Combined RET and MEK Inhibition as a Treatment for RET Fusion-Positive NSCLC With Acquired BRAF Fusion: A Case Report
Jacobi B Hines1, Benjamin C Bowar1, Margaret Colleton1
1Department of Medicine, Section of Hematology and Oncology, University of Chicago Medical Center, Chicago, Illinois.
Abstract:
RET fusions are present in 1% to 2% of NSCLCs. Although RET inhibitors like selpercatinib are effective, resistance inevitably develops. We present the case of a 28-year-old female with recurrent NSCLC and a CCDC6::RET fusion treated with selpercatinib. Testing at the time of progression revealed a new SKAP2 ::BRAF fusion. She was then treated with a combination of selpercatinib and trametinib, which led to a likely partial response, despite the combination demonstrating side effects. This case report details the first known instance of NSCLC with a RET fusion developing resistance by means of a BRAF fusion, treated with combined RET and MEK inhibition.
Insights
This case report describes a patient with non-small cell lung cancer (NSCLC) who developed resistance to RET inhibitors. A new BRAF fusion was identified, and combination therapy showed a partial response.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- RET fusions are oncogenic drivers in a small subset of non-small cell lung cancers (NSCLCs).
- Targeted therapies like selpercatinib are effective against RET fusion-positive NSCLC but acquired resistance is a clinical challenge.
Observation:
- A 28-year-old female with recurrent NSCLC and a CCDC6::RET fusion was treated with selpercatinib.
- Progression of disease revealed a novel SKAP2::BRAF fusion, indicating a new resistance mechanism.
Findings:
- This is the first reported case of NSCLC with a RET fusion developing resistance via a BRAF fusion.
- Combination therapy with a RET inhibitor (selpercatinib) and a MEK inhibitor (trametinib) resulted in a likely partial response.
Implications:
- This case highlights a novel resistance mechanism to RET inhibitors in NSCLC.
- Combined RET and MEK inhibition may represent a potential therapeutic strategy for patients with acquired BRAF fusions following RET-targeted therapy.
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