Metastatic Melanoma Treatment Guide: Options, Outcomes, and What to Expect

Metastatic melanoma, once one of the most lethal cancers, has been transformed by immunotherapy and targeted therapies. With checkpoint inhibitors and BRAF/MEK inhibitors, many patients now achieve long-term survival and even potential cures.

**Understanding Metastatic Melanoma**

What Is Metastatic Melanoma?
- Stage IV melanoma: spread beyond primary site and regional lymph nodes
- Can metastasize to lungs, liver, brain, bones, distant lymph nodes
- Previously median survival <1 year
- Now: 5-year survival approaching 50% with modern treatments

Prognostic Factors:
- Metastatic sites (lung/skin better than liver/brain)
- LDH levels (elevated LDH worse prognosis)
- Number of metastatic sites
- Performance status
- BRAF mutation status
- PD-L1 expression

**Biomarker Testing - Essential First Step**

Required Tests:

BRAF Mutation (40-50% of melanomas):
- V600E mutation most common (80% of BRAF mutants)
- V600K mutation (15-20%)
- Eligible for BRAF/MEK inhibitor combinations
- Rapid response but may develop resistance

PD-L1 Expression:
- Helps predict immunotherapy response
- Not required for treatment eligibility
- Higher expression = better response rates

Tumor Mutational Burden (TMB):
- High TMB predicts better immunotherapy response
- Melanoma typically has high TMB

Other Markers:
- c-KIT mutations (4-6%, rare subtypes)
- NRAS mutations (15-20%, no approved targeted therapy)
- Microsatellite status

**First-Line Treatment Options**

Immunotherapy Approaches:

Single-Agent PD-1 Inhibitors:

Keytruda (Pembrolizumab):
- FDA approved first-line
- 200 mg IV every 3 weeks or 400 mg every 6 weeks
- Up to 2 years of treatment
- Efficacy:
* Response rate: 40-45%
* 5-year survival: 43%
* Median PFS: 8.4 months
* Median OS: Not reached in responders

OPDIVO (Nivolumab):
- 240 mg IV every 2 weeks or 480 mg every 4 weeks
- Similar efficacy to Keytruda
- May have slightly better tolerability

Combination Immunotherapy:

OPDIVO + Yervoy (Nivolumab + Ipilimumab):
- Most effective immunotherapy combination
- OPDIVO 1 mg/kg + Yervoy 3 mg/kg IV every 3 weeks × 4 doses
- Then OPDIVO maintenance 240 mg every 2 weeks
- Efficacy:
* Response rate: 58%
* Complete response: 22%
* 5-year survival: 52%
* Median PFS: 11.5 months
- Higher toxicity: 55% Grade 3-4 side effects
- Best for patients who need rapid, deep response

When to Choose:
- Good performance status
- Can tolerate potential toxicity
- High disease burden requiring rapid response
- PD-L1 negative tumors

Targeted Therapy (BRAF V600 Mutant):

BRAF/MEK Inhibitor Combinations:

Tafinlar + Mekinist (Dabrafenib + Trametinib):
- Tafinlar 150 mg twice daily + Mekinist 2 mg once daily
- Oral therapy (convenience)
- Efficacy:
* Response rate: 64-69%
* Median PFS: 11.4 months
* 5-year survival: 34%
- Rapid response (often within weeks)
- Common side effects: fever, chills, fatigue, rash

Zelboraf + Cotellic (Vemurafenib + Cobimetinib):
- Vemurafenib 960 mg twice daily + Cotellic 60 mg daily (21 days on/7 days off)
- Similar efficacy to Tafinlar/Mekinist

When to Choose Targeted Therapy:
- BRAF V600 mutation positive
- Need rapid tumor shrinkage (symptomatic disease)
- Brain metastases requiring quick response
- Contraindication to immunotherapy
- Patient preference for oral therapy

**Treatment Selection Strategy**

For BRAF Wild-Type (No BRAF Mutation):
1. First-line: OPDIVO + Yervoy combination (if can tolerate)
2. Alternative: Single-agent Keytruda or OPDIVO
3. Clinical trial if available

For BRAF V600 Mutant:
- More complex decision

Favors Immunotherapy First:
- Asymptomatic or slowly progressive disease
- Good performance status
- Normal LDH
- Willing to wait for response
- Seeking long-term durable benefit

Favors Targeted Therapy First:
- Symptomatic disease requiring rapid response
- Elevated LDH
- Liver or brain metastases
- Poor performance status
- Need oral therapy

Emerging Approach: Some centers use targeted therapy to quickly shrink tumors, then switch to immunotherapy for long-term control.

