What are the medications used to treat multiple melanoma?

Medications for Multiple Melanoma

The primary medications for treating melanoma include immune checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab) and BRAF/MEK inhibitor combinations (dabrafenib/trametinib, encorafenib/binimetinib, vemurafenib/cobimetinib), with treatment selection based on BRAF mutation status, disease tempo, and clinical setting. 1, 2

Immunotherapy Agents

Anti-PD-1 Monotherapy

• Nivolumab: 3 mg/kg IV every 2 weeks or 480 mg IV every 4 weeks 2, 3
• Pembrolizumab: 2 mg/kg IV every 3 weeks or 200 mg IV every 3 weeks, or 400 mg IV every 6 weeks 2, 3
• These agents are first-line options for all patients with unresectable/metastatic melanoma, regardless of BRAF status 1, 2

Combination Immunotherapy

• Ipilimumab plus nivolumab: Ipilimumab 3 mg/kg plus nivolumab 1 mg/kg IV every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks 1, 2, 4
• This combination provides superior progression-free survival compared to monotherapy but carries significantly higher toxicity risk (grade ≥3 adverse events: 65% vs 32% for monotherapy) 2
• Ipilimumab monotherapy is NOT recommended as first-line treatment due to inferior outcomes compared to anti-PD-1 agents 2

High-Dose Interleukin-2

• Approved for metastatic disease but rarely used due to availability of more effective and better-tolerated options 1

Targeted Therapy for BRAF-Mutant Melanoma

BRAF/MEK Inhibitor Combinations

All three combinations are FDA-approved and equally valid options 1, 2, 5:

• Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily 2, 5
• Encorafenib 450 mg PO once daily plus binimetinib 45 mg PO twice daily 2, 5
• Vemurafenib 960 mg PO twice daily plus cobimetinib 60 mg PO once daily (21 days on, 7 days off) 2, 5

Critical: BRAF/MEK combination therapy is mandatory—never use BRAF inhibitor monotherapy or MEK inhibitor monotherapy due to poor efficacy and rapid resistance development. 2, 5

Adjuvant Therapy Medications

For Stage IIB-C Melanoma

• Pembrolizumab for 52 weeks (strongly recommended based on KEYNOTE-716 trial) 3
• Nivolumab for 52 weeks (recommended based on CheckMate 76K trial) 3

For Stage IIIA-D BRAF-Mutant Melanoma

Three equivalent first-line options 3:

• Nivolumab for 52 weeks
• Pembrolizumab for 52 weeks
• Dabrafenib plus trametinib for 52 weeks

For Stage IIIA-D BRAF Wild-Type Melanoma

• Nivolumab or pembrolizumab for 52 weeks 1, 3

Intralesional Therapy

• Talimogene laherparepvec (T-VEC): Gene-modified oncolytic virus for injectable cutaneous, subcutaneous, or nodal lesions 1, 2
• Used as primary therapy if patients decline systemic therapy or for limited stage IV disease 2

Adjuvant Interferon Therapy (Historical)

• Interferon α2b and pegylated interferon α2b: Approved for high-risk adjuvant therapy but largely replaced by more effective checkpoint inhibitors 1

Treatment Selection Algorithm

For Unresectable/Metastatic Disease

Step 1: BRAF Mutation Testing

• Mandatory testing using FDA-approved test or CLIA-approved facility to identify any BRAF V600 mutation (V600E, V600K, V600R, V600D, or others) 2, 5

Step 2: For BRAF Wild-Type Patients

• First-line: Nivolumab, pembrolizumab, or nivolumab/ipilimumab combination 2
• Choose combination therapy if patient can tolerate higher toxicity and requires maximal disease control 2

Step 3: For BRAF V600-Mutant Patients

• If rapidly progressive, symptomatic, high tumor burden, or deteriorating health: Start with BRAF/MEK inhibitor combination 2, 5
• If low-volume, asymptomatic disease: Prefer immunotherapy (nivolumab, pembrolizumab, or combination) 2, 5

For Brain Metastases

• **Asymptomatic, untreated brain metastases (<5-10 lesions, <3 cm)**: Ipilimumab/nivolumab combination is preferred first-line treatment, even in BRAF-mutated patients (46% overall response rate, >50% PFS at 18 months) 1
• BRAF-mutant patients with brain metastases: Dabrafenib/trametinib combination shows 58% response rate but shorter PFS (5.6 months median) 1
• Symptomatic brain metastases or leptomeningeal disease: BRAF/MEK inhibitors in BRAF-mutant patients or temozolomide in BRAF wild-type patients, combined with whole brain radiotherapy 1

Sequencing After Progression

• After progression on anti-PD-1 therapy in BRAF-mutant patients: Switch to BRAF/MEK inhibitor combination 2, 5
• After progression on BRAF/MEK inhibitors: Switch to anti-PD-1-based immunotherapy 2, 5
• Patients who progressed rapidly on first-line BRAF inhibitors derive minimal benefit from second-line BRAF/MEK combinations 2

Common Pitfalls to Avoid

• Never use ipilimumab monotherapy as first-line treatment—CheckMate 067 trial demonstrated superior outcomes with anti-PD-1 monotherapy or combination therapy 2
• Never use BRAF inhibitor monotherapy unless combination therapy is absolutely contraindicated 2, 5
• Never use MEK inhibitor monotherapy—trametinib monotherapy shows poor efficacy (22% response rate, 2.8 months median PFS) 2, 5
• Do not use immunotherapy in patients with symptomatic brain metastases requiring steroids—only 21-22% intracranial response rate 1

Treatment Duration

• Immunotherapy: Nivolumab and pembrolizumab were limited to 2 years in pivotal trials, though treatment may continue beyond 2 years in clinical practice 2
• BRAF/MEK inhibitors: Typically continued until progression or unacceptable toxicity 2
• Adjuvant therapy: All regimens are administered for 52 weeks (1 year) 3