Twelve months of adjuvant therapy with dabrafenib (Tafinlar®; Novartis) plus trametinib (Mekinist®; Novartis), led to durable long-term relapse-free survival (RFS) in patients with resected stage III melanoma with BRAF V600 mutations. That is the conclusion from a five-year analysis featuring extended follow-up from the phase III COMBI-AD study. The efficacy of adjuvant treatment with dabrafenib plus trametinib on long-term overall survival (OS) remains to be determined.

Photo: Reinhard Dummer, MD, is a Professor of the University of Zurich and Vice-Chairman of the Department of Dermatology in the University Hospital of Zürich, Switzerland, and is a key thought leader in worldwide cutaneous oncology. Currently, he is heading the Skin Cancer Unit and the Clinical Trial Unit of the Department of Dermatology. Professor Dummer began his medical education in hematology and oncology before successfully completing his dermatology residency in Würzburg, Germany, and Zürich in 1992.Photo courtesy: © 2020 University Hospital of Zürich, Switzerland. Used with permission.

The latest study findings from the phase III COMBI-AD study were published by Reinhard Dummer, M.D, vice-chairman, Department of Dermatology, the University Hospital of Zürich, Switzerland, and colleagues, in the September 2, 2020 issue of The New England Journal of Medicine (NEJM).[1]

Dummer and his colleagues write that an anti-PD-1 therapy with nivolumab and pembrolizumab and a combination of targeted drugs dabrafenib and trametinib have shown significant RFS benefits and are considered to be the current standard-of-care adjuvant therapies in resected melanoma. However, Dummer and his colleagues noted that the durability of these benefits with continued follow-up remains an important open issue.

In the phase III COMBI-AD trial that involved the patients with resected stage III melanoma with BRAF mutations, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer three-year RFS than placebo (58% vs 39%; hazard ratio [HR] 0.47; 95% CI 0.39 to 0.58; p < 0.001).

A three-year comparison of OS between dabrafenib plus trametinib and placebo (86% vs 77%; HR 0.57; 95% CI 0.42 to 0.79; p = 0.0006) in a pre-planned interim analysis that was based on a 26% information fraction did not reach the prespecified significance threshold.

To confirm the long-term stability of the RFS benefit associated with 12 months of adjuvant treatment with dabrafenib plus trametinib, in the article published in the NEJM the study team reported the five-year analyses, including RFS and survival without distant metastasis as the site of the first relapse, based on extended follow-up.

Study design
The study investigators randomly assigned 870 patients who had resected stage III melanoma with BRAF mutations to receive 12 months of oral dabrafenib plus trametinib or two matched placebos. The study primary endpoint was RFS. The OS was not analyzed, since the required number of events to trigger the final OS analysis had not been reached.

The minimum duration of follow-up was 59 months with a median patient follow-up of 60-months for dabrafenib plus trametinib and 58 months for placebo. At 5 years, the percentage of patients who were alive without relapse was 52% (95% CI 48 to 58) with dabrafenib plus trametinib and 36% (95% CI 32 to 41) with placebo (HR for relapse or death, 0.51; 95% CI 0.42 to 0.61).

Sixtyfive percent of patients who were alive without distant metastasis was 65% (95% CI 61 to 71) with dabrafenib plus trametinib and 54% (95% CI 49 to 60) with placebo (HR for distant metastasis or death, 0.55; 95% CI 0.44 to 0.70).

Safety analyses
Updated safety analyses were not performed at this data cut-off because no patients were continuing to receive therapy during the extended follow-up period, and reporting of side effects after that point was at the investigator’s discretion. The vast majority of the participating patients had side effects only during the initial 12 months treatment window. Overall, no clinically meaningful difference in the incidence or severity of serious side effects was reported during the follow-up period between the groups.

Dummer and his colleagues concluded that in the five-year follow-up of a COMBI-AD study, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term side effects.

The study was funded by GlaxoSmithKline and Novartis.

Note
Dabrafenib in combination with trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. The combination is also indicated for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.

Limitation of Use
Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma.

Clinical trials
Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD) – NCT01682083 (EudraCT number, 2012-001266-15)

Highlights of prescribing information
Dabrafenib (Tafinlar®; Novartis) – [Prescribing Information]
Trametinib (Mekinist®; Novartis) [Prescribing Information]

Reference
[1] Dummer R, Hauschild A, Santinami M, et al. Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. NEJM; Published online 2 September 2020. DOI: 10.1056/NEJMoa2005493.

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