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• The EORTC 18071 trial:
  • Was a landmark, double-blind, phase 3 study that established the efficacy of adjuvant immune checkpoint blockade in cutaneous melanoma
• In this trial, patients with completely resected high-risk stage III melanoma were randomized to receive:
  • High-dose ipilimumab (10 mg/kg IV every 3 weeks for 4 doses, then every 3 months for up to 3 years) or placebo
  • The primary endpoint was:
    • Recurrence-free survival (RFS)
• EORTC 18071 demonstrated that:
  • Adjuvant ipilimumab significantly improved compared to placebo:
    • RFS:
      • 5-year RFS:
        • 40.8% vs 30.3%
    • Overall survival:
      • 5-year OS:
        • 65.4% vs 54.4%
    • However, the benefit came at the cost of substantial toxicity:
      • With grade ≥ 3 immune-related adverse events in 41.6% of patients and a 1% treatment-related mortality rate
• This trial was the first to show a survival benefit for adjuvant immunotherapy in melanoma:
  • Leading to regulatory approval of ipilimumab in this setting
• The findings of EORTC 18071 provided the foundation for subsequent trials of immune checkpoint blockade:
  • CheckMate 238:
    • Compared nivolumab (anti–PD-1) to ipilimumab:
      • It showed superior RFS and a markedly improved safety profile for nivolumab:
        • 5-year RFS: 50% vs 39%
        • Grade 3 to 4 adverse events: 14% vs 41%
  • KEYNOTE-054 (EORTC 1325):
    • Compared pembrolizumab (anti–PD-1) to placebo:
      • It also demonstrated a significant RFS benefit:
        • 3-year RFS: 63.7% vs 44.1% with lower toxicity than ipilimumab
• In the context of adjuvant and recurrent therapy:
  • EORTC 18071 established the principle that:
    • Immune checkpoint blockade can reduce recurrence and improve survival after resection of high-risk melanoma:
      • But anti–PD-1 agents (nivolumab, pembrolizumab) have since become preferred due to superior efficacy and tolerability
• For patients with local recurrence after adjuvant therapy:
  • Management is now guided by prior exposure and resistance patterns:
    • With escalation to combination immunotherapy or targeted therapy as appropriate
• References:
  • Adjuvant Ipilimumab Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (EORTC 18071): A Randomised, Double-Blind, Phase 3 Trial. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. The Lancet. Oncology. 2015;16(5):522-30. doi:10.1016/S1470-2045(15)70122-1.
  • Recent Advances in the Treatment of Melanoma. Curti BD, Faries MB. The New England Journal of Medicine. 2021;384(23):2229-2240. doi:10.1056/NEJMra2034861.
  • Systemic Therapy for Melanoma: ASCO Guideline Update. Seth R, Agarwala SS, Messersmith H, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2023;41(30):4794-4820. doi:10.1200/JCO.23.01136.
  • Adjuvant Therapy for Melanoma. Agha A, Tarhini AA. Current Oncology Reports. 2017;19(5):36. doi:10.1007/s11912-017-0594-5.
    Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. Weber J, Mandala M, Del Vecchio M, et al. The New England Journal of Medicine. 2017;377(19):1824-1835. doi:10.1056/NEJMoa1709030.
  • Adjuvant Nivolumab Versus Ipilimumab in Resected Stage IIIB-C and Stage IV Melanoma (CheckMate 238): 4-Year Results From a Multicentre, Double-Blind, Randomised, Controlled, Phase 3 Trial. Ascierto PA, Del Vecchio M, Mandalá M, et al. The Lancet. Oncology. 2020;21(11):1465-1477. doi:10.1016/S1470-2045(20)30494-0.
  • Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238. Larkin J, Del Vecchio M, Mandalá M, et al. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2023;29(17):3352-3361. doi:10.1158/1078-0432.CCR-22-3145.
  • Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. Eggermont AMM, Blank CU, Mandala M, et al. The New England Journal of Medicine. 2018;378(19):1789-1801. doi:10.1056/NEJMoa1802357.
