ABSTRACT
BACKGROUND: Clinical benefit from cytotoxic chemotherapy for metastatic papillary thyroid carcinoma (PTC) is disappointing, and effective therapeutic approaches for these patients are urgently needed. Because kinase-activating mutations in the BRAF proto-oncogene commonly occur in advanced PTC, and inhibition of BRAF(V600E) has shown promising clinical activity in melanoma, BRAF inhibitor therapy may be an effective strategy to treat metastatic PTC. METHODS: The dose escalation portion of a first-in-human, phase I study of vemurafenib, a selective RAF inhibitor, included three patients with metastatic PTC harboring the BRAF(V600E) mutation. Vemurafenib was initially dosed at 240-360 mg twice a day, later escalated to 720 mg twice a day. Response evaluation was performed every 8 weeks per Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Among the three patients, one had a confirmed partial response with reduction of pulmonary target lesions by 31%, and the duration of response was 7.6 months before the disease progressed in the lungs and the bones. The time to progression was 11.7 months. The other two patients had stable disease, and the time to progression was 13.2 and 11.4 months, respectively. CONCLUSIONS: Vemurafenib appears to have a promising clinical activity in patients with metastatic PTC, and our data suggest that the BRAF(V600E) mutant kinase is a relevant target for therapy in this patient population. Further investigation of inhibitors of mutated BRAF kinase in patients with PTC in a phase II study is warranted.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Papillary/drug therapy , Indoles/therapeutic use , Mutation , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Sulfonamides/therapeutic use , Thyroid Neoplasms/drug therapy , Amino Acid Substitution , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Cancer Care Facilities , Carcinoma/drug therapy , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/pathology , Carcinoma, Papillary/genetics , Carcinoma, Papillary/pathology , Carcinoma, Papillary/secondary , Cohort Studies , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Female , Follow-Up Studies , Humans , Indoles/administration & dosage , Indoles/adverse effects , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Male , Middle Aged , Molecular Targeted Therapy/adverse effects , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Mas , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Survival Analysis , Thyroid Cancer, Papillary , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology , Tumor Burden/drug effects , VemurafenibABSTRACT
We present a patient with metastatic BRAF-mutated melanoma who achieved long-term stabilization of leptomeningeal disease (LMD) with sequential whole-brain radiation therapy and vemurafenib. A 53-year-old woman with melanoma that harbored the BRAF V600E mutation and had that metastasized to multiple lymph nodes, lungs, breast, and subcutaneous tissue had developed symptomatic LMD 16 months after starting vemurafenib treatment despite achieving a substantial response at the existing metastatic sites. Vemurafenib was discontinued for 7 days, she received whole-brain radiation therapy (30 Gy in 10 fractions), and 7 days after completing the radiation therapy, she resumed vemurafenib therapy. The neurologic symptoms improved significantly, and a cerebrospinal fluid examination revealed disappearance of melanoma cells. She remained alive with radiologically stable LMD for at least 18 months after the whole-brain radiation therapy.