Response of BRAF inhibitor-associated squamous cell lung carcinoma to drug withdrawal
Jonathan T Blackmon1, Ratika Dhawan, Nina L Terry
1aCovenant College, Lookout Mountain, Georgia bComprehensive Cancer Center cDivision of Hematology Oncology, University of Alabama dDepartment of Radiology, General Radiology and Cardiopulmonary Section, UAB Medicine, Birmingham, Alabama, USA.
Abstract:
Vemurafenib and dabrafenib, two Food and Drug Administration-approved selective BRAF kinase inhibitors (BRAFi), have revolutionized the targeted therapy of cutaneous melanoma. Off-target effects of these drugs paradoxically activate the MAP kinase pathway in BRAF wild-type cells, leading to secondary malignancies. Although cutaneous squamous cell carcinomas are by far the most frequent, emergence of potentially life-threatening secondary tumors from other sites following prolonged therapy is a growing concern. Herein, we provide the first case report of squamous cell lung carcinoma apparently secondary to BRAFi developing in a metastatic melanoma patient on vemurafenib for 23 months. Subsequent BRAFi with dabrafenib for 5 months was accompanied by rapid lung cancer progression with 86% increase in diameter. Withdrawal of BRAFi as the only change in therapy resulted in partial response maintained for more than 8 months. Clinicians should be atuned to the risk of noncutaneous second malignancies induced by BRAFi, particularly in the setting of progression of an isolated lesion after prolonged therapy.
Insights
BRAF inhibitors like vemurafenib can cause secondary lung cancer in melanoma patients. Stopping these drugs led to tumor shrinkage, highlighting the need for clinical awareness.
Area of Science:
- Oncology
- Pharmacology
- Dermatology
Background:
- Selective BRAF kinase inhibitors (BRAFi), including vemurafenib and dabrafenib, are FDA-approved targeted therapies for cutaneous melanoma.
- Paradoxical activation of the MAP kinase pathway in BRAF wild-type cells due to off-target effects of BRAFi can lead to secondary malignancies.
- While cutaneous squamous cell carcinomas are most common, non-cutaneous secondary tumors are an emerging concern with prolonged BRAFi therapy.
Observation:
- This report details the first case of squamous cell lung carcinoma seemingly secondary to BRAFi in a metastatic melanoma patient treated with vemurafenib for 23 months.
- Following vemurafenib, treatment with dabrafenib for 5 months correlated with rapid lung cancer progression (86% increase in diameter).
Findings:
- Withdrawal of BRAFi therapy, with no other changes, resulted in a partial response of the lung cancer, maintained for over 8 months.
- This suggests a direct link between BRAFi treatment and the development or progression of secondary lung cancer.
Implications:
- Clinicians must be vigilant regarding the risk of non-cutaneous secondary malignancies induced by BRAFi.
- Increased awareness is crucial, especially when isolated lesions progress during prolonged BRAFi therapy in melanoma patients.
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