Melanoma

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

early stage melanoma (melanoma in situ, stage I, stage II)

1st line – surgical excision

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1st line –

surgical excision

Early stage melanomas are confined to the skin. This group includes melanoma in situ, stage I, and stage II disease.

The standard of care is wide local excision (WLE) of the primary site, with an appropriate margin.[14] [ ]

The recommended surgical margin increases as tumor thickness increases.[14] A melanoma with greater thickness is more likely to extend wider and deeper than than the clinically and histologically apparent tumor.[87]

Recommended excision margins are: melanoma in situ (confined to the epidermis), margin 0.5-1 cm (margins >0.5 cm may be needed for lentigo maligna subtype melanomas); tumor thickness ≤1 mm, margin 1 cm; tumor thickness 1-2 mm, margin 1-2 cm; tumor thickness >2 mm, margin 2 cm; tumor thickness >4 mm: margin 2 cm.[14][76]

Typically, for invasive melanoma all tissue is removed to the depth of the fascia. The fascia itself is preserved, unless involved by tumor.[14] Peripheral resection margins may be modified to accommodate individual anatomic or functional considerations; however, narrower margins may increase the risk for margin positivity and/or local recurrence.[14]

Mohs micrographic surgery (MMS) may be considered for selected patients with minimally invasive tumors affecting anatomically constrained sites, such as the ears, face, or acral areas.[14] Excised tissue is processed into frozen horizontal sections for immediate histopathologic analysis. The process is repeated until the tumor is completely removed, enabling maximum conservation of healthy tissue.[90] However, permanent (paraffin-fixed) sections are the gold standard for histologic evaluation of excised melanoma.[14] Atypical melanocytes may be more difficult to interpret on frozen sections compared with permanent sections. If MMS is used, the central debulking specimen should be analyzed as a permanent section to provide complete staging information. It may be appropriate to delay wound closure or reconstruction until histologic evaluation of the excised tissue is complete.[14]

One systematic review of comparative studies concluded that survival and local recurrence rates are similar for patients with melanoma on the trunk and extremities who are treated with MMS or WLE.[91] However, a further systematic review which included both comparative and noncomparative studies found that the rate of local recurrence of melanoma was significantly reduced with MMS compared with WLE.[92]

MMS is not currently recommended for treatment of melanoma if standard excision margins can be obtained.[14]

Consider – sentinel lymph node biopsy

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Consider –

sentinel lymph node biopsy

Treatment recommended for SOME patients in selected patient group

A radiotracer or a blue dye is injected intradermally at the site of the primary lesion (before wide local excision) to identify the sentinel node.[14]

SLNB may be performed for selected patients with stage I and stage II melanoma. It permits accurate staging of patients with no clinical or radiologic evidence of nodal metastases, and provides prognostic information. Sentinel lymph node status is the most important prognostic indicator in this group, and can determine next steps in treatment.[14][95]

National Comprehensive Cancer Network guidelines advise that SLNB should be discussed with patients with stage IB or II disease with the following considerations: tumor thickness <0.8 mm with ulceration; tumor thickness 0.8 to 1.0 mm with or without ulceration; tumor thickness >0.5 mm who have additional adverse prognostic features (e.g., age ≤42 years, head/neck location, lymphovascular invasion, and/ or mitotic index ≥2/mm²).

The probability of a positive SLNB is 5% to 10% for these patients, with an increased risk for patients with multiple adverse prognostic features.[14]

SLNB is not generally recommended for patients with tumors <0.8 mm thick without ulceration or adverse prognostic features, unless there is significant uncertainty about the adequacy of microstaging (e.g., positive deep margins or limited sampling of a larger lesion). The risk of positive SLNB in these patients is <5%.[14]

SLNB does not improve overall survival for patients with melanoma, but subgroup analysis of the Multicenter Selective Lymphadenectomy Trial (MSLT)-I showed that SLNB improves the 10-year distant disease-free survival for patients with melanomas between 1.2 and 3.5 mm in thickness.[74] [ ]

UK guidelines recommend considering SLNB as a staging (rather than therapeutic) procedure for patients with a Breslow thickness of 0.8 to 1.0 mm, with at least one of following features: ulceration; lymphovascular invasion; a mitotic index of 2 or more.[56] For people without adverse prognostic features, SLNB should be considered with a Breslow thickness of greater than 1.0 mm.[56] Consider delaying SLNB for pregnant women until postpartum.

When microsatellitosis is present in the initial biopsy, this indicates a pathologic stage of at least N1c in AJCC TNM staging, and therefore these patients should be treated as patients with stage IIIB disease.[14] Patients should be offered sentinel node biopsy, the decision not to perform SLNB may be based on significant patient comorbidities, patient preference, or other factors such as advanced patient age and/or poor functional status.[14] BRAF mutation testing should be completed if adjuvant systemic therapy or clinical trial is being considered.[14]

One phase 3 trial reported that SLNB does not improve overall survival for patients with melanoma, but subgroup analysis of the Multicenter Selective Lymphadenectomy Trial (MSLT)-I showed that SLNB improves the 10-year distant disease-free survival for patients with melanomas between 1.2 and 3.5 mm in thickness.[74] [ ] However, subsequent evidence from a systematic review demonstrated that SLNB is associated with improved overall survival in patients with head and neck cutaneous melanoma.[75]

Consider – adjuvant systemic treatment or observation or clinical trial

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Consider –

adjuvant systemic treatment or observation or clinical trial

Treatment recommended for SOME patients in selected patient group

For patients with resected stage IIB or IIC melanoma with negative sentinel nodes, with no microscopic satellites in the primary biopsy, adjuvant therapy with a PD-1 inhibitor (pembrolizumab or nivolumab) is recommended.[14][96][97]