  • Adjuvant Pembrolizumab Versus Placebo in Resected Stage III Melanoma (EORTC 1325-Mg/Keynote-054): Distant Metastasis-Free Survival Results From a Double-Blind, Randomised, Controlled, Phase 3 Trial. Eggermont AMM, Blank CU, Mandalà M, et al. The Lancet. Oncology. 2021;22(5):643-654. doi:10.1016/S1470-2045(21)00065-6.
  • Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-Mg/Keynote-054 Trial. Eggermont AMM, Blank CU, Mandala M, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2020;38(33):3925-3936. doi:10.1200/JCO.20.02110.

• In a phase III, randomized prospective trial, Hodi et al:
  • Evaluated 676 patients who received ipilimumab, ipilimumab plus a peptide vaccine, or peptide vaccine alone
  • Overall response and disease control:
    • Were highest in the ipilimumab alone cohort
  • Median OS was:
    • 10.1 months for this cohort and overall response was 10.9%
  • Disease control was:
    • 28.5%:
      • With 60% of the ipilimumab cohort having a significant response at 2 years
    • In March 2011, the FDA approved ipilimumab as a second-line treatment for metastatic melanoma
• A subsequent study demonstrated the benefit of ipilimumab in the first-line setting:
  • In a phase III, double-blind clinical trial of 502 metastatic melanoma patients randomized to ipilimumab plus dacarbazine versus placebo plus dacarbazine by Robert et al:
    • The ipilimumab cohort was associated with a significantly higher:
      • OS:
        • 11.2 months vs. 9.2 months
      • Durable response:
        • 19.3 months vs. 8.3 months
  • For patients with metastatic melanoma:
    • The currently approved ipilimumab dose is 3 mg/kg by intravenous infusion given every 3 weeks for four doses
• The clinical use of PD-1 blocking antibodies has been tested in several clinical trials, including a phase I trial of 296 patients with either advanced melanoma or other solid tumors:
  • Treatment with a monoclonal antibody targeting PD-1 (nivolumab):
    • Was associated with a 28% response rate in patients with metastatic melanoma
    • Long-term responses longer than 1 year in 50% of responders
  • Anti–PD-1-based therapy was associated with a lower rate of grade 3 or 4 adverse events compared to ipilimumab
• Additional clinical trials have been performed (NCT01295827 / NCT01704287), including a phase III trial with over 500 patients with metastatic melanoma whose disease was refractory to CTLA-4 blockade:
  • In this trial (KEYNOTE-002), patients were randomized to pembrolizumab (2 mg/kg every 3 weeks), pembrolizumab (10 mg/kg every 3 weeks) or chemotherapy (carboplatin plus paclitaxel, paclitaxel alone, dacarbazine, or temozolomide per institutional standard):
    • PFS was the primary endpoint and was significantly improved with both pembrolizumab arms compared to chemotherapy:
      • 6-month PFS was 34%, 38%, and 16% for pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, and chemotherapy, respectively
  • Toxicity was limited in this trial; the most common adverse events included fatigue, pruritus, and rash:
    • Grade 3 immune-related adverse events (IRAEs) were seen in two patients treated with pembrolizumab 2 mg/kg (hepatitis, hypophysitis) and in eight patients who received pembrolizumab 10 mg/kg (hepatitis, colitis, pneumonitis, and iritis/uveitis)
      

• BRAF mutations:
  • Have been found in approximately 50% of invasive cutaneous melanomas
• The BRAF gene:
  • Encodes for production of B-RAF:
    • A protein involved in cell signaling and growth
• BRIM-3:
  • Was a randomized, open-label, multicenter, phase III study
  • It compared a BRAF inhibitor, PLX4032 (vemurafenib), to dacarbazine:
    • For treatment of previously untreated, unresectable, stage IIIC or stage IV melanoma in patients harboring a BRAF mutation
  • The inhibitor targets the common V600E BRAF mutation
  • Interim analysis of 675 patients revealed:
    • Superiority in OS and PFS for vemurafenib
    • The response rate of patients on vemurafenib:
      • Was 48.4% compared to 5.5% for patients receiving dacarbazine
    • While such a response rate for single modality therapy was essentially unprecedented in the treatment of metastatic melanoma:
      • Enthusiasm was tempered, at least to some extent, by the observation that disease recurrence was observed in the majority of patients 6 to 8 months following initiation of therapy
