Adjuvant therapy for melanoma

Adjuvant therapy in melanoma refers to treatment or treatments that are given after primary treatment in order to lower the risk of recurrence.

Most often the primary treatment for melanoma is surgery.

Adjuvant therapy assists primary treatment by attempting to eliminate any microscopic cells that may have escaped surgical removal.

Radiation is sometimes recommended as an adjuvant treatment if there is a high risk for local occurrence.

Presently, systemic adjuvant therapies can target cells or enhance the immune system.

Adjuvant therapies are recommended for melanomas that are at moderate or high risk of recurrence.

Risk is associated with characteristics of the tumor such as thickness, ulceration, high mitotic rate and involvement of local lymph nodes.

This information is used to determine the stage of melanoma.

Three immunotherapies and one targeted therapy combination are currently FDA approved for adjuvant therapy of melanoma:

Tafinlar and Mekinist were approved in combination 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.

Approval was based on COMBI-AD (NCT01682083), an international, multi-center, randomized, double-blind, placebo-controlled trial in 870 patients with Stage III melanoma with BRAF V600E or V600K mutations.

The major efficacy outcome was relapse-free survival (RFS).

Patients who received the combination treatment had a statistically significant improvement in RFS compared with those receiving placebo.

Nivolumab was approved as an adjuvant treatment for completely resected Stage III or IV melanoma based on a clinical trial comparing Nivolumab to ipilimubab .

Nivolumab is the first PD-1 inhibitor to be approved as an adjuvant therapy in patients with lymph node involvement or metastatic disease who have undergone complete resection.

Patients treated with Nivolumab had fewer side effects, with 9% of patients discontinuing treatment due to adverse reactions and showed a longer time before a recurrence compared to ipilimubab.

Ipilimumab is an anti-CTLA-4 antibody, was approved as an adjuvant therapy in patients with Stage III melanoma based on findings that survival was prolonged when compared to patients treated with placebo.

Interferon use was approved for treatment of high-risk melanoma after surgery, but it is controversial due to its harsh side effects and low impact on recurrence and survival.

Ipilimumab and nivolumab are approved for adjuvant therapy with benefit seen in both BRAF mutant and BRAF wild-type patients.

Single agent BRAF inhibitor, vemurafenib, does not show overall benefit as adjuvant therapy.

In the adjuvant setting for patients with stage III melanoma: nivolumab, an anti-PD-1 antibody which was approved based on data in the Checkmate 238 study which compared patients who received nivolumab vs patients who received ipilimumab.

In the Checkmate 238 study all of the patients had Stage IIIB, IIIC, or stage IV melanoma that had been resected and were randomized on a one to one basis to receive ipilimumab, which was the control arm, or nivolumab, which was the experimental arm: dramatic improvement in relapse free-survival in patients who were treated with nivolumab.

Approval for the combination of two agents, dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, and this combination had previously been approved for treatment of metastatic V600K or V600E mutant melanoma.

The COMBI-AD trial, which was a study of these two drugs, dabrafenib plus trametinib vs a double placebo, the combination demonstrated significant improvement in relapse-free survival, distant metastasis-free survival and overall survival for patients with stage III melanoma.

Adjuvant therapy for melanoma is that we have options: nivolumab, dabrafenib plus trametinib and the prior options, either ipilimumab or adjuvant interferon or observation are less likely going to be implemented.

Ipilimumab and interfernon for patients with stage III melanoma is no longer an appropriate therapy.

Changes in this staging system: in stage III melanoma there are now four sub-stages A, B, C and D.

Patients with stage IIIA in the older staging system had a higher risk of recurrence than in the new staging system which incorporates the thickness of the primary tumor among other features, including nodal involvement, which helps us to concentrate most of the risk to patients with stage IIIC or stage IIID melanoma.

The indication for nivolumab and trametinib and dabrafenib are in patients with stage III resected melanoma but that may not be appropriate for all stage III melanoma patients.

In patients who have a sentinel lymph node biopsy, a complete lymph node dissection is performed if there is a high enough risk primary melanoma, or if there is pathological involvement of the sentinel lymph node.

However, in the MSLT-II study, which compared patients who received a sentinel lymph node biopsy and randomized patients who had a positive sentinel lymph node biopsy to either lymph node basin monitoring with ultrasound or completion node dissection and the data, which was published in June 2017, demonstrated that patients who had completion of node dissection didn’t appear to have any better overall survival or distant metastasis-free survival than those patients who did not have a complete lymph node dissection.

When two drugs, an anti-CTLA4 antibody like ipilimumab and an anti-PD1 antibody like nivolumab are administered together, there is much higher toxicity than when you give either by themselves.

The BRAF-MEK inhibitor combination of dabrafenib plus trametinib has been approved for adjuvant use. immunotherapy.

Dabrafenib plus trametinib vs dabrafenib plus trametinib with pembrolizumab, revealed triplet therapy improved progression free survival compared to the doublet dabrafenib plus trametinib therapy and possibly improved duration of response in patients who got the triple therapy.

In the absence of head-to-head comparisons therapy for BRAF-mutated patients who have stage III melanoma, is just as good to give a BRAF-MEK inhibitor combination therapy as it is to give single agent nivolumab.

Patients are less likely to have severe toxicity with nivolumab, but, are more likely to have permanent toxicity with nivolumab.

If a patient is BRAF-mutated and has a high-risk melanoma that has been removed, the likelihood is that they will need both targeted therapy and immunotherapy over the course of their lifetime to treat their cancer.

BRAF-targeted therapy in the adjuvant setting works differently in the adjuvant setting than it does in the metastatic setting.

The COMBI-AD suggests that patients can stop therapy after 1 year of treatment and have a sustained improvement in relapse-free survival and overall survival compared to those who got placebo.