For patients with microscopic satellites in the primary biopsy, who are sentinel node negative, or did not undergo SNLB, treatment options post wide excision include adjuvant systemic therapy (preferred options nivolumab, pembrolizumab, or dabrafenib plus trametinib if BRAF V600 mutation positive).[14]

Patients with resected stage IB, IIB, or IIC melanoma with positive sentinel nodes, with or without microscopic satellites in the primary biopsy should be treated as patients with primary stage III tumors.[14]

Antibodies to programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) block the interaction of the inhibitory receptor PD-1 on T cells with PD-L1 expressed on tumor cells, thus facilitating antitumor immunity. Systemic adjuvant treatment is not considered for early stage melanoma (stage II) outside of a clinical trial.[14][96]

Adjuvant therapy with a PD-1 inhibitor (pembrolizumab or nivolumab) is recommended for patients with resected stage IIB and IIC melanoma.[96][97] If considered, the benefit and toxicity of treatment should be discussed with the patient. Additionally patient age, performance status, personal or family history of autoimmune disease, and tolerance of risk should be assessed.[14]

The first interim analysis of the Keynote-617 trial reported that at a median follow-up of 14.4 months, pembrolizumab significantly prolonged recurrence-free survival, compared with placebo (hazard ratio [HR] 0.65, 95% CI 0.46 to 0.92) in patients with resected high-risk stage II melanoma.[98] The 12-month recurrence-free survival rate was 90.5% in the pembrolizumab group and 83.1% in the placebo group. Grade 3-5 drug-related adverse events occurred in 78 (16.1%) patients in the pembrolizumab group and 21 (4.3%) patients in the placebo group; 74 (15.3%) versus 12 (2.5%) discontinued because of a drug-related adverse event.[99] Immune-mediated adverse events occurred in 36.2% of patients in the pembrolizumab group, compared with 8.4% in the placebo group. The most common immune-mediated adverse events were hypothyroidism and hyperthyroidism. Most were grade 1-2 in severity.[99] At the second interim analysis, median follow-up of 20.9 months, 15% of patients in the pembrolizumab group and 24% in the placebo group had a first recurrence or died (HR 0.61, 95% CI 0.45 to 0.82).[100]

The prespecified third interim analysis of the secondary outcomes of the KEYNOTE-716 trial reported that adjuvant pembrolizumab significantly improved distant metastasis-free survival, and reduced the risk of recurrence, compared with placebo.[101]

The combination of dabrafenib (a BRAF inhibitor) plus trametinib (a MEK inhibitor) was explored in the COMBI-AD study.[118][117] Patients (n=870) with fully resected stage III melanoma with BRAF V600E or V600K mutations and no prior radiation therapy or systemic therapy were randomized to either dabrafenib plus trametinib or two matched placebos, for 12 months. The trial met its primary endpoint of relapse-free survival, both at the time of the primary interim analysis at 2.8 years and in a subsequent analysis at 5 years. At 5 years of follow-up, relapse-free survival was 52% in the adjuvant dabrafenib plus trametinib group, compared with 36% in the placebo group (hazard ratio 0.51, 95% CI 0.42 to 0.61).[119] This result was consistent across all patient subgroups, regardless of stage III substage and the specific BRAF mutation.

Approximately 41% of patients receiving adjuvant dabrafenib plus trametinib experienced grade 3-4 adverse events, compared with 14% in the placebo group.[118] Furthermore, 26% of patients prematurely ceased adjuvant dabrafenib-trametinib because of toxicity, although no long-term toxicity or treatment-related deaths were reported.[118]

For patients with microscopic satellites in the primary biopsy who are sentinel node negative, or did not undergo SNLB, treatment options post wide excision include observation or entry into a clinical trial.[14]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

nivolumab

dabrafenib

and

trametinib

2nd line – topical imiquimod or radiation therapy

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2nd line –

topical imiquimod or radiation therapy

Topical imiquimod or radiation therapy can be considered for select patients with melanoma in situ or locoregional melanoma with positive margins after biopsy to exclude invasive disease, or post surgical excision when further resection is not feasible.[14][56]

There is evidence that topical imiquimod is safe and well tolerated, with clearance rates ranging from 53% to 92% for patients with melanoma in situ, and can attain unstable locoregional control for patients with metastatic melanoma.[93][94]

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

Consider – sentinel lymph node biopsy

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Consider –

sentinel lymph node biopsy

Treatment recommended for SOME patients in selected patient group

Sentinel lymph node biopsy (SLNB) is based on the concept that a tumor will drain to a particular first lymph node with a lymph node basin. There may be multiple draining lymph node basins and multiple sentinel nodes, depending on individual lymphatic drainage patterns. A radiotracer or a blue dye is injected intradermally at the site of the primary lesion (before wide local excision) to identify the sentinel node.[14]

The probability of a positive SLNB is 5% to 10% for these patients, with an increased risk for patients with multiple adverse prognostic features.[14]

Consider – systemic treatment or observation or clinical trial

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Consider –

systemic treatment or observation or clinical trial

Treatment recommended for SOME patients in selected patient group

For patients with microscopic satellites in the primary biopsy, who are sentinel node negative, or did not undergo SNLB, treatment options include adjuvant systemic therapy (preferred options nivolumab, pembrolizumab, or dabrafenib plus trametinib if BRAF V600 mutation positive).[14]

Patients with stage IB, IIB, or IIC melanoma with positive sentinel nodes, with or without microscopic satellites in the primary biopsy should be treated as patients with primary stage III tumors.[14]

