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Ref Type Journal Article
PMID (42398475)
Authors Hviid C, Melchior LC, Berger SMS, Löfgren JO, Santoni-Rugiu E, Urbanska EM
Title Clonal divergence with acquired BRAF V600E in NSCLC with compound EGFR G719X/S768I after prolonged EGFR-TKI therapy.
Journal Vol Issue Date Pages Journal Short Title
Lung cancer (Amsterdam, Netherlands) 218 2026 Jul 01 109517 Lung Cancer
URL
Abstract Text Uncommon EGFR-mutations represent a heterogeneous subgroup of EGFR-mutant NSCLC with variable TKI sensitivity and limited evidence to guide treatment. Compound uncommon variants such as G719X/S768I are particularly rare. Acquired BRAF V600E is an infrequent resistance mechanism to EGFR-TKIs, mainly described in classical EGFR-mutations.A 73-year-old woman with cardiomyopathy and metastatic NSCLC harbouring a compound EGFR G719X/S768I mutation achieved prolonged disease control on erlotinib and subsequent osimertinib. After more than four years of EGFR-TKI exposure, oligoprogression occurred in a left upper lobe lesion. Rebiopsy revealed acquired BRAF V600E mutation and no detectable EGFR-mutations, while plasma showed no ctDNA. Dabrafenib/trametinib induced regression of the BRAF-driven lesion, whereas other lesions progressed, indicating spatially distinct BRAF-driven and EGFR-dependent clones. Subsequent combined EGFR-BRAF-MEK inhibition provided stable disease but was discontinued due to worsening of heart failure.This case illustrates prolonged EGFR-TKI sensitivity in a rare compound EGFR-mutation followed by true clonal divergence with acquisition of BRAF V600E, highlighting the need for individualised treatment.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E lung adenocarcinoma predicted - resistant Osimertinib Case Reports/Case Series Actionable In a clinical case study, acquisition of BRAF V600E and loss of EGFR G719A and EGFR S768I were identified in the post-progression biopsy of a patient with metastatic lung adenocarcinoma treated with Tagrisso (osimertinib) (PMID: 42398475). 42398475