Successful re-challenge of dabrafenib-trametinib combination therapy in advanced BRAF ^V600E-mutant non-small cell lung cancer after previous cytotoxic chemotherapy, targeted therapy, and immunotherapy: a case report

Background: Patients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF)^V600E-mutant non-small cell lung cancer (NSCLC) benefit from treatment with a combination of BRAF and mitogen-activated protein kinase (MEK) inhibitors, but resistance and disease progression develop in most patients. Pre-clinical studies and case studies of melanoma indicate that acquired resistance to BRAF inhibition may be reversible. However, studies on the effects of dabrafenib-trametinib (D/T) re-challenge for relapse in NSCLC are limited.

Case description: A 58-year-old Chinese woman with a history of smoking and hypertension was diagnosed with stage IV B lung adenocarcinoma with metastasis. The targeted next-generation sequencing (NGS) of the patient's lung tumor biopsy tissues revealed the presence of a BRAF ^V600E mutation with an allele frequency (AF) of 30.54%. The patient was treated with cytotoxic chemotherapy (the 1st line), D/T targeted therapy (the 2nd line), and immune checkpoint inhibitor monotherapy (pembrolizumab, the 3rd line), all of which achieved a partial response (PR) that lasted for a total of 8 months. The 2nd NGS analysis of the lung tissue specimens revealed the presence of a BRAF ^V600E mutation (AF =18.41%) without mutations, which was potentially involved in the resistance to BRAF/MEK inhibition. At the 4th line, she subsequently re-challenged D/T, and achieved a 4th PR, lasting for 5 months. The 3rd NGS analysis revealed the retention of the BRAF ^V600E mutation (AF =0.39%). Her treatment was switched to pembrolizumab (the 5^th line), and the disease remained stable for another 6 months as of the last follow-up in November 2021. She didn't experience any adverse events throughout the treatment.

Conclusions: Our findings suggest that the re-challenge of D/T and immune checkpoint blockage therapies offer another therapeutic option for NSCLC patients with the BRAF ^V600E-mutant who have received extensive prior treatments. In addition, our advanced NSCLC patient with the BRAF ^V600E-mutant also derived long-term clinical benefits from initial chemotherapy, molecular-targeted therapy, and immunotherapy.