BACKGROUND: Rare or compound EGFR variants in non-small cell lung cancer (NSCLC) can create substantial therapeutic uncertainty, particularly when accompanied by additional co-alterations with potential resistance implications. In such settings, molecular tumor boards (MTBs) may integrate genomic, functional, and clinical data to guide treatment selection. CASE PRESENTATION: A 59-year-old Caucasian woman was diagnosed with metastatic lung adenocarcinoma involving the lungs, bones, and lymph nodes. Histopathology showed a TTF-1 positive pulmonary adenocarcinoma with low PD-L1 espression. MOLECULAR FINDINGS: Next-generation sequencing identified a compound EGFR alteration consisting of L858R and Q701L, along with additional alterations in PIK3CA, ATM, and CTNNB1 and loss of CDKN2A/B, MLH1 and BAP1. FUNCTIONAL AND MOLECULAR TUMOR BOARD ASSESSMENT: To resolve this uncertainty, the EGFR mutations were recreated in vitro and characterized within national Network Genomic Medicine (nNGM) preclinical platform. In Ba/F3 models, the EGFR L858R/Q701L co-mutation showed sensitivity to first-, second-, and third-generation EGFR tyrosine kinase inhibitors. After integrating the molecular profile, functional data, and clinical context, the institutional MTB recommended in-label therapy with Osimertinib. OUTCOME: Treatment resulted in rapid clinical improvement and a radiologically confirmed partial remission followed by durable disease control for 18 months. Disease progression occurred thereafter, and the patient died 23.4 months after initial diagnosis. CONCLUSION: This case highlights the importance of functional validation and multidisciplinary tumor board discussion in interpreting complex genomic profiles and guiding personalized therapy in NSCLC.
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