Adjuvant therapy with PD-1 inhibitors (pembrolizumab or nivolumab) is recommended for patients with resected stage IIB and IIC melanoma.[96][97] If considered, the benefit and toxicity of treatment should be discussed with the patient. Additionally patient age, performance status, personal or family history of autoimmune disease, and tolerance of risk should be assessed.[14]

The combination of dabrafenib (a BRAF inhibitor) plus trametinib (a MEK inhibitor) was explored in the COMBI-AD study.[117][118] Patients (n=870) with fully resected stage III melanoma with BRAF V600E or V600K mutations and no prior radiation therapy or systemic therapy were randomized to either dabrafenib plus trametinib or two matched placebos, for 12 months. The trial met its primary endpoint of relapse-free survival, both at the time of the primary interim analysis at 2.8 years and in a subsequent analysis at 5 years. At 5 years of follow-up, relapse-free survival was 52% in the adjuvant dabrafenib plus trametinib group, compared with 36% in the placebo group (hazard ratio 0.51, 95% CI 0.42 to 0.61).[119] This result was consistent across all patient subgroups, regardless of stage III substage and the specific BRAF mutation.

Approximately 41% of patients receiving adjuvant dabrafenib plus trametinib experienced grade 3-4 adverse events, compared with 14% in the placebo group.[117] Furthermore, 26% of patients prematurely ceased adjuvant dabrafenib-trametinib because of toxicity, although no long-term toxicity or treatment-related deaths were reported.[117]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

nivolumab

dabrafenib

and

trametinib

stage III melanoma with negative sentinel nodes

1st line – surgical excision

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1st line –

surgical excision

Initial therapy is with wide local excision.[14]

Consider – systemic treatment or observation or clinical trial

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Consider –

systemic treatment or observation or clinical trial

Treatment recommended for SOME patients in selected patient group

Treatment options post wide excision include adjuvant systemic therapy (preferred options nivolumab, pembrolizumab, or dabrafenib plus trametinib if BRAF V600 mutation positive), observation or entry into a clinical trial.[14]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

nivolumab

dabrafenib

and

trametinib

stage III melanoma with positive sentinel nodes

1st line – nodal basin radiation therapy

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1st line –

nodal basin radiation therapy

In the US, the preferred primary treatment for patients with stage III/B/C/D sentinel node positive melanoma is active nodal basin ultrasound or other radiographic surveillance without complete lymph node dissection if institutional expertise is available.[14]

Consider – systemic therapy or observation

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Consider –

systemic therapy or observation

Treatment recommended for SOME patients in selected patient group

With or without completion node dissection, it is recommended that adjuvant systemic therapy be considered based on the risk of recurrence.[14] In patients with very low tumor volume stage IIIA disease (T1a/b-T2a/N1a or N2a), the toxicity of adjuvant therapy may outweigh the benefit and observation may be the preferred option.[14]

Preferred regimens include nivolumab, pembrolizumab, or dabrafenib plus trametinib if BRAF v600 positive.[14]

T1b-T2a/N1a or N2a pathologic stage IIIA melanoma and SLN tumor deposits ≥0.3 mm in maximum dimension are at higher risk of disease progression and may benefit from adjuvant systemic therapy. Stage IIIA patients with SLN deposits <0.3 mm in maximum dimension demonstrate 5-year MSS similar to those with pathologic stage IB (T2aN0) melanoma, with consideration for less intensive radiologic surveillance and follow-up.[14]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

nivolumab

dabrafenib

and

trametinib

1st line – complete lymph node dissection

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1st line –

complete lymph node dissection

When SLNB is positive, the patient may be a candidate for completion lymph node dissection.[14][56] This is the removal of all lymph nodes in the regional nodal basin.

In the UK, routine completion lymph node dissection would not be offered to patients with stage III melanoma with micrometastatic nodal disease detected by SLNB unless: there are factors that might make recurrent nodal disease difficult to manage, for example, for patients with melanoma of the head, neck for whom stage III adjuvant therapies are contraindicated, or when regular follow-up is not possible; and after discussion with the patient and specialist skin cancer multidisciplinary team.

Complete therapeutic lymph node dissection is recommended for patients with palpable stage IIIB to IIID melanoma, or cytologically or histologically confirmed nodal disease.[56]

In the US in select clinical scenarios, for example, inability to adhere to clinical and imaging surveillance, or when primary tumor characteristics and SLN tumor burden predict a high likelihood of additional positive nodes, completion lymph node dissection may be considered for regional disease control.[14]

Consider – systemic therapy or observation

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Consider –

systemic therapy or observation

Treatment recommended for SOME patients in selected patient group

Preferred regimens include nivolumab, pembrolizumab, or dabrafenib plus trametinib if BRAF v600 positive.[14]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

nivolumab

dabrafenib

and

trametinib

stage III melanoma with clinically positive nodes: resectable

1st line – neoadjuvant systemic therapy

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1st line –

neoadjuvant systemic therapy

Clinically positive (i.e., palpable) lymph nodes are associated with a worse prognosis than nonpalpable lymph nodes with microscopic evidence of melanoma only.[14] Preferred regimens for neoadjuvant systemic therapy for patients with resectable stage III nodal disease include pembrolizumab, nivolumab plus ipilimumab, or dabrafenib plus trametinib for patients who are BRAF V600 mutation positive.[14][96]