    • Also important was the observation that up to 25% of patients who received vemurafenib developed squamous carcinoma of the skin:
      • Often in the form of keratoacanthomas
• Dabrafenib, another agent targeting BRAF V600 mutant melanoma:
  • Demonstrated similarly high OR rates in a phase III trial
• Together, these findings provided the basis for approval of each of these agents as monotherapy in 2011 and 2013, respectively
• MEK, a kinase downstream of RAF in the MAPK pathway, has been targeted in a similar fashion:
  • MEK inhibitors demonstrated benefit as monotherapy in patients with BRAF-mutant metastatic melanoma:
    • Leading to the FDA approval of trametinib in 2013
  • Of note, MEK inhibitors are rarely used as monotherapy for patients with BRAF-mutant metastatic melanoma
• Numerous studies have elucidated acquired mechanisms of therapeutic resistance to BRAF-targeted therapy, and insights gained have led to treatment strategies to enhance responses to therapy:
  • An outcome of this is the use of combined BRAF and MEK inhibition:
    • Based on the observation that most BRAF-mutant melanomas demonstrate MAPK pathway reactivation at the time of therapeutic resistance
  • This combination was tested in clinical trials in patients with BRAF-mutant melanoma:
    • Results demonstrated that treatment with combined BRAF and MEK inhibition (e.g., dabrafenib plus trametinib vs. dabrafenib monotherapy):
      • Was associated with:
        • A higher overall response (76% vs. 54%), and with a longer PFS (9.4 months vs. 5.8 months) than with BRAF inhibitor monotherapy
    • In January 2014, the FDA granted accelerated approval to combined dabrafenib and trametinib for use in combination in patients with unresectable or metastatic BRAF-mutant melanoma
  • The following year, the FDA also approved the BRAF / MEK inhibitor combination of vemurafenib and cobimetinib (coBRIM study), and in 2018, encorafenib and binimetinib were added to the armamentarium (COLUMBUS trial)
  • Importantly, neither BRAF inhibitor nor MEK inhibitor monotherapy is currently deployed in the current melanoma treatment landscape
  • It should also be noted that BRAF inhibitors have been shown to paradoxically stimulate growth in patients with wild-type BRAF status
  • The COMBI-MB clinical trial enrolled patients with melanoma brain metastases to receive dabrafenib and trametinib:
    • Across four patient cohorts, intracranial response ranged from 44% to 59%, although duration of response was relatively short:
      • As such, many medical oncologists prefer to use immunotherapy for brain metastases even in BRAF positive patients given the short duration of benefit with targeted therapy

• The KEYNOTE-054 (EORTC 1325-MG) trial:
  • Was a double-blind, randomized, phase 3 study:
    • Evaluating adjuvant pembrolizumab (200 mg IV every 3 weeks for up to 1 year) versus placebo:
      • In patients with completely resected, high-risk stage III cutaneous melanoma
• The trial demonstrated that adjuvant pembrolizumab:
  • Significantly improved recurrence-free survival (RFS) compared to placebo:
    • With a 3-year RFS rate of 63.7% for pembrolizumab versus 44.1% for placebo (hazard ratio [HR] 0.56, 95% CI 0.47–0.68)
  • This benefit was consistent across subgroups, including:
    • BRAF-mutant and wild-type melanoma, and regardless of PD-L1 status
  • Long-term follow-up (median 6.9 years) confirmed the durability of benefit:
    • With 7-year RFS of 50% for pembrolizumab versus 36% for placebo (HR 0.63, 95% CI 0.53–0.74)
  • Distant metastasis-free survival (DMFS) was also improved:
    • 7-year DMFS:
      • 54% vs 42%; HR 0.64, 95% CI 0.54–0.76
  • The safety profile was favorable:
    • With grade 3 to 4 adverse events in 14% of pembrolizumab-treated patients, and no significant long-term impact on health-related quality of life
• In the context of current management:
  • These results establish adjuvant pembrolizumab as a standard of care for resected high-risk stage III melanoma:
    • Reducing both local and distant recurrence risk
• For local recurrence after adjuvant therapy:
  • Management is multidisciplinary, and the benefit of rechallenge with anti–PD-1 therapy depends on timing and prior response
• References:
  • Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-Mg/Keynote-054 Trial.
