Triple inhibition of ALK, BRAF, and MEK for acquired BRAF V600E after lorlatinib resistance in ALK-rearranged lung adenocarcinoma: a case report

Abstract Background Acquired resistance to ALK tyrosine kinase inhibitors (TKIs) is molecularly heterogeneous, and BRAF V600E as a bypass mechanism after ALK -TKI therapy has been rarely reported. The optimal treatment strategy after its detection remains undefined. Case presentation : A 42-year-old man with stage IVA lung adenocarcinoma (PD-L1 tumor proportion score, 60%) progressed after sintilimab and subsequent platinum-pemetrexed plus bevacizumab. Re-biopsy identified EML4-ALK , and lorlatinib was initiated as first ALK -targeted therapy, achieving durable disease control for over 36 months. In January 2026, thoracic progression prompted repeat next-generation sequencing, revealing persistent ALK rearrangement and newly acquired BRAF V600E. Lorlatinib was continued with dabrafenib and trametinib added. Computed tomography showed marked tumor shrinkage after 1 month, and subsequent follow-up demonstrated continued lesion shrinkage with ongoing disease control for more than 6 months. Conclusion Repeat molecular profiling at ALK -TKI progression is essential. Concurrent ALK/BRAF/MEK inhibition may be effective when post-progression profiling demonstrates persistent ALK rearrangement and acquired BRAF V600E.