One phase 3 trial of patients with resectable, macroscopic stage III melanoma, neoadjuvant nivolumab plus ipilimumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab.[108]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

nivolumab

and

ipilimumab

dabrafenib

and

trametinib

Plus – surgery with or without therapeutic lymph node dissection

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Plus –

surgery with or without therapeutic lymph node dissection

Treatment recommended for ALL patients in selected patient group

Wide local excision of the primary lesion should be performed for all patients with advanced stage III nodal disease.[14] Surgery may include therapeutic lymph node dissection if not performed earlier.[14]

Plus – adjuvant systemic therapy or observation

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Plus –

adjuvant systemic therapy or observation

Treatment recommended for ALL patients in selected patient group

After surgery, patients should be offered adjuvant treatment with a PD-1 inhibitor (nivolumab or pembrolizumab). BRAF/MEK inhibition with dabrafenib plus trametinib is an alternative adjuvant treatment option for patients with an activating BRAF-V600 mutation.[14][96]

If patients have received neoadjuvant pembrolizumab, it is recommended that pembrolizumab is given as adjuvant treatment.[96]

The choice of observation versus adjuvant systemic treatment should take into consideration the patient’s risk of melanoma recurrence and the risk of treatment toxicity.[14]

Adjuvant treatment has been demonstrated to improve the rate of recurrence-free survival compared with patients managed without adjuvant treatment.[111][112]

In the UK, pembrolizumab or nivolumab is recommended as an option for the adjuvant treatment of completely resected stage III melanoma with lymph node involvement in adults.[109][110]

In the CheckMate-238 trial, patients (n=906) with stage IIIB/IIIC and resected stage IV melanoma were randomized to nivolumab or ipilimumab for 1 year.[113] Nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab.

Keynote-054 examined the use of adjuvant pembrolizumab in patients with resected stage III melanoma.[114][115] Patients (n=1019) were randomized to either pembrolizumab or placebo for 1 year. At a median follow-up of 15 months, treatment with pembrolizumab resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified.[114] Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival (a secondary endpoint) at a 3.5-year median follow-up.[116]

Approximately 41% of patients receiving adjuvant dabrafenib plus trametinib experienced grade 3-4 adverse events, compared with 14% in the placebo group.[118] Furthermore, 26% of patients prematurely ceased adjuvant dabrafenib–trametinib because of toxicity, although no long-term toxicity or treatment-related deaths were reported.[118]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

pembrolizumab

nivolumab

and

ipilimumab

dabrafenib

and

trametinib

Consider – nodal basin radiation therapy

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Consider –

nodal basin radiation therapy

Treatment recommended for SOME patients in selected patient group

Radiation therapy (RT) to the nodal basin may be considered instead of or in addition to adjuvant systemic therapy in select patients who are at high risk for nodal recurrent based on the location, size and number of involved nodes, and gross and/or histologic extracapsular extension.[14]

Adjuvant nodal basin RT has been demonstrated to reduce lymph node field recurrence but no improvement has been shown in recurrence-free survival or overall survival in patients with advanced nodal melanoma.[14] Potential toxicities such as limb lymphedema or oropharyngeal complications should be considered against the benefits of treatment.[14]

1st line – surgery with or without therapeutic lymph node dissection

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1st line –

surgery with or without therapeutic lymph node dissection

Wide local excision of the primary lesion should be performed for all patients with advanced stage III nodal disease either post neoadjuvant systemic therapy or as initial treatment.[14] Surgery may include therapeutic lymph node dissection if not performed earlier.[14]

Plus – adjuvant systemic therapy or observation

Back

Plus –

adjuvant systemic therapy or observation

Treatment recommended for ALL patients in selected patient group

After surgery patients should be offered adjuvant treatment with a PD-1 inhibitor (nivolumab or pembrolizumab). BRAF/MEK inhibition with dabrafenib plus trametinib is an alternative adjuvant treatment option for patients with an activating BRAF-V600 mutation.[14][96]

In the UK, pembrolizumab or nivolumab are recommended as an option for the adjuvant treatment of completely resected stage III melanoma with lymph node involvement in adults.[109][110]

Adjuvant treatment has been demonstrated to improve the rate of recurrence-free survival, compared with patients managed without adjuvant treatment.[111][112]

Approximately 41% of patients receiving adjuvant dabrafenib plus trametinib experienced grade 3-4 adverse events, compared with 14% in the placebo group.[118] Furthermore, 26% of patients prematurely ceased adjuvant dabrafenib–trametinib because of toxicity, although no long-term toxicity or treatment-related deaths were reported.[118]

The choice of observation versus adjuvant systemic treatment should take into consideration the patient’s risk of melanoma recurrence and the risk of treatment toxicity.[14]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

pembrolizumab

nivolumab

and

ipilimumab

dabrafenib

and

trametinib

Consider – nodal basin radiation therapy

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Consider –

nodal basin radiation therapy

Treatment recommended for SOME patients in selected patient group

Radiation therapy (RT) to the nodal basin may be considered instead of or in addition to adjuvant systemic therapy in select patient who are at high risk for nodal recurrent based on the location, size and number of involved nodes, and gross and/or histologic extracapsular extension.[14]

stage III melanoma with satellite/in-transit metastases: limited resectable disease

1st line – neoadjuvant systemic therapy + surgery

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1st line –

neoadjuvant systemic therapy + surgery

Lymphatic metastases can be characterized as clinically, radiologically, or pathologically detectable satellite metastases (dermal and/or subcutaneous intralymphatic metastases occurring within 2 cm from the primary melanoma), or in-transit metastases (identified between 2 cm from the primary melanoma and the regional nodal basin). The 2-cm cutoff is consistent with AJCC staging definitions, but satellite and in-transit lymphatic metastases are biologically and prognostically similar.[14]

