Systemic Therapy for Melanoma

Publication Date: August 14, 2023

Treatment

Neoadjuvant Systemic Therapy

Cutaneous Melanoma Eligible for Resection

Recommendation 1.1.
Neoadjuvant pembrolizumab (maximum of 3 courses of 200 mg once every 3 weeks) followed by resection and adjuvant pembrolizumab (maximum of 15 courses of 200 mg once every 3 weeks) should be offered to patients with clinical and resectable stage IIIB–IV cutaneous melanoma. (Evidence Quality - Medium) ( EB , I , B , S )
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Recommendation 1.2.
Patients with clinical and resectable stage IIIB–IV cutaneous melanoma should be offered or referred for enrollment in clinical trials of neoadjuvant therapy where possible. ( IC , , , S )
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Adjuvant Systemic Therapy

Resected (Stage II, III, IV) Cutaneous Melanoma

Recommendation 2.1.1.
Adjuvant pembrolizumab or nivolumab should be offered to patients with resected stage IIB or IIC melanoma. See Table 1 for reasonable doses and schedules. (Evidence Quality - Medium) ( EB , , , S )
Qualifying Statement: The recommendation in favor of nivolumab is based at the time of writing on the conference abstract publication of CheckMate 76k and under the assumption that full publication of that data will not contradict the abstract. See the Clinical Interpretation section in full text guideline for further details.
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Recommendation 2.1.2.
Adjuvant therapy should not be offered to patients with resected stage IIA melanoma outside of enrollment in a clinical trial. ( IC , , , S )
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Recommendation 2.2.
For patients with resected stage IIIA–D disease that is BRAF wild-type, the following adjuvant therapy options should be offered (in no particular order): nivolumab × 52 weeks OR pembrolizumab × 52 weeks. Ipilimumab and high-dose interferon are not recommended for routine use in adjuvant therapy. See (in full text guideline) the Clinical Interpretation section on shared decision making with patients between these options. See Table 1 for recommended dosing and scheduling details. ( EB , H , B , S )
Qualifying Statement: Patients with stage IIIA disease with microscopic sentinel nodal metastasis <1 mm in diameter were not included in the randomized trials that studied efficacy of immune checkpoint inhibitors as adjuvant therapy for melanoma. Both nivolumab and pembrolizumab are United States (US) Food and Drug Administration (FDA) approved as adjuvant treatments for patients with melanoma with lymph node involvement who have undergone complete disease resection. Patients with stage IIIA disease with <1 mm involvement in the sentinel lymph node have a relatively better prognosis and lower risk of relapse. Therefore, treatment should be individualized after discussing risk-benefit quotient with these patients.
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Recommendation 2.3.
For patients with resected stage IIIA–D disease that is BRAF mutant (V600E/K*), the following adjuvant therapy options should be offered (in no particular order): nivolumab × 52 weeks OR pembrolizumab × 52 weeks OR dabrafenib plus trametinib × 52 weeks. See (in full text guideline) the Clinical Interpretation section on shared decision making with patients between these options. See Table 2 for reasonable dosing and scheduling details. ( EB , H , B , S )
Qualifying Statement: Patients with stage IIIA disease with microscopic sentinel nodal metastasis <1 mm diameter were not included in the randomized trials that studied efficacy of immune checkpoint inhibitors and BRAF-targeted agents as adjuvant therapy for melanoma. Nivolumab, pembrolizumab, and dabrafenib plus trametinib are FDA approved as adjuvant treatments for patients with melanoma with lymph node involvement who have undergone complete resection of their disease. Patients with stage IIIA disease with less than 1 mm involvement in the sentinel lymph node usually have a good prognosis and low risk of relapse. Therefore, treatment should be individualized after discussing risk-benefit quotient with these patients.
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Recommendation 2.4.
No recommendation can be made for or against adjuvant BRAF/MEK inhibitor therapy in patients with resected stage III/IV melanoma with BRAF mutations other than V600E/K. (No recommendation) (NR, , , )
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Recommendation 2.5.1.
Patients with resected stage IV melanoma should be offered adjuvant therapy. (Evidence Quality - Medium) ( IC , , , S )
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Reasonable options for therapy are:
Recommendation 2.5.2.
nivolumab alone (Evidence Quality - Medium) ( IC , , , W )
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nivolumab plus ipilimumab followed by nivolumab ( IC , L , , W )
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pembrolizumab alone ( IC , L , , W )
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and dabrafenib plus trametinib (in patients with BRAF V600E/K disease) ( IC , L , , W )
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See (in full text guideline) the Clinical Interpretation section on shared decision making with patients between these options.

