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Advanced Melanoma Therapy
Current Therapeutic Strategies for Advanced Melanoma

Released: May 31, 2023

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Key Takeaways
  • Recent clinical trials have shown significant benefit of adjuvant and neoadjuvant therapy for patients with resected stage IIB-IV melanoma.
  • Immune checkpoint blockade is generally recommended as first-line therapy for patients with unresectable or metastatic melanoma regardless of BRAF V600 mutation status.
  • Patients with BRAF wild-type melanoma should be tested for other uncommon oncogenic mutations that can benefit from specific targeted therapies.

The advent of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) has drastically changed the treatment landscape and improved overall survival for patients with advanced melanoma. The success of these therapies has made melanoma a testing ground for innovative cancer treatments. In the melanoma space, the FDA has approved drugs targeting 4 different immune checkpoint proteins; PD-1, PD-L1, CTLA-4 and LAG-3. In addition, there are 3 FDA-approved combinations of BRAF and MEK inhibitors for treatment of patients with BRAF-mutant melanoma (dabrafenib + trametinib, encorafenib + binimetinib, and vemurafenib + cobimetinib). 

Adjuvant and Neoadjuvant Approaches
Adjuvant therapy should be considered in patients with resected stage IIB-IV melanoma. When discussing adjuvant therapy options with patients, providers should consider immune-based comorbidities (autoimmune conditions, organ transplantation), risk of therapy-related adverse events vs risk of recurrent disease, and other patient-specific factors (age, frequent travel, preference, etc). Tumors should be assessed for actionable somatic mutations in all patients potentially eligible for systemic therapy. Adjuvant nivolumab, pembrolizumab and dabrafenib + trametinib have each demonstrated improved recurrence-free survival in patients with resected melanoma. Nivolumab, pembrolizumab, and dabrafenib + trametinib are each FDA-approved as adjuvant therapies for appropriate patients with resected melanoma. 

Results from recent studies showing the benefit of neoadjuvant ICI therapy are potentially practice changing. The SWOG 1801 trial comparing neoadjuvant-adjuvant pembrolizumab to adjuvant pembrolizumab showed an improved 2-year event-free survival benefit in the neoadjuvant cohort (72% vs 49%; P =.004). 

Selecting First-Line Therapy
Clinical decisions about first-line therapy for patients with metastatic/unresectable melanoma remain nuanced, with multiple factors to be considered including, but not limited to, underlying autoimmune disease, history of organ transplant, patient age, and tumor burden. First-line therapy options include ICIs, BRAF + MEK inhibitors (BRAF-mutant only) and clinical trials (eg, a standard-of-care drug plus an experimental therapy). Combination ICI therapies are frequently recommended for these patients. The CheckMate-067 trial showed front-line ipilimumab (anti-CTLA-4) + nivolumab (anti-PD-1) improved overall survival compared to ipilimumab alone for patients with unresectable melanoma (HR for death: 0.53 [95% CI: 0.44-0.65]). The RELATIVITY-047 trial showed improved progression-free survival in patients with metastatic or unresectable melanoma with front-line nivolumab + relatlimab (anti-LAG-3) compared to nivolumab alone (HR: 0.75 [95% CI: 0.62-0.92]; P =.0006). Results from this study supported the FDA approval of nivolumab + relatlimab in 2022. 

Although there is no biomarker that predicts melanoma response to ICI, in general, we recommend ICI as first-line therapy for patients with metastatic disease unless there is a clear contraindication to immunotherapy even for patients with BRAF V600 mutations. This recommendation is based on results from the DREAMseq trial, which showed the 2-year overall survival in patients with BRAF V600E/K mutations who received ipilimumab + nivolumab as first-line therapy followed by dabrafenib + trametinib at disease progression was significantly improved compared to the reverse sequence (P = .010).

ICI and TKIs have demonstrated antitumor activity in the brain. In patients with asymptomatic brain metastases who received ipilimumab + nivolumab, the 5-year intracranial progression-free survival rate was 46% compared to 15% in the nivolumab monotherapy cohort. TKIs have also demonstrated antitumor activity in the central nervous system, though the durability of response is often limited. For example, encorafenib + binimetinib was associated with an objective response rate of 33% and a median duration of response of 22 weeks. Given the potential durability of antitumor responses observed with ipilimumab + nivolumab, this combination should be considered as first-line therapy in most patients with brain metastases.

Of importance, therapies targeting oncogenic mutations (eg, NRAS, cKIT) or fusions (eg, ROS1, NTRK) are useful in appropriate patients. Melanomas that are BRAF wild-type should undergo next-generation sequencing for uncommon genetic drivers. Corresponding targeted therapies are described in the NCCN Guidelines for cutaneous melanoma.

Future Directions and Patient Considerations
Experimental approaches testing tumor infiltrating lymphocyte therapy have shown promising results in patients with advanced melanoma who progressed on standard-of-care therapy.

The management of therapy-related toxicities is complex and frequently requires a multidisciplinary approach. Using published resources to guide toxicity management (eg, drug prescribing information, NCCN and ASCO guidelines), creating a specialist referral network, encouraging patients to report symptoms, and facilitating rapid evaluation of side effects are key to preventing significant treatment-related morbidity and mortality. 

Overall, the management of patients with melanoma is an evolving field. Providers should develop treatment plans that consider patient comorbidities, tumor burden, and presence of somatic actionable mutations. Participation in clinical trials should be considered at every stage of a melanoma diagnosis.


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