Clonal divergence with acquired BRAF V600E in NSCLC with compound EGFR G719X/S768I after prolonged EGFR-TKI therapy

BACKGROUND: 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. CASE PRESENTATION: 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. CONCLUSION: 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.