Adjuvant BRAF/ MEK for Stage III melanoma patients along with some thoughts on adjuvant care from melanoma Big Dogs

As a follow-up to yesterday's post....here is a look at targeted therapy as adjuvant for melanoma.  Here's a link to several previous reports including an early report on the study below:  Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.  Now, there's this:

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

Hauschile, Dummer, Schadendorf, et al. J Clin Oncol. 2018 Oct 22.

Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo 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.  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.  At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% and 54% in the dabrafenib plus trametinib arm and 40% and 38% in the placebo arm, respectively. Distant metastasis-free survival also favored dabrafenib plus trametinib. The estimated cure rate was 54% in the dabrafenib plus trametinib arm compared with 37% in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration.  Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.

And here are some thoughts on adjuvant treatment from the researchers themselves:

Adjuvant melanoma therapy with new drugs: should physicians continue to focus on metastatic disease or use it earlier in primary melanoma? Grob, Garbe, Ascierto, et al. Lancet Oncol. 2018 Dec.

It is important to differentiate between two concepts of adjuvant therapy in melanoma-what we have come to call late adjuvant and early adjuvant therapy. Early adjuvant therapy is defined as a medical intervention that is done after resection of a primary melanoma to eradicate possible undetectable minimal residual disease, whereas late adjuvant therapy is done when an overt metastatic disease (nodal or visceral) has been completely resected, to control disease better than if the same treatment were given at a later time, in the presence of multiple metastases. Early adjuvant therapy is thus a preventive treatment strategy, whereas late adjuvant therapy aims at anticipating treatment of metastatic disease. For patients with melanoma, 1-year treatment with targeted therapies and immunotherapy have only been assessed in late adjuvant settings, the outcomes of which more or less reproduce the same dramatic effect as they have in metastatic disease. However, early adjuvant therapy could provide greater benefits in terms of public health, since thin melanomas without nodal metastases are so common that they account for most deaths by melanoma. In the early adjuvant setting, a treatment course of less than 1 year might be sufficient to control the disease, with less toxicity and at reduced costs. In this Personal View, we discuss the potential benefit of short-term early adjuvant treatment in patients with stage II melanoma, with the hope that sentinel-node biopsy and the American Joint Committee on Cancer staging will soon be replaced by more relevant biomarkers to identify the most suitable candidates for early adjuvant therapy for this disease.

We've come a long way since the current immunotherapy and targeted treatments for melanoma were FDA approved in 2011.  We have much more to figure out in regard to adjuvant treatments.  And a long way to go in making sure that melanoma treatments are even more effective and accessible for ALL melanoma patients.  May 2019 bring more answers!!! - c