Targeting rare oncogenic mutations in resectable non-small cell lung cancer: emerging perioperative strategies.

Advances in molecular oncology have identified a range of rare but actionable oncogenic alterations in non-small cell lung cancer (NSCLC), such as EGFR exon 20 insertions, MET exon 14 skipping, RET, ROS1, and NTRK fusions, along with BRAF V600E, KRAS G12C, and HER2 mutations. While these alterations collectively account for approximately 20% of NSCLC, evidence guiding perioperative treatment in this population remains limited. This review synthesizes current knowledge and ongoing research regarding neoadjuvant and adjuvant strategies for resectable NSCLC harboring rare mutations. We highlight the clinical efficacy of targeted therapies in advanced stage and explore their potential utility in perioperative settings. Preliminary data suggest that molecular subtype-specific approaches may optimize outcomes, particularly as traditional chemoimmunotherapy appears less effective in several of these genotypes due to immune-cold tumor microenvironment. Moreover, we discuss the evolving role of circulating tumor DNA and minimal residual disease as biomarkers for perioperative treatment guidance. There are several challenges including the lack of randomized perioperative trials, heterogeneity in pathological response assessment, and uncertainty regarding the reliability of surrogate endpoints. With the increasing integration of next-generation sequencing into the standard diagnostic workup of early-stage NSCLC, biomarker-directed perioperative strategies supported by prospective clinical trials enriched for specific genotypes are critical to achieving sustained clinical outcomes in these patient subgroups with rare targetable alterations.