Treatment by Stage
Stage 0 in situ and IA:
- For patients with stage 0 (cancer is limited to the epidermis, the outermost layer of skin) or stage IA (< or= 1 mm thick, with no ulceration) melanoma, treatment recommendations include wide-excision surgery. Discussion of sentinel lymph node biopsy (SLNB) is a consideration in certain stage IA cancers.
Stage IB and IIA:
- Discuss and offer patients SLNB and wide-excision surgery
Stage IIB or IIC:
- Surgery is recommended for stage IIB or IIC; also discuss or offer SLNB
- If SLNB is performed and node positive, then complete dissection of nodal basin is a consideration if there is high risk the cancer has spread
- Alternatively, observation can be recommended or clinical trial or interferon alfa
- Use of interferon alfa is based on lower level of clinical evidence, and its use should be individualized
- Immunotherapy drugs such as pembrolizumab and berahyaluronidase alfa-pmph (Keytruda, Keytruda Qlex) or nivolumab (Opdivo, Opdivo Qvantig) after complete resection.
Stage III:
- For stage III (clinically positive nodes), surgical excision is recommended. A complete lymph node dissection might be recommended. Prior to surgery neoaduvant treatment with immune checkpoint inhibitors or targeted therapy may be given;Adjuvant therapy after surgery may include observation, immunotherapy, targeted therapy or radiation therapy.
- Consider radiation therapy to nodal basin if stage IIIC or IIID disease is present with multiple nodes, large nodes, or macroscopic extranodal extension.
- Ipilimumab (Yervoy) is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy; the recommended regimen is 3 mg/kg every 3 weeks for 4 doses, then 3 mg/ kg every 12 weeks for up to 4 additional doses.
- Nivolumab (Opdivo) is an adjuvant therapy for patients who have undergone complete resection of melanoma with lymph node involvement or metastatic disease. Recommended dosage for adults is 240 mg IV every two weeks or 480 mg every 4 weeks until disease recurrence or unacceptable toxicity for up to one year.
- Nivolumab-relatlimab-rmbw (Opdualag)is a fixed-dose combination of nivolumab and relatlimab used to treat unresectable or metastatic melanoma. Recommended dosage for patients aged 12 years or older is 480 mg nivolumab and 160 mg relatlimab IV every 4 weeks as tolerated or until the melanoma progresses.
- Pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex)is a fixed-dose combination medication given for adjuvant treatment after complete resection. It can also be given to treat unresectable or metastatic melanoma. It is given by subcutaneous injection. Recommended dosage is 2.4 mL subcutaneously (under the skin) every 3 weeks or 4.8 mL subcutaneously every 6 weeks.
For patients with stage III in-transit disease, primary treatment options include the following:
- Complete resection (preferred, if feasible)
- SLNB for resectable disease
- Hyperthermic perfusion/infusion with melphalan for localized multiple lesions in a single extremity or recurrent lesions in a single limb
- Clinical trial
- Intralesional injection (bacillus Calmette-Guérin [BCG], interleukin-2
- Local ablation therapy
- Systemic therapy
- Targeted therapy for melanomas with BRAF mutation
- Topical imiquimod (Aldara, Zyclara)
- Oncolytic immunotherapy with alimogene laherparepvec (Imlygic), indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery. It is administered by injection directly into the melanoma lesions.
- Vusolimogene oderparepvec-wtpg (Tudriqev)
Stage IV with distant metastasis:
- Treatment depends on whether melanoma is limited (resectable) or disseminated (unresectable)
- If limited disease, resection is recommended; alternatively, observation or systemic therapy
- Treatment for limited disease usually includes surgery. Radiation therapy or the immunotherapy drug talimogene laherparepvec (Imlygic) may be an option if the tumors cannot be surgically removed. Adjuvant treatment with immunotherapy or targeted therapy is often recommended.
- For patients with unresectable disease without brain metastases, treatment includes systemic therapy; patients with brain metastases require treatment of the central nervous disease.
Single-Agent Treatment for Advanced or Metastatic Melanoma
Stage IV:
- Clinical trial may be considered
- Pembrolizumab (Keytruda) Adult dosage is 200 mg IV every 3 weeks or 400 mg IV every 6 weeks until disease progression or unacceptable toxicity; it is indicated as first-line treatment for unresectable or metastatic malignant melanoma
- Ipilimumab (Yervoy) 3 mg/kg IV over 90 min; q21 d for a total of four doses or
- Nivolumab (Opdivo) Dosage for adults and pediatric patients weighing 40 kg or more is 240 mg IV every 2 weeks or 480 mg IV every 4 weeks until disease progression or unacceptable toxicity; single agent in the first-line treatment of unresectable or metastatic BRAF wild-type or mutation-positive melanoma.
Targeted Therapy for Melanoma with BRAF Mutations
- Dabrafenib (Tafinlar) 150 mg PO BID (for BRAF V600E mutation); not indicated for wild-type BRAF melanoma
- Trametinib (Mekinist) 2 mg PO qd (for BRAF V600E or V600K mutations); not indicated in patients who have received prior BRAF inhibitor therapy
- Vemurafenib (Zelboraf) 960 mg PO q12 h (for patients with BRAF V600E mutation); not indicated for wild-type BRAF melanoma
- Encorafenib (Braftovi) 450 mg po q d to be used in combination with binimetinib; (for BRAF V600E mutation); not indicated for wild-type BRAF melanoma
- Binimetinib (Mektovi) 45 mg bid in combination with encorafenib; (for BRAF V600E mutation); not indicated for wild-type BRAF melanoma
- Cobimetinib (Cotellic)60 mg q d for first 21 days of each 28 day cycle in combination with vemurafenib; (for BRAF V600E mutation); not indicated for wild-type BRAF melanoma
Combination Treatment Recommendations for Advanced or Metastatic Disease
Stage IV:
- Nivolumab 1 mg/kg IV over 60 min followed by ipilimumab 3 mg/kg IV over 90 min administered on the same day q3wk for 4 doses for BRAF V600 wild-type or mutation-positive, unresectable or metastatic melanoma in previously untreated patients; subsequent single-agent nivolumab doses are 240 mg IV q 2 weeks or 480 mg q 4 weeks until disease progression or unacceptable toxicity
- Nivolumab plus relatlimab (Opdualag) 480 mg nivolumab and 160 mg relatlimab IV q 4 weeks for treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.
