Amaria RN, et al. - This trial was performed to compare two treatment strategies for patients with high-risk, surgically resectable, clinical stage III–IV melanoma: neoadjuvant plus adjuvant dabrafenib and trametinib vs upfront surgery and consideration for adjuvant therapy (standard of care). Compared with the standard of care, neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival in this patient population.

• In this single-centre, open-label, randomised phase 2 trial, conducted at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), researchers randomly assigned patients (1:2) to either upfront surgery and consideration for adjuvant therapy (standard of care group) or neoadjuvant plus adjuvant dabrafenib and trametinib (8 weeks of neoadjuvant oral dabrafenib 150 mg twice per day and oral trametinib 2 mg per day followed by surgery, then up to 44 weeks of adjuvant dabrafenib plus trametinib starting 1 week after surgery for a total of 52 weeks of treatment).
• Eligibility criteria included: adult patients (aged ≥18 years) with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAFV600E or BRAFV600K (ie, Val600Glu or Val600Lys)-mutated melanoma, having an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy of more than 3 years, and no previous exposure to BRAF or MEK inhibitors.
• Researchers excluded cases with metastases to bone, brain, or other sites where complete surgical excision was in doubt.
• Randomisation was not masked and was implemented by the clinical trial conduct website maintained by the trial centre.
• According to disease stage, stratification of patients was done.
• Investigator-assessed event-free survival (ie, patients who were alive without disease progression) at 12 months in the intent-to-treat population was the primary endpoint.

• Seven patients were randomly assigned to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib, between Oct 23, 2014, and April 13, 2016.
• Early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care, the trial was stopped.
• Researchers observed that after a median follow-up of 18·6 months (IQR 14·6–23·1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression, compared with those receiving standard of care (10 [71%] of 14 patients vs none of 7 in the standard of care group; median event-free survival was 19·7 months [16·2–not estimable] vs 2·9 months [95% CI 1·7–not estimable]; hazard ratio 0·016, 95% CI 0·00012–0·14, p<0·0001).
• Findings demonstrated good tolerability of neoadjuvant plus adjuvant dabrafenib and trametinib and no occurrence of grade 4 adverse events or treatment-related deaths was reported.
• Expected grade 1–2 toxicities including chills (12 patients [92%]), headache (12 [92%]), and pyrexia (10 [77%]) were identified as the most common adverse events in the neoadjuvant plus adjuvant dabrafenib and trametinib group.
• In addition, diarrhoea was documented as the most common grade 3 adverse event (2 patients [15%]).