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.
Adjuvant therapy for melanoma Includes anti-PD-1 immunotherapy (nivolumab or pembrolizumab) and BRAF/MEK inhibitor combinations (dabrafenib/trametinib) for patients with resected high-risk disease.
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:10 year analysis among patient with melanoma with a BRAFV 600 E mutation. The risk of death was 25% lower with this combination therapy.
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 interferon 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.
Adjuvant immunotherapy induced improved survival compared with those who did not have adjuvant immunotherapy in patients with stage 3 melanoma.
All patients had stage 3 melanoma that was surgically removed.
Patients who received systemic therapies prior to surgery, and those who received chemotherapy after surgery were excluded.
The 24-month OS rate was 83% for those receiving adjuvant immunotherapy versus 80% when immunotherapy was not given.
Patients with stage 3C resected melanoma who received adjuvant immunotherapy experienced improved survival, 32.8 months vs 28.0 months.
The five-year follow up of a phase 3 trial involving patients with resected stage III melanoma with BRAF mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in longer duration of survival without relapse or distant metastases than placebo with no apparent long term toxic effects (Dummer R).
In adjuvant treatment for stage III melanoma the occurrence of immune related adverse effects was associated with a longer relapse free survival in pembrolizumab arm.
KEYNOTE-054 demonstrated that adjuvant Pembrolizuman in patients with resected high-risk stage III cutaneous melanoma provided a significant and clinically meaningful improvement in distant metastasis free survival in a 3.5 year median follow up, consistent with the improvement in recurrence free survival.
At a minimum of four years follow up, Nivolumab demonstrated sustained recurrence free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long term treatment benefit with Nivolumab.
Injectable talimogene to tumors in a neoadjuvant fashion to enhance T cell activation, attracting cytokines and dendritic cells can enhance systemic responses to immunotherapy when added to checkpoint inhibition in patients with extensive melanoma. with lesions accessible to direct intralesional injection.
Adjuvant therapy for melanoma refers to additional treatment given after surgical removal (resection) of the primary tumor and any involved lymph nodes, with the goal of reducing the risk of recurrence in patients at high risk.
Adjuvant systemic treatment of patients with high risk resectable stage III or IV melanoma with nivolumab, Pembrolizumab, ipilimumab, or dabrafenib plus trametinib in patients with BRAF mutations improves recurrence free survival and is standard of care.
The specific indications and treatment selection depend on disease stage and BRAF mutation status.
Stage IIB-C melanoma: Adjuvant nivolumab or pembrolizumab for 12 months is FDA-approved and recommended by NCCN guidelines based on improved recurrence-free survival (RFS).
For stage IIB-C disease, pembrolizumab demonstrated 36-month RFS of 76.2% versus 63.4% with placebo, while nivolumab showed 12-month RFS of 89.0% versus 79.4% with placebo.
Observation remains an option, particularly given the lack of overall survival (OS) benefit demonstrated to date and the risk of immune-related toxicities, including approximately 15% risk of lifelong endocrine dysfunction.
Stage IIIA-D melanoma: NCCN guidelines recommend 12 months of adjuvant therapy with nivolumab, pembrolizumab, or dabrafenib/trametinib (if BRAF V600E/K mutation-positive).
For stage III disease, pembrolizumab achieved 5-year RFS of 55.4% versus 38.3% with placebo, while nivolumab demonstrated 5-year RFS of 50% versus 39% with ipilimumab.
Observation is preferred for most stage IIIA patients given their higher melanoma-specific survival (88% at 10 years) and lack of OS benefit data.
In the Check Mate 238 trial patients with resected stage IIIB-C or stage IV melanoma, who were treated with nivolumab had a longer recurrence free survival than those who received ipilimumab.
For BRAF wild-type melanoma, anti-PD-1 monotherapy (nivolumab or pembrolizumab) is preferred.
For BRAF V600E/K mutation-positive melanoma, either anti-PD-1 therapy or dabrafenib/trametinib is appropriate.
Neoadjuvant therapy is increasingly favored for resectable stage III disease with clinically positive nodes.
Two trials demonstrated superior event-free survival with neoadjuvant approaches: nivolumab/ipilimumab showed 12-month EFS of 84% versus 57% with adjuvant anti-PD-1, while neoadjuvant pembrolizumab achieved 2-year EFS of 72% versus 49% with adjuvant pembrolizumab.
Major pathologic response following neoadjuvant nivolumab/ipilimumab is associated with >90% 3-year RFS even without additional adjuvant therapy.
The TAMARIS study showed adjuvant treatment was associated with improved OS 2-year OS 90% versus 79% with observation), though this benefit was not observed in patients with stage IIIA disease, age >75 years, or tumors without ulceration.
This is most commonly recommended for stage III melanoma (and sometimes resected stage IV or high-risk stage II), where microscopic cancer cells may remain despite complete surgery.
Current standard approaches emphasize systemic therapies, particularly immunotherapy and targeted therapy for BRAF-mutant cases.
Options:
Primary Adjuvant Therapies
Immunotherapy with checkpoint Inhibitors are the most widely used and recommended for most patients:
Pembrolizumab (Keytruda) — Anti-PD-1 therapy; FDA-approved for resected stage IIB, IIC, III, and IV melanoma. It significantly improves recurrence-free survival (RFS) and has shown long-term benefits.
Nivolumab (Opdivo) — Another anti-PD-1; approved for resected stage IIB/C, III, and IV: often preferred or equivalent to pembrolizumab in many guidelines.
These PD-1 inhibitors are typically given for about 1 year (e.g., every 3–6 weeks).
Targeted Therapy (for BRAF V600-mutant melanoma):
Dabrafenib (Tafinlar) + Trametinib (Mekinist) — BRAF/MEK inhibitor combination; FDA-approved for resected stage III (and some stage IV) BRAF-mutated cases.
This is an alternative to immunotherapy, especially if the tumor has a BRAF mutation that is present in ~40–50% of cutaneous melanomas.
Stage II (high-risk, e.g., IIB/IIC): Adjuvant PD-1 inhibitors (pembrolizumab or nivolumab) may be offered to reduce recurrence risk, though not all patients require it. discuss benefits vs. side effects.
Stage III (and resected stage IV): Adjuvant therapy is strongly recommended for most patients (IIIA–IIID).
Options include PD-1 monotherapy (preferred for many) or BRAF/MEK if mutated.
Combination approaches (e.g., nivolumab + relatlimab) are emerging but primarily for advanced disease; ongoing trials explore expansions.
Stage I/IIA: Generally not recommended outside clinical trials.
Neoadjuvant therapy (given before surgery) is increasingly used for resectable stage III/IV and may shift to perioperative approaches (neo + adjuvant).
Side effects of immunotherapy can include immune-related issues (fatigue, rash, thyroid problems, colitis), while targeted therapies may cause fever, fatigue, or skin changes.
Decisions depend on factors like tumor stage, BRAF status, patient’s overall health, and preferences.
Multidisciplinary input (oncologist, surgeon) is key. For the most personalized advice, consult an oncologist, as guidelines evolve and individual cases vary.
The trend at this time is however is the use of neoadjuvant immunotherapy for stage III melanoma.