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

Adjuvant Therapy

Adjuvant therapy in melanoma is a treatment or treatments that are given after primary treatment in order to lower the risk of recurrence (that the cancer may return). Most often in melanoma, the primary treatment is surgery. Surgery aims to remove all visible tumor on physical examination and scans, such as Xrays and CT scans. It is possible that small numbers of cancer cells may be undetectable and therefore not removed by surgery. Adjuvant therapy aims to assist primary treatment by eliminating any microscopic cells that may have escaped surgical removal.

In addition to surgery, radiation is sometimes recommended as an adjuvant treatment if there is a high risk for local occurrence where the tumor or lymph nodes were surgically removed.

Newer, recently approved systemic (traveling through the bloodstream) adjuvant therapies mean that medicines can target cells or enhance the immune system anywhere in the body.

Risk of Recurrence

Adjuvant therapies are recommended for those at moderate or high risk of recurrence. Risk is associated with characteristics of the tumor such as thickness, ulceration, high mitotic (growth) rate and involvement of local lymph nodes. This information is used to determine the stage of melanoma.

Clinical trials are exploring which patients may be at moderate or high risk for recurrence. Trials are also working to determine if there are other factors that can identify which patients would benefit from adjuvant therapy. A medical oncologist will work with a surgeon to determine whether adjuvant treatment may be helpful in lowering the risk of recurrence.

FDA-Approved Adjuvant Treatments for Melanoma

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

Pembrolizumab (Keytruda^®)

In February 2019, Keytruda was FDA-approved for the adjuvant treatment of patients with melanoma with lymph node(s) involvement, following complete resection. Approval was based on EORTC1325/KEYNOTE-054, a randomized, double-blind, placebo-controlled trial in 1,019 patients with completely resected Stage IIIa, IIIb or IIIc melanoma. The primary efficacy outcome measure was recurrence-free survival (RFS).

Dabrafenib (Tafinlar^®) + Trametinib (Mekinist^®) 

In April 2018, 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 (Opdivo^®)

In December 2017, Opdivo was approved as an adjuvant treatment for completely resected Stage III or IV melanoma based on a clinical trial comparing Opdivo to Yervoy. Opdivo 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 Opdivo had fewer side effects, with 9% of patients discontinuing treatment due to adverse reactions and showed a longer time before a recurrence compared to Yervoy. More time is needed to follow patients and to learn the effect on overall survival.

Ipilimumab (Yervoy^®)

In October 2015, Yervoy, 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. Side effects can be significant, leading to discontinuation of therapy in half of the patients.

Peginterferon alpha 2-b (Sylatron^®)

Interferon was approved in 1995 for treatment of high-risk melanoma after surgery. Its use has been controversial due to its harsh side effects and low impact on recurrence and survival. Interferon has not shown a beneficial effect in advanced melanoma.

So, what does this mean for patients?

With new drug approvals, patients have more and better treatment options than ever before. These advances have changed the way patients are treated.

Patients with early stage disease completely removed by surgery should discuss adjuvant therapies with their treatment team. Some questions to ask include:

• Will adjuvant therapy decrease my chance of recurrence?
• Which adjuvant therapy do you recommend and why?
• What are the side effects?
• How long would I be treated?
• Is there a clinical trial that would be right for me?

What’s next?

Great progress has been made but questions remain. Clinical trials are testing additional treatments, including vaccines, combination immunotherapies and targeted therapies. Clinical trials are examining the best dose, the duration of treatment, drug combinations vs single drugs, and biomarkers that may help doctors choose the best drug for each patient.

Building on the improvement seen in patients with advanced disease, clinical trials have assessed whether patients with early stage melanoma at moderate to high-risk of recurrence would also benefit. Two immunotherapies already approved for metastatic disease (ipilimumab and nivolumab) are now approved for adjuvant therapy with benefit seen in both BRAF mutant and BRAF wild-type patients. Single agent BRAF inhibitor, vemurafenib, did not show overall benefit as adjuvant therapy. However, results of the combination of a BRAF plus MEK inhibitor trial (dabrafenib plus trametinib) compared to placebo is showing a lot of promise and is being reviewed by the FDA.

The bottom line? Both FDA approved therapies and clinical trials can be a good option for patients. All options should be thoroughly discussed with your treatment team.

 

Content reviewed by Douglas Johnson, MD