Analysis of outcomes in resected early-stage NSCLC with rare targetable driver mutations

Given advancements in adjuvant treatments for non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)-targeted therapies, it is important to consider postoperative targeted therapies for other early-stage oncogene-addicted NSCLC. Exploring baseline outcomes for early-stage NSCLC with these rare mutations is crucial.

This study aims to assess relapse-free survival (RFS) and overall survival (OS) in patients with resected early-stage NSCLC with rare targetable driver mutations.

This retrospective single-center study identified stage I-III NSCLC patients with rare targetable mutations who underwent curative surgery. Tissue-based molecular profiling identified mutations in KRASG12C, EGFR Exon20, Erb-B2 receptor tyrosine kinase 2 (ERBB2), ALK, ROS1, B-Raf proto-oncogene (BRAF) V600E, mesenchymal-epithelial transition factor (MET) exon14 skipping, and rearranged during transfection (RET). Baseline patient and tumor characteristics, mutation subtype, and TP53 co-mutation were correlated with RFS and OS using Cox regression. The KRASG12C cohort was used as the reference for survival comparisons.

Among 225 patients, mutations included the following: KRASG12C (n = 101, 45%), MET exon 14 skipping (n = 26, 12%), EGFR Exon 20 (n = 25, 11%), ERBB2 (n = 25, 11%), ALK fusion (n = 16, 7%), ROS1 fusion (n = 14, 6%), BRAF V600E mutation (n = 13, 6%), and RET fusion (n = 5, 2%). Five-year survival probabilities were 76% for stage I, 60% for stage II, and 58% for stage III. RFS was shorter across most mutation subgroups compared to KRASG12C, with ROS1 mutations showing significantly poorer RFS (HR 2.70, p = 0.019). By contrast, all mutation subgroups were associated with better OS than KRASG12C. The incidence of brain metastasis was highest in ERBB2 (22% at 5 years). TP53 co-mutation was associated with significantly worse OS (HR 2.35, p = 0.008).

While RFS was poorer for most mutations compared to KRASG12C, OS generally was better, suggesting a potential role for postoperative targeted therapies. These findings warrant further investigation through prospective studies and clinical trials to optimize adjuvant treatment strategies for patients with early-stage NSCLC harboring rare driver mutations.