Critical appraisal:Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al 2017

Critical Appraisal

Article being appraised

Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med 2017 Sep 10 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28891408.

Applicable clinical question

What is the role of adjuvant systemic therapy in patients with resected stage II/III melanoma?

Key Facts

Study Design

randomised controlled trial - Cochrane tool

Study aims:

To determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.

Number of Patients:

870

438 received combination therapy with dabrafenib plus trametinib
432 received matched placebo tablets for 12 months

Reported outcome(s):

Relapse-free survival, overall survival, distant metastasis-free survival, freedom from relapse and safety.

Results of outcome(s):

Disease recurrence was reported in 163 of 438 (37%) patients in the combination-therapy group, and 247 of 432 (57%) patients in the placebo group.

Relapse-free survival was significantly longer in the combination-therapy group than in the placebo group, representing a 53% lower risk of relapse (HR for relapse or death 0.47; 95% CI 0.39-0.58; p<0.001).

A total of 153 deaths had occurred, 60 (14%) in the combination-therapy group and 93 (22%) in the placebo group.
The estimated rate of overall survival was 97% at 1 year, 91% at 2 years and 86% at 3 years in the combination-therapy group.
The estimated rates for the placebo group were 94% at 1 year, 83% at 2 years and 77% at 3 years (HR for death 0.57; 95% CI 0.42-0.79; p= 0.0006).

The estimated rates of relapse-free survival were 88% at 1 year, 67% at 2 years and 58% at 3 years in the combination-therapy group, as compared with rates of 56%, 44% and 39% respectively, in the placebo group.

Median relapse-free survival had not yet been reached in the combination-therapy group (95% CI 44.5 - not reached) and was 16.6 (95% CI 12.7-22.1) in the placebo group.

Fewer patients had distant metastases or died in the combination-therapy group than in the placebo group (110 (25%) vs 152 (35%); HR 0.51; 95% CI 0.40-0.65; p<0.001).

At least one adverse event was reported in 422 patients (97%) in the combination-therapy group and in 380 (88%) in the placebo group. Serious adverse events occurred in 155 (36%) patients in the combination-therapy group and in 44 (10%) patients in the placebo group.

Includes an economic evaluation

no

Evidence ratings

Level of evidence

II

Risk of bias

Unclear risk of bias

Comments: Please replace this text and include any additional comments in regards to your risk of bias rating

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Risk of bias assessment: Randomised Controlled Trial (Cochrane risk of bias tool)

Random sequence generation

Describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

Not mentioned

What was the risk of bias from the random sequence generation?

Unclear

Allocation concealment

Describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of or during, enrolment.

Not mentioned

What was the risk of bias from the allocation concealment?

Unclear

Blinding

Describe all measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.

Double-blind trial. Outcomes would also not be influenced by lack of blinding

What was the risk of bias from the blinding of participants and personnel and outcome assessors?

Low

Incomplete outcome data

Describe the completeness of outcome data for each main outcome, including attrition and exlusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any re-inclusions in analyses performed by the review authors.

No response

What was the risk of bias from incomplete outcome data?

Low