outcomes with conventional chemotherapy are reasonable and the efficacy of immunotherapy looks promising, the unmet need remains high for Asian patients with KRAS-mutated NSCLC, emphasizing the need for improved biomarker stratification and novel therapeutic approaches,” the researchers said.

Of the 216 patients with KRAS-mutated NSCLC (mean age at initial diagnosis 63.1 years, 70.8 percent men), 54.2 percent were Korean, 25.9 percent Chinese, 13.0 percent Japanese, 5.6 percent Indian, and 1.4 percent Malay. Most (84.7 percent) had been diagnosed with de novo metastatic disease, and 27.0 percent presented with brain metastases. [JTO Clin Res Rep 2022;3:100261]

The most common KRAS mutational subtype was G12D, which was detected in 25.5 percent of patients, followed closely by G12C (24.5 percent) and G12V (19.4 percent). While most NSCLC patients in the cohort were former or current smokers (65.7 percent), never smokers comprised 34.3 percent of the current study sample, a proportion much higher than that observed in Western cohorts. [Clin Cancer Res 2012;18:6169-6177; J Thorac Oncol 2019;14:876-889]

Among never smokers, KRAS G12D was the most dominant mutational subtype (44.6 percent), while G12C was found to be most frequent among current and former smokers (32.4 percent).

All patients received first-line therapy for which cytotoxic chemotherapy was the most common choice (69.9 percent). Other reported first-line interventions included targeted therapy (13.0 percent), immunotherapy (6.5 percent), and their combination (2.8 percent).

The median classical overall survival (OS) was 17.5 months. No notable difference in OS was reported according to KRAS mutational subtype or smoking status. In contrast, treatment modality appeared to significantly affect survival. Those treated with immunotherapy showed significantly better OS (hazard ratio [HR], 0.58, 95 percent confidence interval [CI], 0.41–0.81; p=0.001) than those who did not receive such treatment.

“To the best of our knowledge, this is the largest study published to date that comprehensively analysed patients with metastatic KRAS-mutated NSCLC from a multicentre cohort in Asia,” the researchers said. Eight academic centres across the region participated, including the Samsung Medical Centre in Seoul, the National Cancer Centre in Singapore, and the Guangdong Lung Cancer Institute in China.

“Together with G12D being the most common KRAS mutational subtype, not only among never smokers but in the overall population, these findings suggest that KRAS-mutated lung cancer in Asian patients may be driven by factors other than tobacco smoking and that the distinct biology of Asian patients with KRAS-mutated NSCLC warrants further investigation,” they added.