Clinical and Molecular Outcomes of Dabrafenib/Trametinib-Based Combination Therapy in Acquired BRAF V600E-Mutant NSCLC Following Tyrosine Kinase Inhibitor Resistance: A Preliminary Single-Center Retrospective Study
Dan Xu, Fang Hao, Xia Liu, Xin Wang, Diansheng ZhongIntroduction:
Acquired BRAF V600E is an uncommon resistance mechanism after tyrosine kinase inhibitor (TKI) therapy in oncogene-driven non-small cell lung cancer (NSCLC), and the clinical value of dabrafenib/trametinib-based combination therapy remains unclear. This preliminary single-center retrospective study aimed to describe the clinical, molecular, radiological, and safety outcomes of dabrafenib/trametinib-based combination therapy in patients with acquired BRAF V600E-mutant NSCLC after TKI resistance.
Methods:
Patients with acquired BRAF V600E-mutant NSCLC after prior EGFR/ALK TKI therapy between December 2019 and September 2023 were retrospectively reviewed. Clinical characteristics, treatment outcomes, adverse events, radiological findings, and serial molecular profiles from plasma, tissue, or pleural effusion samples were collected.
Results:
Three eligible patients were identified. The observed progression-free survival after dabrafenib/trametinib combination therapy was 2.2, 7.1, and 14.5 months. Toxicity was heterogeneous, including clinically significant pyrexia, treatment interruption, grade 2 hematologic toxicities, and rapid clinical deterioration in one patient. Among two patients with baseline brain metastases, intracranial lesions remained radiologically controlled during the available followup; however, this finding was descriptive and should not be interpreted as a reliable control rate. Serial molecular testing showed BRAF V600E disappearance after progression in selected cases, suggesting molecular heterogeneity.
Discussion:
Acquired BRAF V600E mutation is a key secondary resistance mechanism after EGFR/ALK TKI therapy. Combining BRAF/MEK and EGFR/ALK inhibitors is a feasible strategy for these patients. However, the varied treatment outcomes and toxicities highlight the high clinical and molecular heterogeneity of this disease. Because of our extremely small sample size and retrospective design, larger prospective studies are needed to confirm these preliminary findings.
Conclusion:
Dabrafenib/trametinib-based combination therapy may show clinical activity in selected patients with acquired BRAF V600E-mutant NSCLC after TKI resistance. However, the extremely small sample size, heterogeneous outcomes, and clinically significant toxicities preclude definitive conclusions regarding efficacy or safety.