Actionable Gene Alterations in Resected Non-Small Cell Lung Cancer: Primary Results From the AGA-R Study

In resected non-small cell lung cancer (NSCLC), molecular testing is currently limited to EGFR mutations and ALK rearrangements, as these guide approved adjuvant therapies. The role of next-generation sequencing (NGS), routinely used in metastatic NSCLC, remains unclear in earlier stages. The prevalence of other driver mutations and their impact on outcomes is not well established.

We retrospectively analyzed clinical, molecular, and survival data from patients (pts) with stage IA-IIIB NSCLC (AJCC 8th) who underwent surgery and NGS at our Institute from January 2020 to December 2023. The primary endpoint was the prevalence of driver alterations. Exploratory analyses assessed recurrence, disease-free survival (DFS), overall survival (OS), and correlation with mutation status.

Of 221 pts, 216 were eligible. Oncogenic alterations were found in 71% (73% in stage I), most commonly KRAS (30%) and EGFR (26%), followed by MET exon 14 skipping (6%), BRAF (4%), HER2 exon 20 mutations (3%), and ALK and RET rearrangements (1%). Alteration distribution differed by sex and smoking status. With a median follow-up of 20 months, 36% of pts experienced recurrence, including 10 stage I cases. Median time to recurrence was 14 months. Recurrence rates were higher in pts with driver mutant NSCLC (39.6%) versus wild-type (29.6%). Highest recurrence was seen in pts with oncogenic fusion positive NSCLC and EGFR exon 20 insertions.

Driver mutations were detected in 70% of resected NSCLC, including stage I. The recurrence patterns observed support integrating NGS into early-stage management and exploring tailored adjuvant therapies, even for stage I tumors.