ArticlesNeoadjuvant 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
Introduction
Upfront surgical management is the current standard of care for patients with clinical stage III melanoma.1, 2 According to the 7th edition of the melanoma American Joint Committee on Cancer staging manual,2 only 30–50% of patients with stage IIIB or IIIC melanoma survive for 5 years after diagnosis. Adjuvant medical therapy is discussed with patients with stage III disease after surgery. However, at the the time of this trial, use of available adjuvant therapies such as interferon alfa and high-dose ipilimumab was heterogenous.
The first adjuvant therapy approved for melanoma was interferon-alfa2b, which achieved significant but mild improvements in disease-free survival (hazard ratio [HR] 0·83, 95% CI 0·78–0·87) and overall survival (0·91, 0·85–0·97) compared with patients undergoing observation or treated with another adjuvant therapy, as determined by a 2013 meta-analysis3 of more than 10 000 patients with stage II–III cutaneous melanoma. More recently, adjuvant treatment with ipilimumab improved 5-year event-free survival (HR 0·76, 95% CI 0·58–0·88), distant metastasis-free survival (0·76, 0·64–0·92), and overall survival (0·72, 0·58–0·88) versus placebo in the EORTC 18071 phase 3 study.4 Although these results were impressive, 54% of patients treated with ipilimumab had grade 3 or 4 adverse events and there were five ipilimumab-related deaths. The choice of placebo as the control group in this trial highlights the continued dilemma and absence of consensus regarding adjuvant therapy for patients with melanoma—better treatments need to be developed for this high-risk population.
Neoadjuvant chemotherapy is the standard of care for many types of cancer, including breast, gastric, oesophageal, and rectal cancers.1 Potential benefits of neoadjuvant therapy include reduced morbidity of definitive surgery, objective assessment of treatment response, and collection of biospecimens for translational research. Neoadjuvant therapy for melanoma has been restricted historically, mainly because of the low activity of chemotherapy in this disease. All prospective neoadjuvant trials in melanoma reported so far have been non-randomised single-arm studies, and thus have not compared clinical benefit in a neoadjuvant group versus a standard of care group.5, 6, 7
Combination targeted therapy with dabrafenib and trametinib is approved for patients with stage IV melanoma with a BRAFV600 mutation, which is present in around 50% of cutaneous melanomas.8 A pooled analysis9 of data from 617 patients treated in randomised trials showed that 67% of patients with stage IV BRAFV600E or BRAFV600K (ie, Val600Glu or Val600Lys) melanoma treated with dabrafenib and trametinib achieved an overall response and 91% achieved disease control, with a well-characterised and manageable toxicity profile.10 Clinical trials assessing dabrafenib and trametinib as adjuvant therapy for patients with stage III melanoma were pending results at the time of this trial. We postulated that dabrafenib and trametinib would be safe and effective in the neoadjuvant setting. Therefore, we did a randomised phase 2 trial to assess event-free survival with neoadjuvant and adjuvant dabrafenib and trametinib compared with standard of care in patients with surgically resectable, clinical stage III and oligometastatic stage IV BRAFV600E or BRAFV600K melanoma.
Section snippets
Study design and participants
We undertook a single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were patients aged at least 18 years with histologically or cytologically confirmed locally advanced clinical stage III or oligometastatic stage IV BRAFV600E or BRAFV600K-mutated melanoma and a life expectancy of more than 3 years. Clinical stage III disease was defined as at least one palpable lymph node metastasis measuring 1·5 cm in
Results
Between Oct 23, 2014, and April 13, 2016, we screened 46 patients and enrolled and randomly assigned 21 eligible patients to treatment: seven to standard of care and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib (figure 1). The demographic and baseline characteristics (including disease stage and tumour burden) were generally well balanced across the two treatment groups, although patients in the standard of care group were younger, were more likely to have had previous surgery, and
Discussion
The results of this study showed that neoadjuvant plus adjuvant dabrafenib and trametinib can produce substantially longer event-free survival in patients with surgically resectable, high-risk, BRAFV600E or BRAFV600K-mutated melanoma, compared with the standard of care upfront surgery and consideration of adjuvant therapy. Furthermore, our results showed that this approach was tolerable and feasible, since all patients in the neoadjuvant plus adjuvant dabrafenib and trametinib remained
References (31)
- et al.
Phase II trial of neoadjuvant temozolomide in resectable melanoma patients
Ann Oncol
(2010) - et al.
Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials
Lancet Oncol
(2016) - et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009) - et al.
Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial
Lancet
(2008) - et al.
Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells
Blood
(2009) - et al.
Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group
Mod Pathol
(2015) - et al.
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis
Lancet
(2014) NCCN clinical practice guidelines in oncology: melanoma, version 3
- et al.
Final version of 2009 AJCC melanoma staging and classification
J Clin Oncol
(2009) - et al.
Interferon alpha for the adjuvant treatment of cutaneous melanoma
Cochrane Database Syst Rev
(2013)