A 65-year-old man presents in the clinic with unintentional weight loss, palpable right axillary lymph nodes, and fatigue. He has a history of stage IIA malignant melanoma of the back. Three years ago, a wide local excision and sentinel lymph node biopsy was completed. The Eastern Cooperative Oncology Group performance status is 1. Cross-sectional imaging of the chest, abdomen, and pelvis demonstrates numerous nodules in the bilateral lung and liver and right axillary adenopathy, suggestive of metastatic disease. Biopsy of a right axillary lymph node reveals metastatic melanoma without a BRAF mutation. Laboratory findings are unremarkable, except for a lactate dehydrogenase level of 500 U/L.   

 

What is the most appropriate option for first-line treatment? 

A 48-year-old man presents to the local emergency department with complaints of vague abdominal pain. He reports symptoms of increasing fatigue, early satiety, and intermittent nausea over the past six months. He gets easily short of breath with minimal activities. He has no significant medical problems and takes no prescription medications. Physical examination reveals a palpable liver edge as well as palpable abdominal masses on deep palpation. Laboratory studies are unremarkable except for a hemoglobin level of 8.5 g/dL (normal range: 12-15.5 g/dL). CT imaging of the abdomen and pelvis, with contrast, reveals radiographic evidence of multifocal abdominal and peritoneal disease, including multiple liver metastases. Ultrasonography-guided biopsy of a liver lesion reveals an epithelioid appearing mesenchymal tumor; immunohistochemistry findings are consistent with a gastrointestinal stromal tumor (GIST). Molecular testing reveals the presence of a PDGFRA exon 18 mutation, specifically D842V. He is referred to you for a new patient consultation. 

 

Which of the following should you recommend now? 

Correct answer: A. Nivolumab with ipilimumab 

 

Rationale: In patients with a good performance status without a BRAF V600 activating mutation, the best initial choice for treatment is a combination (PD-1 inhibitor/CTLA4 inhibitor) or a single-agent PD1 inhibitor therapy. In this case, the patient's tumor does not have a BRAF V600E activating mutation, which precludes encorafenib with binimetinib. The combination of PD1 inhibitor therapy and CTLA4 inhibitor therapy showed overall survival superiority compared with either agent alone in CheckMate 067. High-dose  IL2 was the first treatment for metastatic melanoma with a median OS of 11.4 months; however, given the improved responses with new agents and a higher toxicity profile of high-dose IL2, it is now a less preferred approach.