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Clinical Trial
. 2018 Dec 10;36(35):3441-3449.
doi: 10.1200/JCO.18.01219. Epub 2018 Oct 22.

Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma

Axel Hauschild  1 , Reinhard Dummer  1 , Dirk Schadendorf  1 , Mario Santinami  1 , Victoria Atkinson  1 , Mario Mandalà  1 , Vanna Chiarion-Sileni  1 , James Larkin  1 , Marta Nyakas  1 , Caroline Dutriaux  1 , Andrew Haydon  1 , Caroline Robert  1 , Laurent Mortier  1 , Jacob Schachter  1 , Thierry Lesimple  1 , Ruth Plummer  1 , Kohinoor Dasgupta  1 , Tomas Haas  1 , Mark Shilkrut  1 , Eduard Gasal  1 , Richard Kefford  1 , John M Kirkwood  1 , Georgina V Long  1
Affiliations
Clinical Trial

Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma

Axel Hauschild et al. J Clin Oncol. .

Abstract

Purpose: Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; P < .001) in patients with resected BRAF V600-mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083). We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term.

Methods: In this phase III trial, patients with resected BRAF V600-mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo. We report updated RFS (primary end point) and distant metastasis-free survival. RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model.

Results: At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis-free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration.

Conclusion: Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.

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Figures

Fig 1.
Fig 1.
CONSORT diagram.
Fig 2.
Fig 2.
Relapse-free survival and distant metastasis–free survival. (A) Kaplan-Meier estimates of relapse-free survival and (B) distant metastasis–free survival from the intent-to-treat population at the data cutoff of April 30, 2018.
Fig 3.
Fig 3.
Weibull mixture cure-rate model. Curves fitted to the Weibull mixture cure-rate analysis (solid lines) are overlaid with Kaplan-Meier curves of relapse-free survival (dashed lines) using the data cutoff of April 30, 2018.
Fig 4.
Fig 4.
Kaplan-Meier curve of relapse-free survival by disease stage per American Joint Committee on Cancer (AJCC) 7th edition. Data from patients with baseline stage (A) IIIA, (B) IIIB, (C) IIIC, and (D) IIIB/C disease per AJCC 7th edition are shown with a data cutoff of April 30, 2018.
Fig 5.
Fig 5.
Post hoc analysis of relapse-free survival by disease stage on the basis of American Joint Committee on Cancer (AJCC) 8th edition. Data from patients with baseline stage (A) IIIA, (B) IIIB, (C) IIIC, and (D) IIID disease per AJCC 8th edition are shown with a data cutoff of April 30, 2018.
Fig 6.
Fig 6.
Forest plot of relapse-free survival by subgroup. Number of patients are included in parentheses. Only subgroups with ≥ 20 patients are included. AJCC, American Joint Committee on Cancer.
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References

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