Immunotherapy for the Treatment of Melanoma
Diagnostic tests and biomarkers
- For all patients with stage III and stage IV melanoma, BRAF mutation status should be obtained (LE:2).
- Patients with stage IIB/C melanoma have a high risk of recurrence, therefore BRAF mutation testing can be considered on a case-by-case basis so that treatment options are known at the time of recurrence.
- For all patients with unresectable/metastatic melanoma, NGS is recommended if feasible.
- Although PD-L1 tumor proportion score (TPS) and TMB are associated with ICI response in melanoma, they should not be used for clinical decision-making at the time of manuscript publication.
- MSI and MMR status should not be routinely obtained as a standalone test for patients with melanoma.
- ctDNA is an exciting new tool to track antitumor response to ICIs and is being explored in research settings, however, this biomarker is not routinely used to guide clinical decision-making for patients with melanoma at the time of manuscript publication.
- There are many biomarkers under investigation in melanoma (eg, interferon [IFN]γ gene expression signatures, granzyme B PET imaging, gut microbiome profiling) to predict response to ICIs, but none of those are clinically validated and were not routinely used to guide clinical decision-making at the time of manuscript publication.
- Studies to identify biomarkers to predict risk of developing irAEs and to inform treatment of irAEs are ongoing, but none of these biomarkers were routinely used to guide clinical decision-making at the time of manuscript publication.
Stage II cutaneous melanoma
- For patients with T1b and higher, clinically LN-negative melanoma, SLN mapping and biopsy should be discussed and offered, when feasible (LE:2).
- For patients with resected stage IIB and IIC melanoma, a referral to medical oncology and surveillance with cross-sectional imaging are recommended (LE:3).
- For patients with resected stage IIB and IIC melanoma, adjuvant pembrolizumab (LE:2) or nivolumab (LE:2), surveillance alone, or clinical trial enrollment are all options. A discussion about the potential risks and benefits associated with adjuvant PD-1 inhibition is recommended as part of a shared decision-making process.
- For patients with resected stage I and stage IIA melanoma, close surveillance with total skin examination and physical examination of peripheral LN basins should be continued. These patients may also be considered for clinical trials. Routine imaging for these patients in the absence of symptoms is not recommended.
Stage III and resected stage IV cutaneous melanoma
- For patients with resected stage IIIA melanoma, adjuvant systemic therapy with either an anti-PD-1 ICI (LE:2) or BRAF-targeted therapy (for patients with BRAFV600-mutated disease) (LE:2) should be considered. For patients with resected stage IIIB and above melanoma without contraindications, adjuvant systemic therapy with either an anti-PD-1 ICI (LE:2) or BRAF-targeted therapy (LE:2) should be strongly considered. A discussion about the potential risks and benefits associated with adjuvant therapy versus active surveillance is recommended as part of a shared decision-making process.
- For patients with resected stage III BRAFV600-mutated melanoma, while both treatments have shown a similar RFS benefit, there are no head-to-head prospective data directly comparing initial adjuvant anti-PD-1 ICI therapy to targeted therapy. The toxicity profile of each of these approaches is different, therefore consideration of potential long-term/permanent adverse events associated with each of these approaches should be weighed against the absolute benefit.
- For patients with resected stage IV BRAFV600-mutated melanoma, ICIs have shown an RFS benefit in the adjuvant setting and both ICIs and targeted therapy have shown an OS benefit in the metastatic setting. Although adjuvant targeted therapy for patients with completely resected stage IV BRAFV600-mutated disease may also be considered (LE:5), data for this approach are lacking. The toxicity profile of adjuvant ICI versus adjuvant targeted therapy is different, therefore consideration of potential long-term/permanent adverse events associated with each of these approaches should be weighed against the absolute benefit.
- For patients with resected stage III/IV melanoma, ipilimumab 10 mg/kg or high-dose IFN therapy should no longer be used as adjuvant treatment.
- For patients with resectable stage IIIB to IV (without brain metastases) melanoma, while there were no approved neoadjuvant therapies at the time of manuscript publication, neoadjuvant pembrolizumab continued into the adjuvant setting demonstrated improved EFS compared with adjuvant therapy alone in a randomized, phase II trial (LE:2). Neoadjuvant approaches may be considered after multidisciplinary discussion for patients with high-risk stage III and resectable stage IV melanoma. Consideration for clinical trial enrollment is still preferred for eligible patients with high-risk stage III disease.
