|Ahead of print publication
First-line treatment of NRAS-mutated metastatic melanoma with a MEK inhibitor
Angelika Bickel1, Stefan Diem1, Lukas Flatz2, Björn Stinn3, Marco Siano1
1 Department of Oncology and Haematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
2 Department of Dermatology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
3 Department of Radiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
Department of Oncology and Haematology, Cantonal Hospital St. Gallen, St. Gallen
Source of Support: None, Conflict of Interest: None
Until recently, standard treatment for advanced melanoma comprised basically dacarbazine and interleukin-2, leading to low response rates and significant toxicity. These days, new treatments such as immunotherapy (anti-CTLA4 and anti-PD1 antibodies) and targeted therapy with BRAF/MEK-inhibitor combinations for patients harboring a BRAF mutation are available. In BRAF wild-type patients harboring an NRAS mutation, not fit for immunotherapy treatment options are still dismal. We describe an 84-year-old patient with widespread metastatic melanoma. He presented in July 2015 with a cerebral hemorrhage under anticoagulation for atrial fibrillation. Computed tomography revealed extensive metastatic disease (liver, lung, bones, lymph nodes, heart, and brain). Molecular testing was negative for BRAF but showed the presence of an NRAS mutation in exon 3 (pQ61K [c.181C>A]). The patient received as first-line treatment two cycles of cobimetinib showing a good partial remission and manageable side effects.
Keywords: BRAF wild type, MEK inhibitor, metastatic melanoma, NRAS mutation
| > Introduction|| |
Until recently, standard treatment for advanced melanoma comprised basically dacarbazine (DTIC) and interleukin-2 (IL-2) leading to low response rates and significant toxicity., These days, new treatments such as immunotherapy (anti-CTLA4 and anti-PD1 antibodies) and targeted therapy with BRAF/MEK-inhibitor combinations for patients harboring a BRAF mutation are available. In BRAF wild-type patients harboring an NRAS mutation, not fit for immunotherapy treatment options are still dismal.
| > Case Report|| |
An 84-year-old man with a history of a curatively treated malignant melanoma first diagnosed in 2007 presented in July 2015 with a cerebral hemorrhage after anticoagulation for atrial fibrillation. Computed tomography showed widespread metastatic disease in the liver, lung, lymph nodes, bones, heart, brain, and in several muscles. A biopsy was negative for BRAF mutation but positive for NRAS mutation in exon 3 (pQ61K [c.181C>A]).
His ECOG performance status at presentation was 2 with long-standing fatigue syndrome for several months. The level of Protein-S100 was 0.427 ug/l and lactate dehydrogenase was 338 U/l. Solely, a best supportive care strategy was unacceptable for the patient. Therefore, we considered standard treatment with ipilimumab, approved as first-line agent for metastatic melanoma in Switzerland. For different reasons (age, low-performance status, potential serious side effects, and paracardiac localization of metastasis), he was not deemed suitable for ipilimumab treatment upfront.
Because of promising phase II data with a MEK inhibitor in patients harboring an NRAS mutation, we regarded a treatment with cobimetinib (Cotellic) off label as the best first-line approach. Anti-PD1 antibodies such as pembrolizumab were not available outside clinical trial at that moment and could have been an option in disregard of pseudoprogression.
We started at a low dose of 20 mg daily. After 1 week, we increased the dosage to 60 mg. Apart from a CTC Grade 1 episode of diarrhea after the 1st week with the 60 mg dosage, manageable with loperamide, the patient improved clinically, and his performance status improved. The patient claimed no further side effects. After 2 months of treatment, a CT-scan showed a partial remission on every level [Figure 1] and [Figure 2].
|Figure 1: Chest computed tomography scan - October 8, 2015, pulmonary metastasis|
Click here to view
|Figure 2: Chest computed tomography scan - December 18, 2015, pulmonary metastasis (partial remission)|
Click here to view
After 4.5 months of cobimetinib, we assessed new brain metastases. The patient deteriorated clinically. Therefore, we discussed an immunotherapy with pembrolizumab, a whole brain radiation, or best supportive care. The patient opted for best supportive care.