One potential treatment option for patients with limited resectable satellite/in-transit metastases is neoadjuvant systemic therapy followed by complete excision to margins.[14]

Preferred regimens for neoadjuvant systemic therapy for patients with resectable stage III nodal disease include pembrolizumab, nivolumab plus ipilimumab, or dabrafenib plus trametinib for patients who are BRAF V600 mutation positive.[14][96]

Several trials of neoadjuvant therapy are underway, with preliminary results indicating a promising role for this treatment approach in those who achieve pathologic complete response at the time of surgery.[102][103][104][105][106][107] One phase 3 trial of patients with resectable, macroscopic stage III melanoma, neoadjuvant nivolumab plus ipilimumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab.[108]

Excision to clear margins is recommended, rather than wide excision, as there are no clinical data to support wider surgical margins for satellite/intransit metastasis; however, clear histologic margins should be achieved.[14]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

nivolumab

and

ipilimumab

dabrafenib

and

trametinib

1st line – surgery

Back

1st line –

surgery

One potential treatment option for patients with limited resectable satellite/in-transit metastases is complete excision to margins.[14]

1st line – talimogene laherparepvec

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1st line –

talimogene laherparepvec

One potential treatment option for patients with limited resectable satellite/in-transit metastases is talimogene laherparepvec intralesional therapy.[14]

Some evidence suggests that talimogene laherparepvec, a modified herpes virus that induces tumor lysis and localized expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in tumor lesions, in combination with systemic treatment may increase the effectiveness of the systemic agents.[138] However, one phase 3 trial reported the talimogene laherparepvec did not significantly improve progression-free survival or overall survival when added to pembrolizumab compared with placebo/pembrolizumab in patients with advanced melanoma.[139]

Direct injection of an agent into in-transit metastases has been shown to produce local ablative effects and occasionally a systemic host response with tumor reduction in noninjected metastases.[140]

See local specialist protocol for dosing guidelines.

Primary options

talimogene laherparepvec

1st line – systemic therapy

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1st line –

systemic therapy

One potential treatment option for patients with limited resectable satellite/in-transit metastases is systemic therapy.[14]

Combination systemic therapy is preferred, recommended regimens include nivolumab plus ipilimumab, or nivolumab/relatlimab, but monotherapy with pembrolizumab or nivolumab can be considered for patients who do not want to take on a higher risk of toxicity, or who have comorbidities or autoimmune processes that would elevate the risk of immune-related adverse events.[14]

For patients with BRAF V600 mutation combination regimens include dabrafenib plus trametinib, vemurafenib plus cobimetinib, encorafenib plus binimetinib, or pembrolizumab plus ipilimumab.[14]

Nivolumab plus ipilimumab has been shown to have superior efficacy to ipilimumab monotherapy with ipilimumab for patients with advanced melanoma.[121][122][123]

The CheckMate 204 open-label trial reported that nivolumab plus ipilimumab significantly improved intracranial response rates, overall survival rates, and progression-free survival rates in patients with asymptomatic brain metastases.[124][125]

The CheckMate 067 trial compared nivolumab plus ipilimumab, nivolumab alone, and ipilimumab alone in patients with previously untreated, unresectable stage III or IV melanoma.[123] Median overall survival after a minimum follow-up of 6.5 years was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median melanoma-specific survival was not reached, 58.7 months, and 21.9 months, respectively. Overall survival rates at 6.5 years were 57%, 43%, and 25% in patients with BRAF-mutant tumors, and 46%, 42%, and 22% in those with BRAF wild-type tumors, respectively.[123] One indirect comparison demonstrated that nivolumab plus ipilimumab, and nivolumab/relatlimab have similar progression-free survival and overall survival rates in patients with advanced melanoma.[126]

Early data suggest that those who derive greater benefit from combined nivolumab and ipilimumab than from nivolumab monotherapy have tumors that do not express PD-L1.[122]

Fixed-dose combination of nivolumab/relatlimab has been demonstrated to improve progression-free survival at 12 months, and at 3 years compared with nivolumab alone patients with advanced melanoma.[127][166]

One network meta-analysis reported that for patients with advanced melanoma combination therapy with nivolumab/relatlimab demonstrated similar benefits for progression-free survival and overall response rate as patients treated with nivolumab plus ipilimumab.[129]

Available data on the use of nivolumab/relatlimab demonstrated a median progression-free survival of 10.1 months in the first-line setting.[130] This benefit was seen more frequently in patients with PD-L1 <1% and LAG-3 ≥1%.[130]

Immune-related adverse effects are common in patients treated with nivolumab/relatlimab compared to nivolumab alone.[127] Grade 3 or 4 treatment-related adverse effects are reported to occur in approximately 19% of patients treated with nivolumab/relatlimab compared with ~10% of patients receiving nivolumab alone.[127]

The PD-1 inhibitors nivolumab and pembrolizumab have demonstrated greater efficacy than standard chemotherapy with dacarbazine, and CTLA-4 inhibition with ipilimumab.[131][132]

A 5-year analysis of nivolumab monotherapy as first-line treatment for patients with previously untreated BRAF wild-type advanced melanoma confirmed the significant benefit of nivolumab monotherapy over dacarbazine for all endpoints including long-term survival.[133] Objective response rates are approximately 40% (although an estimated 60% of patients have some degree of tumor regression) and survival can be durable.[131][132][134]

