Molecular tumor board-guided osimertinib therapy in EGFR L858R/Q701L-mutant lung adenocarcinoma supported by functional validation.

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. 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 expression. 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. 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. 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. This case highlights the importance of functional validation and multidisciplinary tumor board discussion in interpreting complex genomic profiles and guiding personalized therapy in NSCLC.