Systemic Therapy Options

Unresectable/Metastatic Cutaneous Melanoma

Recommendation 3.1.
For patients with BRAF wild-type, unresectable and/or metastatic cutaneous melanoma, the following treatment options should be offered (in no particular order): nivolumab plus ipilimumab followed by nivolumab OR nivolumab plus relatlimab OR nivolumab OR pembrolizumab. See Table 2 for recommended dosing and scheduling details. See (in full text guideline) the Clinical Interpretation section on shared decision making with patients between these options. ( EB , H , B , S )
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Recommendation 3.2.1.
For patients with BRAF mutant (V600) unresectable and/or metastatic cutaneous melanoma, one of the following treatment options should be offered as first-line therapy: nivolumab plus ipilimumab followed by nivolumab OR nivolumab plus relatlimab OR nivolumab OR pembrolizumab OR dabrafenib plus trametinib OR encorafenib plus binimetinib OR vemurafenib plus cobimetinib. See Table 2 for recommended dosing and scheduling details. See (in full text guideline) the Clinical Interpretation section on shared decision making with patients between these options. ( EB , H , B , S )
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Recommendation 3.2.2.
Combination therapy with nivolumab plus ipilimumab is preferred as first-line therapy over BRAF/MEK inhibitor combination therapy (dabrafenib plus trametinib). ( EB , H , , S )
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Combination therapy with nivolumab plus ipilimumab is preferred as first-line therapy over BRAF/MEK inhibitor combination therapy (other BRAF/MEK inhibitors). (, L , , )
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See (in full text guideline) the Clinical Interpretation section on shared decision making with patients between these options.
Recommendation 3.3.
After progression on anti-PD-1-based therapy, patients with unresectable and/or metastatic BRAF wild-type cutaneous melanoma may be offered ipilimumab or ipilimumab containing regimens. Patients should be offered or referred for enrollment in clinical trials where possible. ( IC , L , , W )
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Recommendation 3.4.
After progression on 1st line anti-PD-1-based therapy, patients with BRAF mutant (V600) unresectable and/or metastatic cutaneous melanoma may be offered combination BRAF/MEK inhibitor therapy as described in Recommendation 3.2.1. Similarly, those who have progressed after combination BRAF/MEK inhibitor therapy may be offered anti-PD-1-based therapy as described in Recommendation 3.2.1. ( IC , L , , W )
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Recommendation 3.5.
For patients with injectable (cutaneous or subcutaneous or nodal) unresectable lesions who are not eligible or do not desire the recommended systemic therapies, T-VEC may be offered as primary therapy. ( EB , L , B , W )
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Non-Cutaneous Melanoma (Stage II or Greater)

Recommendation 4.1.1.
HLA-A*02:01-positive patients with metastatic uveal melanoma should be offered tebentafusp (20 μg on day 1, 30 μg on day 8, and 68 μg weekly after that until progression). (Evidence Quality - Medium) ( EB , I , B , S )
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Recommendation 4.1.2.
For all patients with uveal melanoma other than those addressed by Recommendation 4.1.1., no recommendation for or against any specific systemic therapy may be made at this time. Patients should be offered or referred for enrollment in clinical trials where possible. (No recommendation, Evidence Quality - Very Low) (, VL, , )
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Recommendation 4.2.
In the absence of further data, the consensus of the Expert Panel is that patients with unresectable and/or metastatic mucosal melanoma may be offered therapy as described in Recommendations 3.1. through 3.5. Patients should be offered or referred for enrollment in clinical trials where possible. (Evidence Quality - Very Low) ( IC , VL, , W )
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Recommendation 4.3.
No recommendation for or against any specific systemic therapy for patients with any other form of non-cutaneous melanoma may be made at this time. Patients should be offered or referred for enrollment in clinical trials where possible. (No recommendation) (, , , )
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Recommendation Grading