**Treatment Duration**

Immunotherapy:
- Continue until disease progression or toxicity
- Typically up to 2 years
- Some patients achieve durable responses off therapy
- Retreatment possible if recurs after initial response

Targeted Therapy:
- Continue until progression
- Often 12-18 months before resistance develops
- Subsequent options available after progression

**Managing Brain Metastases**

Special Considerations:
- Present in 40-60% of metastatic melanoma patients
- Previously very poor prognosis

Modern Treatment Approaches:

Small, Asymptomatic Lesions (<1 cm):
- Systemic therapy first (immunotherapy or targeted therapy)
- Both can cross blood-brain barrier
- Response rates 50-60%
- Stereotactic radiosurgery (SRS) as backup

Large or Symptomatic Lesions:
- Stereotactic radiosurgery or surgery first
- Then systemic therapy
- Avoid whole-brain radiation if possible

OPDIVO + Yervoy:
- Intracranial response rate: 55%
- Best systemic option for brain mets

BRAF/MEK Inhibitors:
- Rapid intracranial responses
- Good for urgent brain metastases

**Second-Line and Beyond**

After Immunotherapy Progression:

If No Prior BRAF Inhibitor (and BRAF mutant):
- Tafinlar + Mekinist targeted therapy
- Often effective after immunotherapy failure

If No Prior Immunotherapy:
- Keytruda or OPDIVO + Yervoy
- Can still respond

Clinical Trials:
- Novel immunotherapy combinations
- New targeted agents
- Cellular therapies (TIL, CAR-T)

After Targeted Therapy Progression:

Immunotherapy (If Not Previously Used):
- OPDIVO + Yervoy or Keytruda
- Response rates 30-40%
- Can achieve durable responses

Alternative Targeted Therapy:
- Different BRAF/MEK combination
- Investigational agents targeting resistance mechanisms

Chemotherapy:
- Dacarbazine, temozolomide
- Carboplatin + paclitaxel
- Lower response rates but may provide palliation

**Clinical Trial Opportunities**

Promising Approaches:

Tumor Infiltrating Lymphocyte (TIL) Therapy:
- Personalized cellular therapy
- High response rates in trials
- May gain FDA approval soon

LAG-3 Inhibitors + PD-1:
- OPDUALAG (relatlimab + nivolumab) approved
- For patients after PD-1 failure

Novel Combinations:
- Immunotherapy + targeted therapy
- Multi-checkpoint blockade
- Oncolytic virus therapy

**Monitoring During Treatment**

Imaging Schedule:
- CT scans every 12 weeks typically
- PET/CT for baseline and confirmation
- Brain MRI if brain metastases present

Response Patterns:

Pseudoprogression (Immunotherapy):
- Temporary increase in tumor size
- Due to immune infiltration
- Occurs in 5-10% of cases
- Continue treatment if clinically stable

Hyperprogression (Rare):
- Rapid tumor growth after starting treatment
- Very rare with PD-1 inhibitors
- Switch treatment immediately

**Survival and Outcomes**

Historical vs. Modern Era:

Pre-2011 (Before Immunotherapy):
- Median survival: 6-9 months
- 5-year survival: <10%
- Chemotherapy only option

Current Era (2024-2026):
- Median survival: >3 years with immunotherapy
- 5-year survival: 40-52% with OPDIVO + Yervoy
- 5-year survival: 43% with Keytruda
- Some patients remain disease-free >10 years

Long-Term Survivors:
- 20-30% of patients achieve complete response
- Many discontinue therapy after 2 years disease-free
- Durable off-treatment responses common
- Some may be "cured"

**Quality of Life Considerations**

Side Effect Management:
- Immunotherapy side effects usually manageable
- Steroids effective for most immune-related adverse events
- Targeted therapy side effects predictable
- Supportive care essential

Practical Considerations:
- Immunotherapy: IV infusion every 2-6 weeks
- Targeted therapy: Daily oral pills
- Treatment center visits
- Impact on work and activities
- Financial toxicity

Psychosocial Support:
- Anxiety about scans and progression
- Support groups helpful
- Counseling if needed
- Palliative care involvement early

**Questions to Ask Your Oncologist**

- What is my BRAF mutation status?
- Should I start with immunotherapy or targeted therapy?
- What are my chances of long-term survival?
- How will you monitor for brain metastases?
- What happens if first treatment stops working?
- Am I eligible for clinical trials?
- What side effects should I expect?

**Patient Success Story**

"When diagnosed with stage IV melanoma in my lungs and liver in 2022, I was terrified. My BRAF test was negative, so we started OPDIVO + Yervoy. After the first scan at 12 weeks, my tumors had shrunk by 60%. By 6 months, I had a complete response. I completed 2 years of treatment and have been off therapy for 8 months with no evidence of disease. I feel great and am back to all my normal activities. Modern immunotherapy gave me my life back."

Our team can help you access the latest melanoma treatments and connect you with specialized melanoma centers for comprehensive care.