Neoadjuvant Dabrafenib/Trametinib for High-Risk, Surgically Resectable BRAF-Mutated Melanoma

Results from a phase II study provide proof of concept for studying neoadjuvant approach

An open-label, randomised phase II study conducted at the University of Texas MD Anderson Cancer Center shows that neoadjuvant and adjuvant dabrafenib/trametinib combination therapy significantly improved event-free survival (EFS) versus standard of care in high-risk, surgically resectable, stage III and IV melanoma with BRAF mutations. The study findings provide proof of concept and support further investigation of neoadjuvant treatment in that setting.

Combined BRAF/MEK inhibition generate a response in melanoma patients with stage IV disease and BRAF mutations. The existing standard of care for patients with clinical stage III melanoma is surgery and consideration for adjuvant treatment. However, research efforts in melanoma are fast evolving but the drugs from recently reported positive adjuvant trials are still not approved by regulatory agencies. Furthermore, in a study background the authors underlined that adjuvant treatment is not sufficient to cure most of patients in that setting.

The study investigators speculated that neoadjuvant targeted therapy with combination of BRAF and MEK inhibitors might provide benefit in such high-risk population. Rodabe Amaria and Peter Prieto contributed equally, while Michael Davies and Jennifer Wargo share senior authorship of the paper published in February 2018 issue of the Lancet Oncology.

Eligible patients in this study were adults with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV melanoma with BRAFV600E or BRAFV600K mutations. Furthermore, the study team enrolled patients with good performance status, a life expectancy of more than 3 years, and no previous treatment with BRAF or MEK inhibitors. Exclusion criteria considered presence of bone and brain metastases, as well as metastases in other sites where complete surgical excision was not possible.

The patients were randomly assigned (1:2) to either upfront surgery and consideration for adjuvant therapy (standard of care group) or neoadjuvant plus adjuvant dabrafenib and trametinib. The medical treatment in the latest group consisted of 8 weeks of neoadjuvant oral therapy with dabrafenib 150 mg twice per day and trametinib 2 mg per day. The neoadjuvant treatment was followed by surgery and starting one week after the surgery the patients received up to 44 weeks of adjuvant dabrafenib plus trametinib.

The patients were stratified by disease stage. The primary endpoint was investigator-assessed EFS at 12 months in the intent to treat population.

Between October 2014 and April 2016, the study team randomly assigned 7 patients to standard of care group, and 14 to neoadjuvant plus adjuvant dabrafenib/trametinib. The trial was stopped early after a prespecified interim safety analysis revealed significantly longer EFS with neoadjuvant plus adjuvant dabrafenib/trametinib.

After a median follow-up of 18.6 months, significantly more patients receiving neoadjuvant plus adjuvant dabrafenib/trametinib were alive without progression of disease than those receiving standard of care (71% versus 0%). The median EFS was 19.7 months versus 2.9 months (hazard ratio 0.016, p < 0.0001).

Neoadjuvant treatment was well tolerated. There was no grade 4 adverse events (AEs) or treatment-related deaths. The most common AEs in the neoadjuvant group were grade 1–2 toxicities such as chills, headache, and pyrexia. The most common grade 3 AE was diarrhoea.

The authors pointed out that although the trial finished after only a quarter of the participants had been accrued and limited results generalisability, the study findings provide proof of concept and support the rationale for investigating neoadjuvant treatment in that setting. The study is continuing accrual as a single-arm trial of neoadjuvant plus adjuvant treatment with dabrafenib/trametinib.

Reference

Amaria RN, Prieto PA, Tetzlaff MT, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncology 2018; 19(2):181-193.