What is the comparison between immunotherapy and targeted therapy for Stage 3 melanoma?

From the Guidelines

For stage 3 melanoma, immunotherapy is the preferred treatment option due to its ability to provide durable responses and longer-term protection against recurrence, as supported by recent guidelines and studies 1. When considering treatment options for stage 3 melanoma, it's essential to weigh the benefits and drawbacks of immunotherapy and targeted therapy. Immunotherapy, which includes anti-PD-1 agents like pembrolizumab and nivolumab, has been shown to induce durable clinical responses in a significant proportion of patients 1.

• The standard immunotherapy options include:
  • Pembrolizumab (Keytruda) at 200mg IV every 3 weeks for up to 1 year
  • Nivolumab (Opdivo) at 240mg IV every 2 weeks or 480mg every 4 weeks for up to 1 year
• These medications work by enhancing the immune system's ability to recognize and attack cancer cells. In contrast, targeted therapy with BRAF/MEK inhibitor combinations is an alternative option for patients with BRAF-mutated melanomas, which account for approximately 40-50% of cases 1.
• Common combinations include:
  • Dabrafenib (150mg twice daily) plus trametinib (2mg once daily)
  • Encorafenib plus binimetinib, taken orally for up to 1 year
• Targeted therapy works by directly blocking the specific molecular pathways driving cancer growth in BRAF-mutated melanomas. However, immunotherapy is generally preferred due to its potential for long-term disease control, even after stopping treatment, as highlighted in recent studies 1. BRAF testing is essential before making treatment decisions, and the final choice should be individualized based on the patient's specific disease characteristics, comorbidities, and preferences after discussion with their oncologist.

From the FDA Drug Label

Adjuvant Treatment of Stage III Resected Melanoma The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%).

The FDA drug label does not directly compare immunotherapy vs targeted therapy for Stage 3 melanoma. However, it provides information on the safety of KEYTRUDA (pembrolizumab), an immunotherapy option, in patients with resected Stage III melanoma.

• Key points:
  • Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA.
  • Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA.
  • The most common adverse reactions leading to permanent discontinuation were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Based on the available information, immunotherapy with KEYTRUDA is a treatment option for resected Stage III melanoma, but the label does not provide a direct comparison with targeted therapy 2.

From the Research

Stage 3 Melanoma Immunotherapy vs Targeted Therapy

• The optimal therapy for stage 3 melanoma remains controversial, with both immune checkpoint inhibitors (ICIs) and targeted therapies being widely used as adjuvant treatment 3.
• A network meta-analysis of 27 randomized controlled trials found that nivolumab and pembrolizumab demonstrated significantly better disease-free survival (DFS) and tolerability than ipilimumab (10 mg/kg) for BRAF wild-type melanoma 3.
• For BRAF mutation-positive melanoma, ICIs (nivolumab + ipilimumab, nivolumab, pembrolizumab, ipilimumab; 10 mg/kg) exhibited comparable efficacy to dabrafenib + trametinib, and all these therapies showed significantly better DFS than placebo 3.
• The development of combination immunotherapy has been a major step in the treatment of advanced-stage melanoma, with approvals obtained for the immune checkpoint inhibitors ipilimumab, nivolumab, pembrolizumab, and the combination ipilimumab plus nivolumab 4.
• Anti-PD-1 agents (nivolumab and pembrolizumab) have been placed at the center of practically all combination therapy development strategies in melanoma due to their unique therapeutic index (high efficacy and low toxicity) 4.

Adjuvant Therapy for Stage 3 Melanoma

• Adjuvant pembrolizumab, nivolumab, or dabrafenib and trametinib are associated with a significant improvement in both relapse-free survival (RFS) and distant metastasis-free survival (DMFS) for patients with resected high-risk stage 3 disease 5.
• The choice of adjuvant treatment could influence the choice of subsequent treatments in neo-adjuvant or metastatic settings 6.
• For patients with BRAFV600-mutant cutaneous melanoma, two options are available in the adjuvant setting: anti-PD-1 blockers (nivolumab or pembrolizumab) or BRAF plus MEK inhibitors (dabrafenib plus trametinib) 6.

Treatment Options for BRAF-Mutated Advanced Melanoma

• Three different combinations of BRAF/MEK inhibitors have been approved for the treatment of BRAF-V600 mutation-positive metastatic melanoma, showing comparable efficacy and unique toxicity profiles 7.
• Several immune-checkpoint inhibitors, including pembrolizumab, nivolumab, and the combination of nivolumab plus ipilimumab, are also available options for untreated metastatic melanoma patients 7.
• A novel approach has emerged by combining immune-checkpoint inhibitors and targeted agents, based on preclinical hints of synergy, prompting clinical results from large randomized trials 7.