A randomized controlled trial compared pembrolizumab monotherapy with ipilimumab (a fully human immunoglobulin G1 [IgG1] monoclonal antibody that blocks CTLA-4) monotherapy for patients with advanced melanoma.[131] Patients treated with pembrolizumab had a better response rate, 6-month progression-free survival, and 12-month survival, compared with patients treated with ipilimumab. Six-month progression-free survival was approximately 47% in the two pembrolizumab groups (2 weeks vs. 3 weeks dosing interval), compared with 27.5% in the ipilimumab group. Serious treatment-related adverse events were less common in the pembrolizumab groups, compared with the ipilimumab groups.[131] Further analysis after 22 months demonstrated a persistent survival benefit with pembrolizumab, compared with ipilimumab.[135] The 7-year follow-up study reported that pembrolizumab improved survival rates compared with ipilimumab (median overall survival of 32.7 months vs. 15.9 months, respectively; HR 0.70; 95% CI 0.58 to 0.83; 7-year overall survival of 37.8% and 25.3%).[136]

Adverse events of immunotherapeutic agents for advanced melanoma may include thyroiditis, skin reactions, colitis, pneumonitis, hepatitis, arthropathies, and cardiac and neurological toxicities.[137] Immunotherapy-related adverse events can affect any organ and presentation can vary greatly between patients.

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

and

ipilimumab

nivolumab/relatlimab

pembrolizumab

nivolumab

dabrafenib

and

trametinib

vemurafenib

and

cobimetinib

encorafenib

and

binimetinib

pembrolizumab

and

ipilimumab

stage III melanoma with satellite/in-transit metastases: borderline resectable or unresectable disease

1st line – systemic therapy

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1st line –

systemic therapy

US guidelines recommend systemic therapies as the preferred initial treatment.[14] Preferred systemic therapy regimens include nivolumab plus ipilimumab, or nivolumab/relatlimab, or monotherapy with pembrolizumab or nivolumab in certain circumstances, for example, for patients with low-volume in-transit disease, the high risk of toxicities associated with combination regimens may outweigh the benefits.[14] For patients who have previously received systemic therapy, either as active treatment or adjuvant therapy, the selection of the systemic therapy regimen should be informed by prior response.[14]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

and

ipilimumab

nivolumab/relatlimab

pembrolizumab

nivolumab

Consider – radiation therapy

Back

Consider –

radiation therapy

Treatment recommended for SOME patients in selected patient group

Definitive or palliative radiation therapy (RT) can be considered for unresectable melanoma, depending on the goal of treatment. Definitive RT has the intent of durable irradiated tumor control. Palliative RT has the intent of relieving symptoms caused by tumor.[14]

Consider – localized and regional treatments

Back

Consider –

localized and regional treatments

Treatment recommended for SOME patients in selected patient group

In the UK, limited excision surgery should be offered as a first-line option to patients with stage III in-transit metastases.[56]

Talimogene laherparepvec has been associated with a response rate (lasting ≥6 months) of 16% in highly selected patients with unresectable metastatic melanoma.[14] Efficacy was demonstrated in AJCC 7th Edition stage IIIB and IIIC disease, and was more likely to be seen in patients who were treatment naïve. Talimogene laherparepvec has shown similar efficacy across clinically detected/macroscopic AJCC 8th Edition stage III disease.[14] In the UK, talimogene laherparepvec is only recommended for patients with unresectable melanoma in adults with systemic therapy is not suitable.[56][167]

Isolated limb infusion or perfusion (ILI/ILP) is primarily used for patients with limb-only disease with progression on/contraindications to standard therapies.[14] This procedure should only be done at centers with experience with ILI/ILP. In the UK, ILI/ILP would only be considered for patients in whom surgery is not feasible, or who have recurrent in-transit metastases.[56]

stage IV metastatic melanoma

oligometastatic distant metastases

1st line – resection

Back

1st line –

resection

Resection is recommended as a potential first-line treatment for patients with oligometastatic metastatic disease.[14][56]

Treatment plans should be discussed by a multidisciplinary team.[14][56]

1st line – stereotactic ablative therapy

Back

1st line –

stereotactic ablative therapy

Stereotactic ablative therapy is recommended as a potential first-line treatment for patients with oligometastatic metastatic disease.[14][56]

Treatment plans should be discussed by a multidisciplinary team.[14][56]

1st line – talimogene laherparepvec

Back

1st line –

talimogene laherparepvec

Talimogene laherparepvec intralesional therapy is recommended as a potential first-line treatment for patients with oligometastatic metastatic disease with accessible lesions.[14]

Treatment plans should be discussed by a multidisciplinary team.[14][56]

Direct injection of an agent into in-transit metastases has been shown to produce local ablative effects and occasionally a systemic host response with tumor reduction in noninjected metastases.[140]

See local specialist protocol for dosing guidelines.

Primary options

talimogene laherparepvec

1st line – systemic therapy

Back

1st line –

systemic therapy

Systemic therapy is recommended as a potential first-line treatment for patients with oligometastatic metastatic disease.[14]

Treatment plans should be discussed by a multidisciplinary team.[14][56]

Preferred systemic options include nivolumab plus ipilimumab; nivolumab/relatlimab; pembrolizumab; nivolumab. For patients with BRAF V600 mutation systemic options include dabrafenib plus trametinib; vemurafenib plus cobimetinib; encorafenib plus binimetinib; pembrolizumab plus ipilimumab. Considerations for using combination therapy versus monotherapy should include the patient’s desire for potentially improved efficacy and willingness to take on a higher risk of toxicity, the absence of comorbidities or autoimmune processes that would elevate the risk of immune-related adverse effects, the tumor burden and patient social support and preparedness to work with medical team to handle toxicities.[14]

Nivolumab plus ipilimumab has been shown to have superior efficacy to ipilimumab monotherapy with ipilimumab for patients with advanced melanoma.[121][122][123]

