Elsevier

The Lancet Oncology

Volume 19, Issue 2, February 2018, Pages 181-193
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(18)30015-9Get rights and content

Summary

Background

Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation.

Methods

We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were 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. Eligible patients had to have 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. Exclusion criteria included metastases to bone, brain, or other sites where complete surgical excision was in doubt. We 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). Randomisation was not masked and was implemented by the clinical trial conduct website maintained by the trial centre. Patients were stratified by disease stage. The primary endpoint was investigator-assessed event-free survival (ie, patients who were alive without disease progression) at 12 months in the intent-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT02231775.

Findings

Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped 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. 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 than those receiving standard of care (ten [71%] of 14 patients vs none of seven 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). Neoadjuvant plus adjuvant dabrafenib and trametinib were well tolerated with no occurrence of grade 4 adverse events or treatment-related deaths. The most common adverse events in the neoadjuvant plus adjuvant dabrafenib and trametinib group were expected grade 1–2 toxicities including chills (12 patients [92%]), headache (12 [92%]), and pyrexia (ten [77%]). The most common grade 3 adverse event was diarrhoea (two patients [15%]).

Interpretation

Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III–IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This trial is currently continuing accrual as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib.

Funding

Novartis Pharmaceuticals Corporation.

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

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