| > Discussion|| |
Until recently, standard treatment for metastatic melanoma was chemotherapy with DTIC and IL-2, with a disease control rate of 20% or less and a median overall survival of about 8–10 months. Toxicity was important (major toxicities include fever, chills, hypotension, increased capillary permeability, cardiac arrhythmias, oliguria, volume overload, delirium, and rash)., New approaches such as the anti-CTLA4 antibody ipilimumab (Yervoy) show 10%–15% response rates, manageable but considerable toxicity profile with mainly autoimmune-related side effects and durable responses in around 20% of patients. The longest overall survival follow-up is nearly 10 years.,,, The onset of response is delayed and can occur weeks to months after treatment initiation. Anti-PD1 agents such as pembrolizumab (Keytruda) and nivolumab (Opdivo) show higher response rates but markedly less side effects., Response occurs earlier than with ipilimumab, usually within weeks after treatment start. Patients with NRAS mutant melanoma treated with MEK inhibitors before or after treatment with checkpoint inhibitors, show improved outcome and survival as wild-type patients. When treatment was planned, pembrolizumab was approved (licensed) after disease progression to ipilimumab in BRAF wild-type patients in our country.
On the other hand, targeted therapies in patients harboring a BRAF mutation show high response rates with resistance development during the course of treatment. The median progression-free survival for vemurafenib is 6.2 months and in the combination with cobimetinib is 9.9 months.,, Treatment response is usually rapid, making it an ideal upfront choice for high burden disease and symptomatic patient like ours.
Mutations of BRAF are present in 40%–60% and of NRAS in about 15%–25% of advanced melanomas patients. A phase II study with MEK162 showed activity in patients with NRAS-mutated melanoma. This was the first targeted therapy to show activity in patients with NRAS-mutated melanoma. The most common Grade 3–4 adverse event was an increased creatinine phosphokinase, diarrhea, dehydration, acneiform dermatitis, irregular heart rate, malaise, small intestinal perforation, and general physical deterioration. According to these results, a randomized phase III trial comparing MEK 162 (binimetinib) to chemotherapy (DTIC) was performed and recently published. The NRAS mElanoma and MEK inhibitOr (NEMO) trial is the largest controlled study of patients with NRAS-mutant melanoma. The MEK inhibitor – binimetinib prolonged significantly progression-free survival and improved response rates compared to DTIC. The benefit was seen in treatment-naive patients and in those who previously received immunotherapy.
Our patient was symptomatic, elderly, and according to our experience, not suitable for ipilimumab treatment. Contraindication for ipilimumab in our case is based on our experience, and no other cases are reported in literature so far. According to the before mentioned characteristics of novel targeted agents and immune therapies, we wished a rapid onset of response and good likelihood of response, symptom relief, and low toxicity. Therefore, we opted for a MEK inhibitor and cobimetinib in this situation. Off-label treatment with a MEK inhibitor proved us right so far, with a chance of durable response and the opportunity to apply immunotherapy at the first signs of progression with lower hazard for fatal toxicity due to pseudoprogression.
We conclude that treatment of melanoma patients is getting challenging and specialized with the uprising of new treatment modalities. MEK inhibitors are a valid option in BRAF wild-type patients harboring an NRAS mutation, who are not deemed suitable for immunotherapy.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, et al.
Phase III multicenter randomized trial of the dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999;17:2745-51.
Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: Long-term survival update. Cancer J Sci Am 2000;6 Suppl 1:S11-4.
Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al.
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-26.
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al.
Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521-32.
Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al.
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375-84.
Kirchberger MC, Ugurel S, Mangana J, Heppt MV, Eigentler TK, Berking C, et al.
MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients. Eur J Cancer 2018;98:10-6.
Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al.
Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014;371:1867-76.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al.
Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al.
Dabrafenib and trametinib versus dabrafenib and placebo for val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015;386:444-51.
Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, et al.
MEK162 for patients with advanced melanoma harbouring NRAS or val600 BRAF mutations: A non-randomised, open-label phase 2 study. Lancet Oncol 2013;14:249-56.
Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, et al.
Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017;18:435-45.
[Figure 1], [Figure 2]