A previously fit and well 40-year-old man presented to the accident and emergency department with a short history of dyspnoea, lethargy, fatigue and chest pain. Aside from an appendectomy in childhood, there was no other significant medical history and the patient had been on no regular medications. He had no known drug allergies. His exercise tolerance had deteriorated to the point that he was able to mobilize only for short distances before having to rest: his Eastern Cooperative Oncology Group performance status (PS) was 2. On examination, there was a large mass in the left axilla. Testicular examination was normal and laboratory investigations showed a raised lactate dehydrogenase (LDH) level of 1241 IU/l (normal level 160–430). Germ cell tumour markers were within the normal range.
Chest x-ray showed bilateral masses throughout the lung fields; a subsequent CT scan confirmed multiple lung nodules, right- and left-sided axillary lymphadenopathy with a left pleural effusion, and liver metastases. A CT scan of the brain was normal, and there was no evidence of metastases.
Biopsy of the axillary lesion confirmed an ulcerated nodular melanoma with a V600E BRAF mutation.
The patient was reviewed in the medical oncology clinic 2 days later, which he attended in a wheelchair. His PS was now 3. A baseline ECG was normal with a corrected QT interval (QTc) of 470 ms. He was started on the serine/threonine-protein kinase B-Raf (BRAF) inhibitor vemurafenib at a dose of 960 mg twice daily. Four weeks later the axillary lymphadenopathy was palpably smaller and the lethargy and shortness of breath had improved, but a repeat ECG showed a prolonged QTc of 525 ms. Vemurafenib was halted for 2 weeks, by which time QTc had normalized. Vemurafenib was restarted at a reduced dose of 720 mg twice daily.
There was significant improvement on repeat imaging following 3 months' treatment, with resolution of dyspnoea. When he returned to clinic his PS had improved to 1. A staging CT scan showed a decrease in both the lung metastases and the lymphadenopathy. LDH had decreased to 378 IU/l.
His disease remained quiescent for a further 2 months, but on further review in clinic, his LDH had risen and there were new, palpable lymph nodes in the inguinal regions, as well as 4 cm hepatomegaly. A CT scan confirmed progressive disease and the patient was considered for second line immunotherapy with the checkpoint inhibitor pembrolizumab.
What are the molecular mechanisms of BRAF mutations?
What is the evidence for inhibition of BRAF in melanoma?
What are the side effects of the BRAF inhibitors?
What is the mechanism of resistance to BRAF inhibition?
What is the evidence for combination therapy in BRAF-mutated melanoma?
Around 40% of patients with melanoma have mutations in BRAF, a gene encoded by the rapidly accelerated fibrosarcoma (RAF) family of protein kinases (other genes being ARAF and CRAF...