  • Eggermont AMM, Blank CU, Mandala M, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2020;38(33):3925-3936. doi:10.1200/JCO.20.02110.
    Adjuvant Pembrolizumab Versus Placebo in Resected Stage III Melanoma (EORTC 1325-Mg/Keynote-054): Distant Metastasis-Free Survival Results From a Double-Blind, Randomised, Controlled, Phase 3 Trial. Eggermont AMM, Blank CU, Mandalà M, et al. The Lancet. Oncology. 2021;22(5):643-654. doi:10.1016/S1470-2045(21)00065-6.
  • Seven-Year Analysis of Adjuvant Pembrolizumab Versus Placebo in Stage III Melanoma in the EORTC1325 / KEYNOTE-054 Trial. Eggermont AM, Kicinski M, Blank CU, et al. European Journal of Cancer (Oxford, England : 1990). 2024;211:114327. doi:10.1016/j.ejca.2024.114327.
  • Adjuvant Pembrolizumab Versus Placebo in Resected Stage III Melanoma (EORTC 1325-Mg/Keynote-054): Health-Related Quality-of-Life Results From a Double-Blind, Randomised, Controlled, Phase 3 Trial. Bottomley A, Coens C, Mierzynska J, et al. The Lancet. Oncology. 2021;22(5):655-664. doi:10.1016/S1470-2045(21)00081-4.
  • Adjuvant Pembrolizumab Versus Placebo in Resected Stage III Melanoma (EORTC 1325-Mg/Keynote-054): Long-Term, Health-Related Quality-of-Life Results From a Double-Blind, Randomised, Controlled, Phase 3 Trial. Bührer E, Kicinski M, Mandala M, et al. The Lancet. Oncology. 2024;25(9):1202-1212. doi:10.1016/S1470-2045(24)00338-3.
  • Recent Advances in the Treatment of Melanoma. Curti BD, Faries MB. The New England Journal of Medicine. 2021;384(23):2229-2240. doi:10.1056/NEJMra2034861.

• The CheckMate 238 trial:
  • Is a pivotal Phase III clinical study evaluating the efficacy of nivolumab (Opdivo) versus ipilimumab (Yervoy):
    • As adjuvant therapy for patients with resected stage IIIB, IIIC, or IV melanoma
• The trial demonstrated that adjuvant nivolumab significantly improved recurrence-free survival compared to ipilimumab, with a more favorable safety profile
• This benefit was sustained at 4 and 5 years:
  • 4-year RFS rates of 51.7% for nivolumab versus 41.2% for ipilimumab (HR 0.71, 95% CI 0.60–0.86)
  • 5-year RFS rates of 50% versus 39%
• Distant metastasis-free survival and overall survival were also numerically higher with nivolumab:
  • Though the OS difference was not statistically significant at the time of reporting
• Importantly, nivolumab was associated with a much lower rate of grade 3 to 4 adverse events:
  • 14.4% vs. 45.9% for ipilimumab:
    • Fewer treatment discontinuations due to toxicity
• In the context of local recurrence after adjuvant therapy:
  • Post hoc analyses from CheckMate 238 indicate that patients who recur early (≤ 12 months) after adjuvant nivolumab:
    • Have limited benefit from anti–PD-1 monotherapy as subsequent systemic therapy:
      • But may derive greater benefit from ipilimumab-based regimens or targeted therapy if BRAF-mutant
  • Patients with late recurrence (> 12 months):
    • May still respond to anti–PD-1 rechallenge
  • Thus, the trial not only established nivolumab as a standard adjuvant therapy for resected stage III / IV melanoma but also informs management strategies for local recurrence after prior immune checkpoint blockade
• Trial Summary:
  • Name: CheckMate 238 (NCT02388906)
  • Design:
    • Randomized, double-blind, multicenter phase III trial
    • Population:
      • 906 patients with completely resected stage IIIB, IIIC, or IV cutaneous melanoma (AJCC 7th edition)
    • Intervention:
      • Nivolumab 3 mg/kg IV q 2 weeks
      • Ipilimumab 10 mg/kg IV q 3 weeks × 4, then q 12 weeks (every three months)
        • Both for up to one year or until recurrence or unacceptable toxicity
    • Primary Endpoint:
      • Recurrence-free survival (RFS)
    • Secondary Endpoints:
      • Overall survival (OS)
      • Distant metastasis-free survival (DMFS)
      • Safety

• Conclusions:
  • Nivolumab significantly improved RFS compared with ipilimumab
  • Better safety profile for nivolumab:
    • Substantially fewer high-grade adverse events
  • Nivolumab became a standard adjuvant treatment for resected high-risk melanoma based on these findings
    

• References:
  • Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. Weber J, Mandala M, Del Vecchio M, et al. The New England Journal of Medicine. 2017;377(19):1824-1835. doi:10.1056/NEJMoa1709030.
  • Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238. Larkin J, Del Vecchio M, Mandalá M, et al. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2023;29(17):3352-3361. doi:10.1158/1078-0432.CCR-22-3145.
  • Adjuvant Nivolumab Versus Ipilimumab in Resected Stage IIIB-C and Stage IV Melanoma (CheckMate 238): 4-Year Results From a Multicentre, Double-Blind, Randomised, Controlled, Phase 3 Trial. Ascierto PA, Del Vecchio M, Mandalá M, et al. The Lancet. Oncology. 2020;21(11):1465-1477. doi:10.1016/S1470-2045(20)30494-0.
  • Outcomes With Postrecurrence Systemic Therapy Following Adjuvant Checkpoint Inhibitor Treatment for Resected Melanoma in CheckMate 238. Weber J, Del Vecchio M, Mandalá M, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2024;42(31):3702-3712. doi:10.1200/JCO.23.01448.
  • Recent Advances in the Treatment of Melanoma. Curti BD, Faries MB. The New England Journal of Medicine. 2021;384(23):2229-2240. doi:10.1056/NEJMra2034861.

• Melanoma ranks behind only small-cell carcinoma of the lung:
  • As the most common tumor that metastasizes to the brain
• An unusual feature of brain metastases:
  • Is their propensity for hemorrhage:
    • Which occurs much more frequently with melanoma than other primary tumors
    • Hemorrhage occurs in:
      • 33% to 50% of patients with brain metastases from melanoma
• Prognosis worsens with an increasing number of lesions and the presence of neurologic symptoms:
  • Median survival has historically:
    • Been reported to be 3 to 4 months
  • With the description of combined immune checkpoint blockade for patients with brain metastasis by Tawbi et al:
    • The prognosis for such patients has significantly improved
    • In this phase II study of 94 melanoma patients with nonirradiated measurable brain metastases, Tawbi et al:
      • Described a rate of radiologic clinical benefit of 57% and complete response rate of 26%
    • As such, surgical resection is utilized less commonly than it has been historically
    • Currently, patients with brain metastases are generally treated with:
      • A combination of immune checkpoint blockade and gamma knife radiation:
        • With the use of additional systemic or local therapies under the guidance of a multidisciplinary treatment team
    • The role of targeted therapy remains unclear:
      • Although BRAF / MEK inhibition appears to have superior control in extracranial rather than intracranial disease
    • Stereotactic radiosurgery:
      • Is an important option for patients with small to medium brain metastases who have a reasonable life expectancy:
        • With no signs of increased intracranial pressure
    • Whole brain radiation therapy:
      • Is not commonly utilized in contemporary treatment strategies

• Epidemiology and Significance of Brain Metastases in Cutaneous Melanoma:
  • Cutaneous melanoma has a high propensity for central nervous system involvement:
    • With brain metastases occurring in over one third of patients with advanced disease and up to 75% at autopsy
  • Brain metastases are a major cause of morbidity and mortality in this population:
    • Contributing significantly to neurologic complications and death
• Historically, the prognosis for patients with melanoma brain metastases has been poor:
  • But recent advances in systemic and local therapies have improved outcomes
• Prognosis and Prognostic Factors:
  • Median overall survival for patients with melanoma brain metastases has improved from 4 to 6 months in the pre-immunotherapy era to:
    • 8.9 to 13 months in recent cohorts
  • Prognosis is adversely affected by the presence of:
    • Leptomeningeal disease
    • Elevated serum lactate dehydrogenase (LDH)
    • Multiple brain metastases at diagnosis
    • Extracranial disease
    • The presence of neurological symptoms
  • Notably, LDH levels greater than twice the upper limit of normal at the time of brain metastasis onset:
    • Are associated with poor prognosis and predict limited benefit from radiotherapy
• Management Strategies:
  • Management of brain metastases in cutaneous melanoma is multimodal and individualized
