EGFR appears to be, and BRAF may be too

Introduction: Acquired BRAF alterations are an uncommon mechanism of resistance to EGFR inhibitors in non-small cell lung cancer (NSCLC). The emergence of BRAF V600E together with the apparent loss of the original EGFR mutation is exceptionally rare and has been only sporadically reported. Case presentation: A 69-year-old never-smoker was diagnosed with stage IB lung adenocarcinoma in 2020 and underwent lobectomy. Following metastatic recurrence in 2022, retrospective molecular testing of the surgical specimen identified an EGFR L858R mutation, and treatment with osimertinib was initiated, resulting in disease control for more than three years. In October 2025, the patient developed pulmonary and adrenal disease progression. Biopsy of the recurrent lesion confirmed lung adenocarcinoma with PD-L1 expression > 50% and identified a BRAF V600E mutation, while the previously detected EGFR mutation was no longer identified. Discussion: Suspecting acquired resistance driven by clonal evolution, treatment with carboplatin and pemetrexed was started while osimertinib was continued, leading to a complete metabolic and radiological response after four cycles. Conclusions: This case highlights an unusual mechanism of resistance to osimertinib, characterized by the emergence of BRAF V600E and the apparent loss of the original EGFR mutation. Repeat tumor biopsy at the time of progression remains essential to identify resistance mechanisms and guide treatment decisions.