Disclaimer

Overview

Title

Systemic Therapy for Melanoma

Authoring Organization

Publication Month/Year

August 14, 2023

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Target Patient Population

Adult patients with melanoma (cutaneous and noncutaneous)

Target Provider Population

Oncologists who treat patients with melanoma

Inclusion Criteria

Male, Female, Adult, Older adult

Health Care Settings

Ambulatory, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Treatment, Management

Diseases/Conditions (MeSH)

D008545 - Melanoma

Keywords

melanoma, cutaneous melanoma, skin cancer

Source Citation

Source Seth R, Agarwala SS, Messersmith H, et al. Systemic Therapy for Melanoma: ASCO Guideline Update. J Clin Oncol. 2023 August 14. doi: 10.1200/JCO.23.01136

Supplemental Methodology Resources

Data Supplement

Methodology

Number of Source Documents
130
Literature Search Start Date
January 1, 2000
Literature Search End Date
March 7, 2022
Description of External Review Process
ASCO has a rigorous review process for guidelines. After the draft has been approved by the Expert Panel, the guideline is independently reviewed and approved by the Clinical Practice Guideline Oversight Committee (CPGC). Select members of the CPGC are asked to critically review the guideline prior to the next scheduled CPGC meeting. The CPGC members then present the results of their reviews to the full committee, discuss the review with the full committee, and the CPGC votes on whether to approve the guideline (with recusals from members who have relationships with affected companies). Approved ASCO Guidelines are then submitted to the Society’s journal for consideration of publication.
Description of Public Comment Process
ASCO Guidelines are available for open comment for a 2 to 3‐week period. Guideline recommendations available for open comment are posted on asco.org/open‐comment‐guidelines. Prospective reviewers must contact ASCO to request to review the draft guideline recommendations and are required to sign a non‐disclosure and confidentiality agreement before receiving the draft guideline recommendations. Reviewers must identify themselves by name and affiliation; anonymous comments will not be accepted. Guidelines staff review and summarize comments and bring relevant comments to the Expert Panel Co‐ chairs, and to the entire panel if necessary. Any changes made from the open comment process will be reviewed by the entire panel prior to CPGC approval. Comments are advisory only and ASCO is not bound to make any changes based on feedback from open comment. ASCO does not respond to reviewers or post responses to comments; however, major edits to the draft will be reflected in the open comment discussion.
Specialties Involved
Dermatology, Oncology, Medical Oncology, Oncology
Description of Systematic Review
The Protocol specifies the purpose of the guideline product, target patient population, clinical outcomes of interest, key features of the systematic literature review, and a proposed timeline for completion. ASCO staff, the Expert Panel Co‐Chairs, and possibly other panel members selected by the Co‐Chairs (the Expert Panel Steering Committee), will typically draft the protocol for full panel review. A standard protocol worksheet is used for consistency. Once the Co‐Chairs have approved a first draft of the Protocol, the Protocol will be shared with the full Expert Panel. At the discretion of the Guidelines Director, the CPGC leadership and/or the CPGC Methodology Subcommittee may review the Protocol to make suggestions for revision intended to clarify aspects of the plan for developing the guideline. These suggestions are sent to the Expert Panel Co‐Chairs. Work on the systematic literature review can proceed upon the sign‐off of the Protocol by the Expert Panel.
List of Questions
See Full Text
Description of Study Criteria
See Supplement.
Description of Search Strategy
Upon approval of the Protocol, a systematic review of the medical literature is conducted. ASCO staff use the information entered into the Protocol, including the clinical questions, inclusion/exclusion criteria for qualified studies, search terms/phrases, and range of study dates, to perform the systematic review. Literature searches of selected databases, including The Cochrane Library and Medline (via PubMed) are performed. Working with the Expert Panel, ASCO staff complete screening of the abstracts and full text articles to determine eligibility for inclusion in the systematic review of the evidence. Unpublished data from meeting abstracts are not generally used as part of normal ASCO guideline development (“Meeting