Early data suggest that those who derive greater benefit from combined nivolumab and ipilimumab than from nivolumab monotherapy have tumors that do not express PD-L1.[122]

The PD-1 inhibitors nivolumab and pembrolizumab have demonstrated greater efficacy than standard chemotherapy with dacarbazine, and CTLA-4 inhibition with ipilimumab.[131][132]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

and

ipilimumab

nivolumab/relatlimab

pembrolizumab

nivolumab

dabrafenib

and

trametinib

vemurafenib

and

cobimetinib

encorafenib

and

binimetinib

pembrolizumab

and

ipilimumab

widely disseminated metastases without brain metastases

1st line – systemic therapy

Back

1st line –

systemic therapy

For patients with widely disseminated metastases without brain metastases systemic therapy is the preferred treatment option with symptomatic extracranial disease.[14]

Nivolumab plus ipilimumab has been shown to have superior efficacy to ipilimumab monotherapy with ipilimumab for patients with advanced melanoma.[121][122][123]

Early data suggest that those who derive greater benefit from combined nivolumab and ipilimumab than from nivolumab monotherapy have tumors that do not express PD-L1.[122]

The PD-1 inhibitors nivolumab and pembrolizumab have demonstrated greater efficacy than standard chemotherapy with dacarbazine, and CTLA-4 inhibition with ipilimumab.[131][132]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

and

ipilimumab

nivolumab/relatlimab

pembrolizumab

nivolumab

dabrafenib

and

trametinib

vemurafenib

and

cobimetinib

encorafenib

and

binimetinib

pembrolizumab

and

ipilimumab

Consider – palliative resection

Back

Consider –

palliative resection

Treatment recommended for SOME patients in selected patient group

Palliative resection can be considered in addition to systemic treatment for patients with widely disseminated metastases without brain metastases with symptomatic extracranial disease.[14]

Consider – radiation therapy

Back

Consider –

radiation therapy

Treatment recommended for SOME patients in selected patient group

Radiation therapy can be resection can be considered in addition to, or in place of palliative resection for patients with widely disseminated metastases without brain metastases with symptomatic extracranial disease.[14]

Consider – talimogene laherparepvec

Back

Consider –

talimogene laherparepvec

Treatment recommended for SOME patients in selected patient group

Talimogene laherparepvec intralesional therapy can be considered in addition to or in place of palliative resection and radiation therapy for patients with widely disseminated metastases without brain metastases with symptomatic extracranial disease.[14]

Direct injection of an agent into in-transit metastases has been shown to produce local ablative effects and occasionally a systemic host response with tumor reduction in noninjected metastases.[140]

See local specialist protocol for dosing guidelines.

Primary options

talimogene laherparepvec

Consider – best supportive/palliative care

Back

Consider –

best supportive/palliative care

Treatment recommended for SOME patients in selected patient group

Patients with widely disseminated metastases without metastases should be considered for best supportive/palliative care when needed.[14]

widely disseminated metastases with brain metastases

1st line – surgery

Back

1st line –

surgery

For patients with brain metastases a multidisciplinary evaluation (i.e., neurosurgery, radiation oncology, medical oncology) prior to initiation of treatment is strongly recommended.[14]

Patients with a higher burden of intracranial disease associated with symptoms will often require brain directed therapies. Surgery is the preferred option for large, symptomatic lesions or single lesions in resectable areas, particularly when there is diagnostic uncertainty or when additional tissue sampling may drive future therapeutic decisions.[14]

Postoperative radiation to the resection cavity may be considered to decrease the risk of local recurrence.

Adjuvant WBRT is not recommended after resection for melanoma brain metastases.

The selection of initial treatment will depend on a combination of clinical factors, such as the extent of intracranial disease, including factors such as the size, number, and location of metastases guides the initial treatment of brain metastases, and that brain-directed therapy is preferred for patients with symptomatic metastases as there are sparse data supporting the efficacy of upfront systemic therapy.[14]

In patients with other high-risk clinical scenarios (e.g., hemorrhage, eloquent cortex, brainstem), brain-directed therapy may be preferred over systemic therapy.[14]

The context in which the brain metastases developed should be considered when selecting initial treatment.[14] In patients who develop brain metastases while on systemic therapy, brain-directed therapy may be preferred.

Plus – treatment of symptoms

Back

Plus –

treatment of symptoms

Treatment recommended for ALL patients in selected patient group

The management of symptoms for patients with brain metastases includes corticosteroids (lowest dose possible), and may include standard first-line anticonvulsants for patients who experience seizures.[14]

For patients with symptomatic brain metastases initially requiring corticosteroids, surgical resection, SRS, or BRAF/MEK inhibition, it may be useful to reduce corticosteroid dose prior to transitioning to immunotherapy.[14]

Consider – stereostactic radiosurgery

Back

Consider –

stereostactic radiosurgery

Treatment recommended for SOME patients in selected patient group

SRS is the preferred radiation modality for treating melanoma brain metastases, and is used to deliver high-dose radiation to multiple lesions, usually in the brain or spine.[14]

Large lesions should be treated with fractionated SRS to decrease the risk of radionecrosis.

Adjuvant WBRT is not recommended after SRS/SRT for melanoma brain metastases.