- For patients with resectable clinically or radiographically detectable stage III disease, standard of care treatment includes TLND (LE:2). There were no positive clinical trial data to support de-escalating the extent of operation, regardless of receipt of neoadjuvant or adjuvant systemic therapy, at the time of manuscript publication.
Stage IV cutaneous melanoma
Available agents and indications for treatment-naïve disease
- Regardless of BRAFV600 mutation status, either single-agent anti-PD-1 therapy (LE:2) or front-line combination therapy with either ipilimumab plus nivolumab (LE:2) or nivolumab plus relatlimab (LE:2) is recommended, depending on the clinical scenario.
- For first-line therapy of stage IV melanoma, ipilimumab plus nivolumab is preferred over other anti-PD-1-based regimens in patients with poor prognostic features such as liver metastases, brain metastases, BRAF mutation, or high LDH.
- For patients with melanoma with poor prognostic features in whom combination therapy is desired but who may not tolerate TRAEs (ie, elderly patients or patients with poor Eastern Cooperative Oncology Group performance status [ECOG PS]), treatment with nivolumab plus relatlimab is a preferred combination regimen.
- For patients with low volume melanoma or histology that has demonstrated exceptional responses to anti-PD-1 monotherapy (desmoplastic melanoma), or for patients who are less likely to tolerate high-grade irAEs (eg, patients with a poor ECOG PS or concurrent autoimmune comorbidities), single agent anti-PD-1 therapy may be considered in the frontline.
- For patients with BRAFV600-mutated melanoma, despite the approval for vemurafenib, cobimetinib, and atezolizumab, the role of triplet therapy (as opposed to sequential combination ICI therapy followed by targeted therapy) is not clear but may be considered in selected patients (LE:2).
Patients with CNS metastases
- For patients with MBMs, initial evaluation should include patient factors such as neurological symptoms, performance status, and corticosteroid use. The optimal combination and sequencing of treatments such as surgery, stereotactic radiosurgery, and systemic treatment, is currently not established and warrants expeditious multidisciplinary discussion and collaborative management. For patients with MBMs for whom systemic therapy is considered appropriate following expedited multidisciplinary evaluation, the sequencing of targeted therapy (for BRAFV600-mutated disease) versus ICIs should be considered on a case-by-case basis.
- For patients with asymptomatic MBMs for whom steroids have been tapered to the lowest tolerated dose and for whom potential toxicities are tolerable, ipilimumab plus nivolumab is recommended in the frontline (LE:1). There are no data supporting the use of nivolumab plus relatlimab in patients with MBMs. Multidisciplinary management is required for management of all patients with MBMs.
- For patients with MBMs, ipilimumab should be dosed at 3 mg/kg in combination with nivolumab 1 mg/kg (ie, standard dosing).
Emerging data on immunotherapy for previously-treated stage IV disease
- Patients with metastatic melanoma should be fully restaged (including a restaging brain MRI) at the time of disease progression.
- For all patients with advanced melanoma whose disease has progressed on any anti-PD-1-based ICI therapy without an anti-CTLA-4 agent, there is no clear standard of care subsequent line therapy and thus treatment with ipilimumab plus nivolumab (LE:2), BRAF-targeted agents (if appropriate) if not already done (LE:2), or enrollment in clinical trials evaluating strategies including adoptive cell therapies, novel combinations, and other strategies, should be strongly encouraged in shared decision-making with the patient.
- For all patients with advanced melanoma whose disease has progressed on anti-PD-1 therapy and clinical trial enrollment is not feasible, dual ICI therapy or BRAF-targeted therapy (if appropriate) should be considered, with choice of therapy taking anticipated toxicities and phenotype of resistance (primary versus secondary) into account.
- For patients whose best response is PD or <6 months of SD following at least 6 weeks of therapy with a single anti-PD-1 agent (ie, primary anti-PD-1 ICI resistance), combination ipilimumab plus nivolumab is preferred (LE:2) and ipilimumab monotherapy (LE:2) or ipilimumab plus pembrolizumab (LE:3) can be considered.
- For patients who initially benefited from anti-PD-1-based monotherapy for at least 6 months, discontinued therapy, and then ultimately progressed, re-induction with single-agent anti-PD-1 can be considered on progression of disease (LE:3).
