Insights on Concomitant Driver Alterations in EGFR-Mutated NSCLC

By: Julia Cipriano, MS
Posted: Tuesday, October 15, 2024

Renhua Guo, MD, of the First Affiliated Hospital of Nanjing Medical University, China, and colleagues provided a profile of EGFR-positive non–small cell lung cancer (NSCLC) with concomitant driver mutations. Their findings, which were published in JCO Precision Oncology, may aid in the development of individually tailored therapeutic strategies.

“Our observations…further support the value of next-generation sequencing,” the investigators concluded. “Focusing on actionable alterations, our work…illustrates the importance of investigating concomitant driver alterations in EGFR-positive NSCLC [and] sets the stage for future research on a broader range of co-occurring pathogenic alterations.”

The investigators retrospectively reviewed next-generation sequencing data from more than 10,000 Chinese patients with classical EGFR-positive NSCLC who had not started targeted therapy. A validation cohort comprised 136 patients from The Cancer Genome Atlas database.

A total of 334 patients (3.1%) were found to harbor concomitant driver mutations; those in KRAS (53.9%), ERBB2 (24.3%), MET (16.5%), and BRAF (3.3%) were identified most frequently. According to the investigators, KRAS variations in concomitant vs single drivers frequently exhibited hyperexchange characteristics (25.6% vs 8.2%; P < .001). There was an observed increase in the incidence of ERBB2 amplification (40.7% vs 16.5%; P < .001) and p.S310F/Y mutations (44.4% vs 4.3%; P < .001) in EGFR/ERBB2 vs ERBB2 drivers. Compared with MET single drivers, EGFR/MET drivers were found to have a higher frequency of MET amplification (71.4% vs 43.3%).

Concomitant drivers had a median of four additional mutations, with TSC2 (4.0%), CD274 (1.2%), and TP53 (63.2%) being the most frequently co-altered genes. Based on a clonality analysis, EGFR mutations were more likely to appear as clonal events, whereas the co-drivers tended to be subclonal. Patients with concomitant drivers or concomitant MET amplification were found to have a worse prognosis.

Disclosure: Dr. Guo reported no conflicts of interest. For full disclosures of the other study authors, visit ascopubs.org.

JCO Precision Oncology