What are the latest treatment options for advanced melanoma?

Latest Developments in Advanced Melanoma Treatment

First-Line Therapy for Advanced Melanoma

For patients with advanced melanoma, anti-PD-1 monotherapy (pembrolizumab or nivolumab) is the preferred first-line treatment regardless of BRAF mutation status, based on superior survival outcomes and lower toxicity compared to ipilimumab. 1

Standard First-Line Options

Anti-PD-1 Monotherapy:

• Pembrolizumab or nivolumab demonstrates superior efficacy over ipilimumab with hazard ratios for death of 0.63-0.69 (P<0.001) 2
• 12-month overall survival rates: 68-74% with pembrolizumab versus 58% with ipilimumab 2
• Grade 3-5 treatment-related adverse events occur in only 10-13% of patients on anti-PD-1 therapy versus 20% with ipilimumab 1, 3
• Median time to response is 2.1-3.5 months 1

Combination Immunotherapy:

• Nivolumab plus ipilimumab combination shows superior progression-free survival (HR 0.51) and overall survival (HR 0.61) compared to ipilimumab alone 1
• However, this combination carries significantly higher toxicity with grade 3-4 adverse events in 46-59% of patients 1, 3
• Reserve this combination for patients with symptomatic, bulky metastases or rapidly progressive disease where rapid response is critical 1

BRAF-Mutant Melanoma Specific Considerations

For BRAF V600-mutant disease, anti-PD-1 monotherapy should still be prioritized over BRAF/MEK inhibitor combinations as first-line therapy based on superior overall survival. 4

• First-line pembrolizumab demonstrates longer overall survival than dabrafenib/trametinib (HR 2.91,95% CI 1.55-5.46) despite similar progression-free survival 4
• BRAF/MEK inhibitor combinations (dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib) are appropriate first-line alternatives when rapid disease control is needed 1
• BRAF/MEK inhibitors show faster time to response (median ~1.5 months) but shorter duration of response (5-7 months) 1
• Resistance to BRAF/MEK inhibitors co-occurs with immune evasion mechanisms 4

Critical pitfall: BRAF inhibitor monotherapy should only be used when contraindications exist to BRAF/MEK combination therapy, as monotherapy shows inferior outcomes 1

Adjuvant Therapy Advances

For completely resected Stage IIB-C melanoma, pembrolizumab or nivolumab for 52 weeks is now standard of care based on substantial recurrence-free survival benefits. 5

Stage-Specific Adjuvant Recommendations

Stage IIB-C Disease:

• Pembrolizumab 200 mg IV every 3 weeks or 400 mg IV every 6 weeks for 52 weeks (strongly recommended) 5
• Nivolumab 3 mg/kg IV every 2 weeks or 480 mg IV every 4 weeks for 52 weeks (recommended alternative) 5
• Both agents show similar efficacy and toxicity profiles in this population 5

Stage IIIA-D Disease:

• Three equivalent first-line options exist: nivolumab for 52 weeks, pembrolizumab for 52 weeks, or dabrafenib/trametinib for 52 weeks (for BRAF V600E/K mutant disease only) 5
• Nivolumab demonstrates superiority over high-dose ipilimumab with 12-month recurrence-free survival of 70.5% vs 60.8% (HR 0.65, P<0.001) 5
• Grade 3-4 adverse events: 14.4% with nivolumab versus 45.9% with ipilimumab 5
• Pembrolizumab shows 12-month recurrence-free survival of 75% vs 61% for placebo (HR 0.57, P<0.001) 5

For BRAF-mutant Stage III disease:

• Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily for 52 weeks is an equivalent option 1, 5
• This regimen is only recommended for Stage IIIA (with ≥1 nodal metastasis >1 mm) or Stage IIIB/C as defined by AJCC 7th edition 1
• Not recommended for resected Stage IV disease as this population was excluded from pivotal trials 1

Critical testing requirement: BRAF mutation testing is mandatory for all Stage III-IV melanoma to determine eligibility for dabrafenib/trametinib, specifically identifying V600E or V600K mutations 5

Important note: PD-L1 testing is not required for adjuvant therapy selection, as benefit occurs regardless of PD-L1 expression status 5

