American Society of Clinical OncologyMedical Oncology2023advanced

Systemic Therapy for Melanoma

Published by American Society of Clinical Oncology · GRADE

19Recommendations

130References

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Summary

AI-generated

Systemic treatment for melanoma has changed rapidly since the introduction of ipilimumab in 2011, substantially improving overall and long-term survival. Due to the increasing availability of new therapies, rising melanoma incidence, and treatment costs, rational evidence-based selection of appropriate therapy is essential.

melanomapembrolizumabnivolumabrelatlimabipilimumabtebentafuspASCOmedical oncology

Key Takeaways

1
Neoadjuvant pembrolizumab is newly recommended for patients with resectable stage IIIB-IV cutaneous melanoma.
2
Adjuvant nivolumab or pembrolizumab is newly recommended for resected stage IIB-C cutaneous melanoma.
3
Adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease.
4
Nivolumab plus relatlimab is an option for unresectable or metastatic cutaneous melanoma regardless of BRAF mutation status.
5
Nivolumab plus ipilimumab followed by nivolumab is preferred over BRAF/MEK inhibitor therapy as first-line treatment.
6
Tebentafusp is recommended for HLA-A*02:01-positive patients with metastatic uveal melanoma.

What's New in This Version

Neoadjuvant pembrolizumab added for resectable stage IIIB-IV. Adjuvant nivolumab or pembrolizumab added for stage IIB-C. Adjuvant nivolumab + ipilimumab added for stage IV. Nivolumab + relatlimab added as an option for unresectable/metastatic regardless of BRAF mutation. Nivolumab + ipilimumab preferred over BRAF/MEK inhibitor therapy in first line. T-VEC removed as option for BRAF wild-type progressing on anti-PD-1. Ipilimumab regimens removed for BRAF-mutated disease after progression on other therapies.

Key Recommendations

Neoadjuvant Therapy

1.1
Neoadjuvant pembrolizumab (maximum of three 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.
StrongEvidence: ModerateEvidence based, benefits outweigh the harms
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.
StrongEvidence: Not applicableInformal consensus

Adjuvant Therapy

2.1.1
Adjuvant pembrolizumab or nivolumab should be offered to patients with resected stage IIB or IIC melanoma.
StrongEvidence: ModerateEvidence based
2.1.2
Adjuvant therapy should not be offered to patients with resected stage IIA melanoma outside of enrollment in a clinical trial.
StrongEvidence: Not applicableInformal consensus
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 x 52 weeks OR pembrolizumab x 52 weeks. Ipilimumab and high-dose interferon are not recommended for routine use in adjuvant therapy.
StrongEvidence: HighEvidence based, benefits outweigh the harms
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 x 52 weeks OR pembrolizumab x 52 weeks OR dabrafenib plus trametinib x 52 weeks.
StrongEvidence: HighEvidence-based, benefits outweigh harms
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.
NAEvidence: NANo Recommendation
2.5.1
Patients with resected stage IV melanoma should be offered adjuvant therapy.
StrongEvidence: ModerateInformal consensus
2.5.2
Reasonable options for therapy are nivolumab alone, nivolumab plus ipilimumab followed by nivolumab, pembrolizumab alone, and dabrafenib plus trametinib (in patients with BRAF V600E/K disease).
WeakEvidence: varies by optionInformal consensus

Unresectable and/or Metastatic Disease

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.
StrongEvidence: HighEvidence based, benefits outweigh harms
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.
StrongEvidence: HighEvidence based, benefits outweigh harms
3.2.2
Combination therapy with nivolumab plus ipilimumab is preferred as first-line therapy over BRAF/MEK inhibitor combination therapy.
StrongEvidence: High for dabrafenib plus trametinib, Low for other BRAF/MEK inhibitorsEvidence based
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.
WeakEvidence: LowInformal consensus
3.4
After progression on first-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. Similarly, those who have progressed after combination BRAF/MEK inhibitor therapy may be offered anti–PD-1–based therapy.
WeakEvidence: LowInformal consensus
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, talimogene laherparepvec may be offered as primary therapy.
WeakEvidence: LowEvidence based, benefits outweigh harms

Noncutaneous Melanoma

4.1.1
HLA-A*02:01-positive patients with metastatic uveal melanoma should be offered tebentafusp.
StrongEvidence: ModerateEvidence based, benefits outweigh harms
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.
Not applicableEvidence: Very LowNo 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.
WeakEvidence: Very LowInformal consensus
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.
Not applicableEvidence: Not applicableNo recommendation

Scope & Objectives

Clinical Topic

Melanoma

Objectives

To provide guidance to clinicians regarding the use of systemic therapy for melanoma.

Target Patient Population

Adult patients with melanoma (cutaneous and noncutaneous).

Target Providers

Clinicians who treat patients with melanomaMedical oncologistsRadiation oncologistsSurgical oncologistsCommunity oncologists

Patient Criteria & Setting

Therapeutic Area

Oncology

Guideline Scope

TreatmentManagement

Inclusion Criteria

Adult patients with melanoma
Patients with resectable stage IIIB-IV cutaneous melanoma
Patients with resected cutaneous melanoma
Patients with unresectable or metastatic cutaneous melanoma
HLA-A*02:01-positive patients with metastatic uveal melanoma

Special Populations

BRAF-mutant melanoma patientsBRAF wild-type melanoma patientsHLA-A*02:01-positive patientsPatients with brain metastasesPatients with multiple chronic conditions

Evidence Grading

System: GRADE

Evidence Levels

LowOur confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.

HighWe are very confident that the true effect lies close to that of the estimate of the effect.

ModerateWe are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

Very lowWe have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Recommendation Strength

WeakThe desirable effects probably outweigh the undesirable effects (or vice versa for negative recommendations), but appreciable uncertainty exists. Most informed people would choose the recommended course of action, but a substantial number would not.

StrongThe desirable effects of an intervention outweigh its undesirable effects (or vice versa for negative recommendations). All or almost all informed people would make the recommended choice.

Safety & Contraindications

Monitoring Guidance

Appropriate monitoring for toxicity and disease progression is necessary, especially for longer dosing cycles (e.g., up to 6 weeks) of anti-PD-1 regimens.

Authors & Contributors

Rahul SethDO; Sanjiv S. AgarwalaMD; Hans MessersmithMPH; Krishna C. AlluriMD; Paolo A. AsciertoMD; Michael B. AtkinsMD; Kathryn BollinMD; Matias ChaconMD; Nancy DavisMD; Mark B. FariesMD; Pauline FunchainMD; Jason S. GoldMD; Samantha GuildJD; David E. GyorkiMBBS; Varinder KaurMD; Nikhil I. KhushalaniMD; John M. KirkwoodMD; Jennifer Leigh McQuadeMD; Michael O. MeyersMD; Anthony ProvenzanoMD; Caroline RobertMDPhD; Mario SantinamiMD; Amikar SehdevMPHMD; Vernon K. SondakMD; Gilliosa SpurrierMSc; Umang SwamiMSMD; Thach-Giao TruongMD; Katy K. TsaiMD; Alexander van AkkooiMDPhD; and Jeffrey WeberMDPhD

Guideline Features

Dosing informationFlowcharts includedBased on systematic reviewMultidisciplinaryPatient involvement

Learning Context

Difficulty

advanced

Learning Paths

Systemic TherapyMelanomaNeoadjuvant TreatmentAdjuvant TreatmentImmunotherapyBRAF Targeted TherapyUveal Melanoma