SRS may be offered to patients with resected brain metastases depending on the size of the cavity (<5 cm).[14][147]

Cavities larger than 5 cm can be treated with SRT.[14]

SRS, as either gamma knife or linear accelerator radiosurgery, has shown a survival benefit in brain metastases treated with either modality.[148] These techniques seem to have comparable efficacy in both survival rates and decreased size of tumor, with a lower adverse-effect profile compared with whole-brain irradiation.[149]

For patients with melanoma brain metastasis (MBM), radiation therapy combined with immune checkpoint inhibitors improves the effective rate of treatment.[150] Evidence has demonstrated that immune checkpoint inhibitors plus radiation therapy significantly improves overall survival for patients with MBM.[151][152][153][154] The addition of radiation therapy may enhance the immune checkpoint inhibitor efficacy and induce more durable response via the abscopal effect.[155][156] One study reported that immune checkpoint inhibitors plus radiation therapy nonsignificantly increased ≥3 neurological adverse effects, and ≥3 radiation necrosis compared with radiation therapy alone for patients with MBM.[152]

Consider – palliative whole-body radiation therapy

Back

Consider –

palliative whole-body radiation therapy

Treatment recommended for SOME patients in selected patient group

The American Society for Clinical Oncology suggests that SRS, whole-brain radiation (WBRT), or a combination of SRS plus WBRT may all be considered as options for patients with more than four unresected brain metastases, with a KPS ≥70. For patients with a better prognosis, or if effective systemic therapy is available, SRS may be the preferred option.[147]

However, the NCCN do not recommend adjuvant WBRT after SRS/SRT for melanoma brain metastases.[14]

Consider – systemic therapy

Back

Consider –

systemic therapy

Treatment recommended for SOME patients in selected patient group

It is likely that many patients presenting with brain metastases will need both systemic therapy and local brain-directed therapy over their course of treatment.[14]

Nivolumab plus ipilimumab has been shown to have superior efficacy to ipilimumab monotherapy with ipilimumab for patients with advanced melanoma.[121][122][123]

Early data suggest that those who derive greater benefit from combined nivolumab and ipilimumab than from nivolumab monotherapy have tumors that do not express PD-L1.[122]

The PD-1 inhibitors nivolumab and pembrolizumab have demonstrated greater efficacy than standard chemotherapy with dacarbazine, and CTLA-4 inhibition with ipilimumab.[131][132]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

and

ipilimumab

nivolumab/relatlimab

pembrolizumab

nivolumab

dabrafenib

and

trametinib

vemurafenib

and

cobimetinib

encorafenib

and

binimetinib

pembrolizumab

and

ipilimumab

1st line – systemic therapy

Back

1st line –

systemic therapy

In patients with lower volume of asymptomatic brain metastases as well as those with extensive extracranial disease, an initial course of systemic therapy may be preferred.[14]

It is likely that many patients presenting with brain metastases will need both systemic therapy and local brain-directed therapy over their course of treatment.[14] However, for patients with <3 cm asymptomatic brain metastases, who do not require corticosteroids, and have had no prior systemic treatment may be considered for systemic therapy, no brain-directed therapy may be required in the absence of intracranial progression.[14]

Nivolumab plus ipilimumab has been shown to have superior efficacy to ipilimumab monotherapy with ipilimumab for patients with advanced melanoma.[121][122][123]

Early data suggest that those who derive greater benefit from combined nivolumab and ipilimumab than from nivolumab monotherapy have tumors that do not express PD-L1.[122]

Immune-related adverse effects are common in patients treated with nivolumab/relatlimab compared to nivolumab alone.[127]Grade 3 or 4 treatment-related adverse effects are reported to occur in approximately 19% of patients treated with nivolumab/relatlimab compared with ~10% of patients receiving nivolumab alone.[127]

The PD-1 inhibitors nivolumab and pembrolizumab have demonstrated greater efficacy than standard chemotherapy with dacarbazine, and CTLA-4 inhibition with ipilimumab.[131][132]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

and

ipilimumab

nivolumab/relatlimab

pembrolizumab

nivolumab

dabrafenib

and

trametinib

vemurafenib

and

cobimetinib

encorafenib

and

binimetinib

pembrolizumab

and

ipilimumab

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Melanoma

Treatment algorithm

early stage melanoma (melanoma in situ, stage I, stage II)

surgical excision

sentinel lymph node biopsy

adjuvant systemic treatment or observation or clinical trial

Primary options

topical imiquimod or radiation therapy

Primary options

sentinel lymph node biopsy

systemic treatment or observation or clinical trial

Primary options

stage III melanoma with negative sentinel nodes

surgical excision

systemic treatment or observation or clinical trial

Primary options

stage III melanoma with positive sentinel nodes

nodal basin radiation therapy

systemic therapy or observation

Primary options

complete lymph node dissection

systemic therapy or observation

Primary options

stage III melanoma with clinically positive nodes: resectable

neoadjuvant systemic therapy

Primary options

surgery with or without therapeutic lymph node dissection

adjuvant systemic therapy or observation

Primary options

nodal basin radiation therapy

surgery with or without therapeutic lymph node dissection

adjuvant systemic therapy or observation

Primary options

nodal basin radiation therapy

stage III melanoma with satellite/in-transit metastases: limited resectable disease

neoadjuvant systemic therapy + surgery

Primary options

surgery

talimogene laherparepvec

Primary options

systemic therapy

Primary options

stage III melanoma with satellite/in-transit metastases: borderline resectable or unresectable disease

systemic therapy

Primary options

radiation therapy

localized and regional treatments

stage IV metastatic melanoma

resection

stereotactic ablative therapy

talimogene laherparepvec

Primary options

systemic therapy

Primary options

systemic therapy

Primary options

palliative resection

radiation therapy

talimogene laherparepvec

Primary options

best supportive/palliative care

surgery

treatment of symptoms

stereostactic radiosurgery

palliative whole-body radiation therapy

systemic therapy

Primary options

systemic therapy

Primary options