A woman in her 40s presented to the emergency department with headache and unintentional weight loss…Investigations revealed a widely metastatic pan-negative melanoma of unknown primary. She had multiple lines of treatment including combination immunotherapy and chemotherapy. Next-generation sequencing identified an SKAP2-BRAF fusion protein, and she was commenced on an MEK inhibitor...The patient received brain stereotactic radiation, followed by combination immunotherapy with ipilimumab 3 mg/kg and nivolumab...She developed progression of disease...She proceeded to dacarbazine...On recovery, she was rechallenged with another immuno therapy PD1 inhibitor, pembrolizumab...A BRAF fusion protein was identified and she was commenced on an MEK inhibitor trametinib...On starting trametinib, there was a dramatic clinical improve ment along with a fall in LDH from 2248 IU/L to 576 IU/L, and she had a partial response seen on restaging scans after 6 weeks...The response was not maintained and her cancer progressed radiologically and clinically within weeks of the initial response...She died from progression of her cancer.