Intratumoral immunotherapy in melanoma
- T-VEC monotherapy is well tolerated, easily administered, and should be considered as part of the treatment plan for patients with predominantly injectable disease at any point in the treatment course for melanoma as part of a multidisciplinary approach.
- Intratumoral therapies may be considered throughout the treatment course, although with T-VEC, responses in non-injected visceral lesions are rare (LE:2).
- Some members of this Expert Panel have used T-VEC in immunosuppressed patients after careful, case-by-case consideration.
Evaluation and management of response to immunotherapy
- For patients with melanoma receiving ICIs, radiographic measurement of response is useful but not universally predictive of clinical benefit and the information obtained must be placed in the larger clinical context (LE:3).
- The decision to continue ICI therapy beyond initial radiographic progression should be based on melanoma-associated symptoms, disease kinetics, and the presence or absence of irAEs.
- For patients with melanoma with clinical symptoms of ongoing disease, irAEs, or who are treated beyond progression, repeated radiographic assessment after a short interval (4–8 weeks) may guide decision-making.
- For clinically stable patients with melanoma receiving ICIs who develop an isolated site of progression, local therapy may be considered while systemic ICI therapy is continued.
- While the optimal duration of ICI treatment for patients with unresectable or metastatic melanoma has yet to be determined by prospective data, retrospective data support discontinuation of ICI therapy after 1 year using confirmed CR, CMR on FDG-PET/CT, or pCR (LE:3). Prolonged PR or SD may also serve as potential thresholds for treatment discontinuation after 1 year, however, PFS is lower for these patients (LE:3). There are no data to support treatment with ICIs beyond 2 years.
Special patient populations
- For the special patient populations discussed in this guideline, it is critical to consider clinical trials in all stages of treatment (eg, neoadjuvant, adjuvant, metastatic).
- For patients with melanoma, performance status and comorbidities should take precedence over numerical age when determining eligibility for therapy with ICIs (LE:3).
- Patients with melanoma who have altered immune systems at baseline should not be automatically excluded from receiving ICI therapy. Given that immunotherapy is potentially curative for melanoma, these patients should be referred to an experienced cancer center for consideration of treatment. Shared decision-making between patient, provider, and collaborative care team to initiate ICI therapy is essential when discussing risks versus benefits of ICIs for these patients.
- For solid organ transplant recipients with melanoma, the shared decision to initiate ICI therapy should be informed by a careful risk-benefit discussion in consultation with the transplantation team, weighing the chance of long-term melanoma specific survival against the substantial risk of allograft loss resulting in the need for life-supporting interventions (eg, dialysis, insulin, etc) or death.
- For patients with pre-existing autoimmune disease with melanoma, the shared decision to initiate ICI therapy should be informed by a careful risk-benefit discussion in coordination of care with relevant specialty providers weighing the chance of long-term melanoma specific survival against the risk of flare of autoimmune disease.
- PLWH and melanoma should not be routinely excluded from receipt of ICI therapy either on or off clinical trials (LE:1). Data have demonstrated that it is safe to use ICIs in PLWH who are compliant on HAART unless there is a specific contraindication to ICI therapy (eg, low CD4 count or uncontrolled viremia).
- For pregnant patients with melanoma, there are no clinical trial data to inform the efficacy or safety of ICIs. Initiation or continuation of ICI treatment in pregnant patients warrants a careful risk-benefit conversation with the patient and the individuals they choose to be involved with their decision-making (eg, family, intimate partner, and friends) along with multidisciplinary evaluation including high-risk obstetrics (LE:4).
- For patients with melanoma receiving non-steroid therapeutic immune suppression, reduction or modification of immune suppression should be discussed, when appropriate, prior to initiation of ICI therapy (LE:5).
- For patients with melanoma who are receiving high-dose corticosteroids, the dose of corticosteroids should be reduced to ≤10 mg prednisone (or equivalent) per day, if possible, prior to initiation of ICI therapy (LE:3). This does not apply to corticosteroids for solid organ allograft preservation. For patients who are unable to taper to ≤10 mg prednisone per day, individual consideration is required with possible subspecialty co-management.
Patients with non-cutaneous melanoma
- Patients with non-cutaneous melanoma should be advised that although these are rare subsets of melanoma, clinical trial strategies may be available that lead to long-term, high-quality survival.
- For patients with rare melanoma subtypes, referral to an experienced provider at an academic medical center is recommended.
