S.E. is a 67-year-old male retired airline pilot who presents with difficulty breathing, fatigue, abdominal pain, and numerous hardened black lumps on his left arm.
Relevant Medical History
• Hypertension (well-controlled)
Laboratory Tests/Clinical Presentation
• Pathology report of fine needle aspiration biopsy showed metastatic melanoma
• Eastern Cooperative Oncology Status (ECOG) performance status of 3
• MRI and PET/CT show metastases in liver, lungs, bone, and lymph nodes
• BRAF V600K mutation-positive per THxIDTM BRAF Kit
• Renal function is within normal limits
• Elevated liver transaminases
• Serum lactate dehydrogenase is 8,156 U/L
• Blood pressure is 128/76 mm Hg
Initial Treatment Plan
In addition to initiating radiotherapy for the bone metastases, S.E.’s oncologist would like to start systemic therapy for metastatic melanoma; however, he anticipates that S.E. will likely clinically deteriorate within the next 3 months.
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Dabrafenib plus trametinib, nivolumab, and dabrafenib alone all are designated Category 1 in the 2015 NCCN Guidelines for melanoma and therefore are appropriate options for patients with BRAF V600 mutant type metastatic melanoma who are expected to experience clinical deterioration in 12 weeks or less.1
High-dose interleukin-2 and ipilimumab are only appropriate in patients who are anticipated to be clinically stable for more than 12 weeks.1
Dabrafenib plus trametinib is preferred over dabrafenib alone because the combination provides superior clinical efficacy, but with decreased tolerability in some, compared with single-agent BRAF inhibition.1,2,3
In addition, dabrafenib alone is only FDA-approved for patients with the BRAF V600E mutation, while patients with the V600K mutation should receive both dabrafenib and trametinib.4
Moreover, BRAF inhibitors are associated with a high response rate of 50% in patients with a V600 mutated BRAF gene, and tumor regression may be seen in days to weeks after starting the drug.1,2
In a patient with very rapid clinical deterioration, dabrafenib plus trametinib is the most appropriate treatment choice. Because of the rapid response of lesions to dabrafenib and trametinib, initiation of radiotherapy may be delayed and may not be necessary in this patient.
The safety of concurrent radiation, dabrafenib and trametinib has not been established. The 2-year progression-free and overall survival of metastatic melanoma patients presenting with high LDH and treated with dabrafenib/trametinib appears to be low.5
Rapid tumor regression has been observed in a subset of very advanced metastatic melanoma patients treated with nivolumab, pembrolizumab, or the combination of nivolumab and ipilimumab, and therefore could be considered as initial therapy even in patients with high tumor burdens and rapidly progressive disease.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Melanoma. V 3.2015. Available at: www.nccn.org/professionals/physician/gls/pdf/melanoma.pdf.
- Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107-14.
- Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877-88.
- Tafinlar (dabrafenib) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202806s002lbl.pdf.
- Long GV, Stroyakovskiy D, Gogas H, et al. Overall survival in COMBI-d, a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. J Clin Oncol. 2015;33 (suppl; abstr 102).
- Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-30.