Melanoma Treatment

• Management of melanoma depends on disease stage, pathologic/histologic result, LN status and presence of genetic mutations
• In situ or early-stage melanoma may be treated by surgical resection alone
• In-transit disease may be managed by local, regional or systemic therapy, or enrollment into a clinical trial, depending on patient’s health status and tumor burden
  • Complete surgical excision with negative margins is preferred for patients with single or a few resectable in-transit metastases
  • Intralesional local injection is an option for patients with limited number of in-transit metastases
• For metastatic disease, management depends on resectability and history of previous therapies
  • Resectable disease management options include surgical resection and systemic therapy
  • Management of disseminated disease includes clinical trial, systemic therapy, local agents or palliative care
  • Surgical therapy, radiation therapy and/or intralesional injection are used to treat local lesions

• Treatment options include immune checkpoint inhibitor and BRAF-targeted therapy
• May be considered in patients with resected advanced melanoma
  • Not recommended for stages I-II if not enrolled in a clinical trial
• Decision to give adjuvant therapy should be based on patient’s risk of recurrence and/or mortality

Clinical Trial

• Considered candidates for ongoing clinical trials are patients with all stages of melanoma
• Highly considered for patients due to the advances in the development of new drugs and combination of agents which help in reversing or interrupting aberrant molecular pathways that aid in the growth of the tumor

Systemic Therapy

• Additional treatment modalities for patients with either resectable or unresectable disease
• Preferred treatment modality for unresectable or systemic nodal recurrence and disseminated unresectable distant metastatic melanoma
• Recommended 1st-line regimens for advanced or metastatic disease include immune checkpoint inhibitors Pembrolizumab, Nivolumab, Ipilimumab/Nivolumab, Nivolumab and Relatlimab-rmbw, and Pembrolizumab/low-dose Ipilimumab combination therapy, targeted therapy combination agents Dabrafenib/Trametinib, Encorafenib/Binimetinib, Vemurafenib/Cobimetinib if BRAF V600 mutation-positive, and clinical trial
• Second-line regimens include Ipilimumab monotherapy, targeted therapy agents, high-dose Interleukin-2 (IL-2), Ipilimumab/Talimogene laherparepvec (T-VEC), intralesional therapies T-VEC, intralesional IL-2, BCG, Interferon (IFN), and cytotoxic agents

Immunotherapy

• Anti-PD-1 agents, eg Pembrolizumab (Lambrolizumab) and Nivolumab
  • Antibodies which inhibit programmed death (PD-1) receptors that diminish effector responses of T-cell against cancer
  • Monotherapy with either Pembrolizumab or Nivolumab is the preferred treatment regimen for advanced cutaneous melanoma and used as adjuvant postoperative therapy for Stages III-IV
  • Preferred 1st-line treatment regimens for advanced or unresectable melanoma unresponsive to other drugs and disease progression after therapy with Ipilimumab and BRAF inhibitor, together with BRAF-targeted therapy, if BRAF V600 positive
  • A large phase I trial had shown long-lasting clinical responses with low toxicity
  • Phase II and III trials have shown that Pembrolizumab has higher response rates and lesser toxicity compared to Ipilimumab
  • Also used as adjuvant therapy in patients with stage IIIB/C disease with clinically positive nodes or clinically occult nodal disease, resected stage III with clinical or microscopic satellite/in-transit disease, completely resected stage IV melanoma, and with stage III/IV nodal recurrence
    • Pembrolizumab may be given to patients with stage IIIA disease with at least 1 nodal metastasis >1 mm and stage IIIB/C
    • Nivolumab may be considered in satellite, in-transit recurrence if complete excision to clear margin was achieved