Data”). However, abstract data from reputable scientific meetings and congresses may be included on a case‐by‐case basis after review by the CPGC leadership. Expert Panels should present a rationale to support integration of abstract data into a guideline. The CPGC leadership will consider the following inclusion criteria for the unpublished scientific meeting data: 1) whether the data were independently peer reviewed in connection with a reputable scientific meeting or congress; 2) the potential clinical impact of the unpublished data; 3) the methodological quality and validity of the associated study; 3) the potential harms of not including the data; and 4) the availability of other published data to inform the guideline recommendations.
Description of Study Selection
Literature search results were reviewed and deemed appropriate for full text review by two ASCO staff reviewers in consultation with the Expert Panel Co-Chairs. Data were extracted by two staff reviewers and subsequently checked for accuracy through an audit of the data by another ASCO staff member. Disagreements were resolved through discussion and consultation with the Co-Chairs if necessary. Evidence tables are provided in the manuscript and/or in Data Supplement.
Description of Evidence Analysis Methods
ASCO guideline recommendations are crafted, in part, using the GuideLines Into DEcision Support (GLIDES) methodology. ASCO adopted a five‐step approach to carry out quality appraisal, strength of evidence ratings and strength of recommendations ratings. The ASCO approach was primarily adapted from those developed by the AHRQ,, USPSTF, and GRADE, however with the validation of the GRADE methodology, the sole use of GRADE is being evaluated by the Clinical Practice Guidelines Committee.
Description of Evidence Grading
High: High confidence that the available evidence reflects the true magnitude and direction of the net effect (i.e., balance of benefits v harms) and that further research is very unlikely to change either the magnitude or direction of this net effect. Intermediate: Moderate confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research is unlikely to alter the direction of the net effect; however, it might alter the magnitude of the net effect. Low: Low confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research may change either the magnitude and/or direction this net effect. Insufficient: Evidence is insufficient to discern the true magnitude and direction of the net effect. Further research may better inform the topic. The use of the consensus opinion of experts is reasonable to inform outcomes related to the topic.
Description of Recommendation Grading
ASCO uses a formal consensus methodology based on the modified Delphi technique in clinically important areas where there is limited evidence or a lack of high‐quality evidence to inform clinical guidance recommendations. Evidence Based: There was sufficient evidence from published studies to inform a recommendation to guide clinical practice. Formal Consensus: The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. Therefore, the Expert Panel used a formal consensus process to reach this recommendation, which is considered the best current guidance for practice. The Panel may choose to provide a rating for the strength of the recommendation (i.e., "strong," "moderate," or "weak"). The results of the formal consensus process are summarized in the guideline and reported in the Data Supplement (see the Supporting Documents" field). Informal Consensus: The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. The recommendation is considered the best current guidance for practice, based on informal consensus of the Expert Panel. The Panel agreed that a formal consensus process was not necessary for reasons described in the literature review and discussion. The Panel may choose to provide a rating for the strength of the recommendation (i.e., "strong," "moderate," or "weak"). No recommendation: There is insufficient evidence, confidence, or agreement to provide a recommendation to guide clinical practice at this time. The Panel deemed the available evidence as insufficient and concluded it was unlikely that a formal consensus process would achieve the level of agreement needed for a recommendation.
Description of Funding Source
ASCO provides funding for Guideline Development.
Company/Author Disclosures
ASCO Conflict of Interest Policy complies with the CMSS Code for Interactions with Companies. ASCO requires disclosure by individuals involved in drafting, reviewing, and approving guideline recommendations.
Percentage of Authors Reporting COI
100