Second-Line and Subsequent Therapy

After first-line anti-PD-1 failure, switch to ipilimumab/nivolumab combination if not previously given, with overall response rate of 21% and 12-month overall survival of 55%. 6

Second-Line Options (Category 2A)

The following regimens are acceptable second-line options, though evidence is less robust than first-line data 1:

• Nivolumab monotherapy (supported by phase III data in previously treated patients, though results less robust than first-line) 1
• Pembrolizumab 1
• Nivolumab/ipilimumab combination 1
• Dabrafenib/trametinib (for BRAF V600 mutations) 1
• Vemurafenib/cobimetinib (for BRAF V600 mutations) 1
• Encorafenib/binimetinib (for BRAF V600 mutations) 1

Sequencing consideration: BRAF-targeted therapy remains effective following immunotherapy failure, and checkpoint inhibitors retain activity after kinase-inhibitor progression 1

Special Populations and Scenarios

Brain Metastases:

• Checkpoint inhibitors, including ipilimumab/nivolumab combination, can be safely used and show significant efficacy in patients with brain metastases 1
• Stereotactic radiotherapy is preferred over whole brain irradiation 1, 6

Injectable Metastases:

• Talimogene laherparepvec (T-VEC) is an option for unresectable Stage IIIB/C or Stage IVM1a disease 1
• T-VEC plus ipilimumab combination is a Category 2B option for second-line therapy only (not first-line), based on improved response rate but no PFS/OS benefit 1

KIT-Mutant Melanoma:

• Imatinib may provide disease control in patients with activating KIT mutations, though response rate is <50% and it is not a preferred agent 1

Emerging Therapies

Relatlimab/nivolumab (anti-LAG3 plus anti-PD-1) shows similar progression-free survival and overall response rate to ipilimumab/nivolumab with a trend toward better safety profile. 7

• No difference in PFS (HR 0.99,95% CI 0.75-1.31) or ORR (RR 0.99,95% CI 0.78-1.27) compared to ipilimumab/nivolumab 7
• Trend toward lower risk of grade ≥3 treatment-related adverse events (RR 0.71,95% CI 0.30-1.67) 7

Triplet combinations (PD-L1/BRAF/MEK inhibitors):

• Atezolizumab/vemurafenib/cobimetinib shows superior PFS (HR 0.56,95% CI 0.37-0.84) and ORR (RR 3.07,95% CI 1.61-5.85) compared to ipilimumab/nivolumab in BRAF-mutant patients 7

Treatment Duration and Monitoring

Continue anti-PD-1 therapy until disease progression, unacceptable toxicity, or maximum response is achieved. 6

• Consider stopping anti-PD-1 therapy after 2 years in patients with partial response 6
• Published trials show discontinuation rates of 45-77% with median follow-up <2 years 1
• Further data needed to determine if treatment beyond 2 years is necessary for maintaining disease control 1

Treatment beyond progression may be considered in selected patients who continue to derive clinical benefit without substantial adverse events. 1

Critical Management Principles

Multidisciplinary tumor board discussion is mandatory for all Stage IV melanoma patients at centers with extensive melanoma experience. 1, 6

Immune-related adverse events require aggressive management:

• Monitor for colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic toxicities 6
• Evaluate clinical chemistries including liver enzymes, creatinine, ACTH, and thyroid function at baseline and before each dose 8
• Withhold therapy for severe (grade 3) and permanently discontinue for life-threatening (grade 4) immune-mediated adverse reactions 8

Common pitfalls to avoid:

• Do not delay immunotherapy initiation while awaiting molecular testing in clearly metastatic disease, as checkpoint inhibitors do not require mutation-specific selection 9
• Do not use traditional RECIST criteria alone; employ immune-related response criteria as pseudoprogression can occur 9
• Do not rely on chemotherapy as first-line treatment, as immunotherapy demonstrates dramatically superior outcomes 6
• Do not fail to obtain BRAF mutation testing in all advanced disease, as this is mandatory for treatment planning 6

Clinical trial enrollment remains the number one priority in all settings given ongoing therapeutic advances. 1, 6