• Ipilimumab
  • A monoclonal antibody to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) that is considered the treatment of choice for unresectable or metastatic disease
    • Blocks CTLA-4 function in down regulating T-cell activation, thus allowing the immune system to attack tumor cells
  • High dose Ipilimumab is an alternative treatment option for sentinel node positive melanoma stage III and stage III with clinically positive node/s and as adjuvant therapy for nodal recurrences
    • No longer recommended as 1st-line therapy in patients with stage IIIA disease due to reported toxicities but may be considered in patients with resected stage IV disease previously given anti-PD-1 agents
    • Indications for Ipilimumab reinduction are the following: Absence of remarkable systemic toxicity during previous therapy, relapse occurring after first clinical response, or progression following disease stability >3 months
  • Response rate is <20%; though it may take months for a clinical response to become discernible, this response, however, is durable
  • Has shown improvement in progression-free survival and OS in trials of patients with advanced or unresectable disease
  • When combined with Nivolumab for patients with metastatic or unresectable disease, may improve relapse-free survival but with increased toxicity compared to Nivolumab or Ipilimumab monotherapy
    • Ipilimumab/Nivolumab combination therapy is the preferred 1st-line treatment for patients with asymptomatic BRAF-mutated cutaneous melanoma
    • For management of brain metastases, Ipilimumab/Nivolumab combination therapy is the preferred 1st-line treatment
  • Requirements for Ipilimumab/Nivolumab combination therapy: Agreeable to possible adverse effects, absence of comorbidities, compliance guaranteed by patient, with support system, absent/low tissue PD-L1 expression
  • Close monitoring is needed as immune-mediated reactions may be severe eg colitis, hepatitis, skin inflammation

• High-dose Interleukin-2 (IL-2)
  • Second-line or subsequent treatment option for advanced cutaneous melanoma 
  • May be given to select patients with small brain metastases and no significant peritumoral edema
  • Demonstrated durable complete response in few patients with metastatic melanoma that have been previously treated; however, randomized trials failed to show improvement in OS
  • High-dose IL-2 can cause serious cardiac and pulmonary side effects, thus is generally given for young healthy patients

Targeted Therapy (Signal Transduction Inhibitors)

• BRAF inhibitors, eg Dabrafenib, Encorafenib, Vemurafenib in combination with MEK (mitogen-activated protein kinase) inhibitors (Binimetinib, Cobimetinib, Trametinib) (eg Dabrafenib/Trametinib, Encorafenib/Binimetinib, Vemurafenib/Cobimetinib)
  • Inhibition of BRAF activity slows or stops proliferation of tumor cells and promotes apoptosis
  • A MEK1 and MEK2 selective inhibitor can control growth and induce cell death in some melanoma tumors with BRAF mutation
  • Recommended 1st-line regimen for metastatic or unresectable stage III/IV melanoma with BRAF V600E/K mutations if immunotherapy is unavailable or contraindicated
    • May be associated with fewer cutaneous toxicity than monotherapy
  • Combination regimen is preferred than monotherapy due to its superior response rate, PFS and OS 
  • Comparison of Dabrafenib/Trametinib and Vemurafenib/Cobimetinib combination therapy to Dabrafenib and Verumafenib monotherapy showed improved response rate, duration of response, PFS and OS 
  • Studies showed improved PFS and OS with Encorafenib/Binimetinib combination therapy when compared to Vemurafenib monotherapy
    • Encorafenib/Binimetinib may be considered in patient with BRAF V600E/K mutation-positive distant metastatic or unresectable melanoma
  • Dabrafenib/Trametinib combination therapy is preferred in patients with brain metastases with reported higher rates of response
    • Dabrafenib/Trametinib is a recommended adjuvant treatment option for patients with resected stage III or recurrent disease with BRAF V600E/K mutations solely with clinically occult nodal metastases, limited to stage IIIA with at least 1 nodal metastases >1 mm or stage IIIB/C; not recommended as adjuvant therapy for patients with resected stage IV melanoma
  • Vemurafenib or Dabrafenib monotherapy may only be considered when a patient with BRAF V600E/K mutation-positive distant metastatic or unresectable melanoma has contraindications for combination therapy
  • Binimetinib monotherapy may be considered in patients with NRAS-mutated tumors with disease progression after immune checkpoint inhibitor therapy
    • Demonstrated good response rate and improvement in PFS compared to Dacarbazine monotherapy

• BRAF/MEK + PD(L)-1 checkpoint inhibitors combination (eg Dabrafenib/Trametinib + Pembrolizumab or Vemurafenib/Cobimetinib + Atezolizumab) may be considered as second-line or subsequent therapy in certain circumstances
• BRAF fusions and non-V600 mutations (eg Trametinib)
  • Fusions in BRAF and non-V600 mutation have been shown to respond to MEK inhibitors and BRAF/MEK inhibitor combination
• KIT inhibitor, eg Dasatinib, Imatinib, Nilotinib, Ripretinib
  • Imatinib may be considered in patients ineligible for or unresponsive to immunotherapies or BRAF-targeted therapies 
  • C-KIT inhibitors are available in phase II and phase III trials for patients with unresectable stage III or IV mucosal or acral melanomas positive for the C-KIT mutation
  • A 23% response rate with Imatinib was seen in a phase II study of patients with metastatic melanoma positive for KIT mutation; however, limited duration of responses was shown

