Summary Background Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is ...controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. Methods In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov , number NCT02434107 . Follow-up is ongoing, but the trial no longer recruiting patients. Findings Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20–54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9–82·1; 55 events) in the observation group and 74·9% (69·5–80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. Interpretation Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. Funding German Cancer Aid.
Summary Background Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, ...including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS -mutated or Val600 BRAF -mutated advanced melanoma. Methods In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS -mutated or BRAF -mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS -mutated melanoma, twice-daily MEK162 45 mg for BRAF -mutated melanoma, and twice-daily MEK162 60 mg for BRAF -mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov , number NCT01320085 , and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment). Findings Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6–8·7; IQR 2·2–5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS -mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF -mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 60% patients with NRAS -mutated melanoma and 15 37% patients with the BRAF -mutated melanoma), rash (six 20% and 16 39%), peripheral oedema (ten 33% and 14 34%), facial oedema (nine 30% and seven 17%), diarrhoea (eight 27% and 15 37%), and creatine phosphokinase increases (11 37% and nine 22%). Increased creatine phosphokinase was the most common grade 3–4 adverse event (seven 23% and seven 17%). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes. Interpretation To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments. Funding Novartis Pharmaceuticals.