- For all patients with advanced rare melanoma subtypes, immunotherapy is recommended in the frontline setting with consideration for potential contraindications and toxicities.
- For all patients with rare melanoma subtypes, molecular mutation testing is recommended. The discovery of an actionable mutation offers the opportunity for targeted therapy or enrollment in molecularly-directed clinical trials.
- For patients with localized uveal melanoma, eye-directed therapy at a subspecialty center should be considered for primary treatment.
- In the surveillance of patients with uveal melanoma, liver monitoring is recommended, which may be tailored to the patient’s risk of recurrence (LE:2).
- For patients with uveal melanoma oligometastatic to the liver only, liver-directed therapy should be considered (LE:1) and can be considered for use in conjunction with immunotherapy on multidisciplinary discussion (LE:5).
- For adult patients with untreated HLA-A*02:01-positive unresectable or metastatic uveal melanoma, treatment with tebentafusp-tebn (LE:2) or clinical trial enrollment is recommended.
- For patients with mucosal melanoma, a risk benefit discussion about definitive surgical resection at a specialty care center as a frontline consideration should be held, with the role of immunotherapy best determined by multidisciplinary evaluation.
Patient education and QOL support
- When providing education to patients with melanoma receiving ICIs, and their caregivers, it is important to present information in a clear, concise, and easily understandable format. The treating oncology team should proactively identify barriers to care (eg, language barrier, lack of access to reliable internet/phone, after-hours communication) and attempt to address these barriers as early as possible.
- The oncology team should establish realistic expectations with patients and their caregivers in terms of toxicity management (eg, need for holding doses, initiation of steroids) and goals of treatment.
- For patients with melanoma receiving ICIs and their caregivers, a clear, ongoing line of communication with the oncology team is necessary as irAEs may present at any time during or after treatment. It is important to emphasize to patients that irAEs may present with symptoms that could be mistaken as cancer-related (eg, fatigue due to autoimmune adrenal insufficiency), therefore ongoing communication between the oncology team and the patient and their caregivers is imperative for early identification and management. The oncology team should identify and confirm the best method for communication with each patient and their caregivers. Patients and caregivers should be encouraged to contact the oncology team promptly to report new or worsening symptoms suggestive of an irAE. Counseling should be provided on what symptoms would warrant reporting during evening, weekend, and holiday hours.
- The oncology team should perform ongoing assessments of the patient’s understanding of the importance of reporting symptoms of irAEs. A thorough review of systems probing for irAEs should be obtained at each follow-up visit.
- For patients with melanoma receiving ICIs, QOL support requires a patient-centered approach. The patient and their caregivers should be offered multidimensional resources, including psychosocial support, dietary counseling, pain management, patient and survivor and caregiver support groups, comprehensive skin examinations, physical and/or occupational therapy, and financial counseling. Patients may require these services at any point during their care, including after ICI discontinuation and during survivorship years.
- For all patients with melanoma benefiting from immunotherapy, a survivorship plan should be considered early on. Recognizing and managing affective disorders associated with prior cancer treatment and diagnosis, transitioning to a new care team, anxiety associated with surveillance imaging, and defining life ‘post-cancer’ are all key survivorship considerations.
- For patients with melanoma with reproductive potential, pregnancy prevention should be addressed prior to initiation of immunotherapy. For patients with melanoma being considered for immunotherapy who wish to preserve fertility, referral to an oncofertility specialist should be strongly considered.
- The oncology team should provide support and education for the optimal management of long-term, fixed immune-related toxicities (eg, hypoadrenalism, hypothyroidism, diabetes). This includes management and education about the long-term effects of steroid use with regular assessment of bone health.
Immunotherapy for the Treatment of Melanoma
October 18, 2023
Last Updated Month/Year
November 6, 2023
Supplemental Implementation Tools
External Publication Status
Country of Publication
Male, Female, Adult, Older adult
Health Care Settings
Nurse, nurse practitioner, physician, physician assistant
D008545 - Melanoma
melanoma, cutaneous melanoma, skin cancer, Cancer immunotherapy
Pavlick AC, Ariyan CE, Buchbinder EI, et al
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0
Journal for ImmunoTherapy of Cancer 2023;11:e006947. doi: 10.1136/jitc-2023-006947
Sullivan RJ, Atkins MB, Kirkwood JM, et al; An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0; Journal for ImmunoTherapy of Cancer 2018;6:44. doi: 10.1186/s40425-018-0362-6