• Multikinase inhibitor, eg Sorafenib
  • Active against the Raf/MEK/ERK pathway and the vascular endothelial growth-factor signaling
  • Sorafenib has minimal activity in melanoma as a single agent but combination studies continue as results of usage with Carboplatin plus Paclitaxel were encouraging

• ROS1 fusions (eg Crizotinib, Entrectinib)
  • Fusions in ROS1 are uncommon (<1%) across melanoma subtypes
• Tropomyosin receptor kinase (TRK) inhibitor, eg Entrectinib, Larotrectinib
  • Targets the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded by NTRK1, NTRK2 and NTRK3 genes by competitive inhibition
  • For patients with NTRK gene fusion-positive metastatic or unresectable melanoma

Chemotherapy

• Eg albumin-bound Paclitaxel, Cisplatin/Vinblastine/Dacarbazine, Dacarbazine, Paclitaxel with or without Carboplatin, Temozolomide
• Halts or slows down growth of cancer cells by interfering with the cells’ ability to reproduce
• Treatment option for patients with treatment failure or ineligible for immunotherapy or targeted therapy 
• Generally not used as initial therapy for advanced disease as it is less effective than Ipilimumab and Vemurafenib
• Dacarbazine (DTIC), may be considered for the treatment of advanced or metastatic melanoma if clinical trial, immunotherapy, or new targeted drug is unavailable
• Temozolomide is an oral alkylating agent that hydrolyzes to the same moiety as DTIC but has better CNS penetration
• Another chemotherapeutic agent that has shown modest response rates for advanced or metastatic melanoma is Paclitaxel with or without Carboplatin

Local Therapy

• Intralesional injection with Talimogene laherparepvec (T-VEC), BCG and IL-2 may be options for local recurrence, satellite recurrence and/or unresectable stage III in-transit metastasis
• T-VEC is also a treatment option for unresectable or systemic nodal recurrence and disseminated unresectable distant metastatic disease with at least 1 cutaneous, subcutaneous, or nodal lesion or aggregation of lesions >10 mm in diameter
  • Recommended option for patients with unresectable stage III in-transit disease 
  • Associated with 16% response rate lasting >6 months in highly selected patients with unresectable metastatic melanoma and Stage IV-M1a disease
• Intralesional IL-2 may be considered in patients with local disease if T-VEC is unavailable
  • May produce complete response rate as high as 70% as local therapy and is far less toxic compared to IV doses
• Other intralesional treatment options in the absence of T-VEC include BCG and IFN
• Topical Imiquimod is an immune response modifier that may also be used as an adjunct after excisional surgery
  • May be given for local (very low-volume), satellite and/or in-transit recurrence
  • Studies are limited by different treatment regimens and absence of long-term follow-up
  • The risk of an inflammatory reaction and a low threshold for a repeat biopsy to check for residual or recurrent disease should always be considered
• Topical Diphencyprone (DPCP) or Diphenylcyclopropenone underwent clinical trials for patients with in-transit melanoma, with 1 study showing complete clearance in 46% of patients

Regional Therapy

• For multiple regional in-transit and/or satellite lesions confined to an extremity, hyperthermic isolated limb perfusion or infusion with Melphalan with or without tumor necrosis factor-alpha or Actinomycin-D has shown high rates of tumor response and palliation
  • However, impact on OS has not been shown in controlled studies

Observation

• An acceptable option when surgery is not possible
  • Though therapies directed toward reducing tumor burden may improve disease outcome, these treatment modalities have not been demonstrated to be superior to observation

• Carbon dioxide laser ablation therapy and limited excision are options for local recurrence, satellite recurrence and/or stage III in-transit metastasis
• Palliative resection may also be considered in patients with distant metastatic disease for symptomatic extracranial disease
• Palliative radiotherapy is especially helpful in alleviating symptoms particularly that of brain or bone metastases and of nerve compression 
  • Shrinks tumor size, prevents development of additional tumors, and destroys any residual cancer cells following surgery