  • Key components include:
    • Surgery
    • Stereotactic radiosurgery (SRS)
    • Whole-brain radiation therapy (WBRT)
    • Immunotherapy
    • Targeted therapy
  • Stereotactic radiosurgery (SRS):
    • Is preferred for patients with a limited number of brain metastases
  • Whole-brain radiation therapy (WBRT):
    • Is reserved for those with multiple or leptomeningeal metastases:
      • Given its association with neurocognitive toxicity
  • Systemic therapies:
    • Specifically immune checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab) and BRAF / MEK inhibitors for BRAF-mutant melanoma:
      • Have demonstrated intracranial activity and improved survival
    • Combined modality therapy, particularly the integration of RT with systemic agents:
      • Has been shown to improve local and distant intracranial control and overall survival:
        • Especially when RT is administered before or during systemic therapy
    • The American Society of Clinical Oncology (ASCO), Society for Neuro-Oncology (SNO), and American Society for Radiation Oncology (ASTRO) recommend:
      • Ipilimumab plus nivolumab (regardless of BRAF status) or dabrafenib plus trametinib (for BRAF V600E mutation) for asymptomatic patients:
        • With local therapy deferred until intracranial progression
    • Management decisions should be tailored based on:
      • BRAF status
      • Number and size of metastases
      • Presence of symptoms
      • Extent of extracranial disease
  • Role and Timing of Radiation Therapy:
    • Radiation therapy remains a cornerstone for local control of brain metastases in melanoma
    • SRS:
      • Is the standard for patients with a limited number of lesions, offering high rates of local control with minimal neurotoxicity
    • WBRT:
    • Is now less commonly used due to its detrimental neurocognitive effects and limited impact on overall survival
    • The combination of RT with immunotherapy or targeted therapy:
      • Improves outcomes without increasing the risk of radiation necrosis or other neurotoxicities
    • The timing of RT is critical:
      • Optimal results are observed when RT is delivered before or concurrently with systemic therapy
    • RT is particularly important for:
      • Symptomatic or progressive lesions
      • When rapid local control is required
• Areas Needing Further Evidence:
  • Despite these advances, there remains a need for additional randomized trials to define the optimal sequencing and combination of RT with systemic therapies:
    • As well as to clarify the best management strategies for patients with multiple or symptomatic brain metastases
• In summary, brain metastasis in cutaneous melanoma:
  • Is a common and serious complication with historically poor prognosis, but outcomes have improved with the advent of effective systemic and local therapies
  • Radiation therapy, particularly SRS, remains central to management, especially when integrated with immunotherapy or targeted agents, and should be individualized based on patient and disease characteristics
• References:
  • Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. Tawbi HA, Forsyth PA, Algazi A, et al. The New England Journal of Medicine. 2018;379(8):722-730. doi:10.1056/NEJMoa1805453.
  • Melanoma Brain Metastasis Presentation, Treatment, and Outcomes in the Age of Targeted and Immunotherapies. Bander ED, Yuan M, Carnevale JA, et al. Cancer. 2021;127(12):2062-2073. doi:10.1002/cncr.33459.
  • Melanoma Brain Metastases: A Retrospective Analysis of Prognostic Factors and Efficacy of Multimodal Therapies. Internò V, Sergi MC, Metta ME, et al. Cancers. 2023;15(5):1542. doi:10.3390/cancers15051542.
  • Clinical Management of Multiple Melanoma Brain Metastases: A Systematic Review. Goyal S, Silk AW, Tian S, et al. JAMA Oncology. 2015;1(5):668-76. doi:10.1001/jamaoncol.2015.1206.
  • The Impact of Current Treatment Modalities on the Outcomes of Patients With Melanoma Brain Metastases: A Systematic Review. van Opijnen MP, Dirven L, Coremans IEM, Taphoorn MJB, Kapiteijn EHW. International Journal of Cancer. 2020;146(6):1479-1489. doi:10.1002/ijc.32696.
  • Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. Vogelbaum MA, Brown PD, Messersmith H, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2022;40(5):492-516. doi:10.1200/JCO.21.02314.
  • Stereotactic Radiosurgery and Anti-Pd-1 + ctla-4 Therapy, Anti-Pd-1 Therapy, Anti-Ctla-4 Therapy, BRAF/MEK Inhibitors, BRAF Inhibitors, or Conventional Chemotherapy for the Management of Melanoma Brain Metastases. Dohm AE, Nakashima JY, Kalagotla H, et al. European Journal of Cancer (Oxford, England : 1990). 2023;192:113287. doi:10.1016/j.ejca.2023.113287.
  • Melanoma Brain Metastasis: The Impact of Stereotactic Radiosurgery, BRAF Mutational Status, and Targeted and/or Immune-Based Therapies on Treatment Outcome. Kotecha R, Miller JA, Venur VA, et al. Journal of Neurosurgery. 2018;129(1):50-59. doi:10.3171/2017.1.JNS162797.
  • Systemic Therapy for Melanoma: ASCO Guideline Update. Seth R, Agarwala SS, Messersmith H, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2023;41(30):4794-4820. doi:10.1200/JCO.23.01136.
  • Recommended First-Line Management of Brain Metastases From Melanoma: A Multicenter Survey of Clinical Practice. Jablonska PA, Fong CH, Kruser T, et al. Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 2022;168:89-94. doi:10.1016/j.radonc.2022.01.037.
  • Changing Therapeutic Landscape for Melanoma With Multiple Brain Metastases. Jiang C, Wallington DG, Anker CJ, et al. Neurosurgery. 2020;87(3):498-515. doi:10.1093/neuros/nyaa076.

• Following an established track record set by other malignancies:
  • Such as breast cancer (trastuzumab / pertuzumab) and leukemia / GIST (imatinib):
    • Melanoma has undergone a paradigm change in cancer treatment
• Of note, to date, all targeted therapy agents used to treat melanoma have the advantage of oral administration:
  • Given the ease of administration and the often-profound disease control seen with these agents, it is our practice to routinely molecularly characterize tumors of patients with metastatic disease:
    • So that targeted therapy treatment options can be integrated into an overall treatment strategy
• While the MAPK pathway is the most commonly targeted pathway in melanoma:
  • Using BRAF / MEK inhibition:
    • A number of other mutations have been targeted and described
    • These less common mutations are of significant interest in a disease with an overall high prevalence
• In the case of KIT mutations, several case reports have demonstrated a benefit for individual patients with KIT mutations treated with a KIT inhibitor:
  • In a phase II study, 28 patients with unresectable metastatic KIT-mutated melanoma were treated with imatinib mesylate:
    • In this study, 16% of patients had durable responses that lasted more than a year
  • Continued work is needed to identify and develop mechanisms to block additional known pathogenic mutations in melanoma

• Common sites of distant metastasis in melanoma patients are, in order of decreasing frequency:
  • Skin and subcutaneous tissues (40%)
  • Lungs (12% to 36%)
  • Liver (15% to 20%)
  • Brain (12% to 20%)
  • Other sites include the:
    • Gastrointestinal tract
    • Bone
    • Adrenal gland
    • Distant skin
    • Soft tissue, and / or lymph nodes
    • Less commonly:
      • The spleen or pancreas
• Historically, patients with systemic metastases have had a poor prognosis:
  • With a median survival ranging from 6 to 12 months
• Fortunately, a wave of effective systemic therapies have ushered in a new era of treatment options for patients with unresectable or distant metastatic disease
• Indeed, the approach to treatment for such patients is now associated with improved and sometimes durable long-term survival and continues to evolve
• Contemporary systemic therapy represents the mainstay of treatment for most patients with distant metastatic disease:
  • Although surgery (curative or palliative) and other modalities (e.g., intralesional therapy):
    • Continue to play an evolving role in carefully selected patients as part of a multidisciplinary approach to the care of such patients
• In view of continued advances in the clinical arena and the common need to often consider second- or subsequent line treatments, clinical trials represent an important and attractive option for many patients
• Surgery:
  • The decision to perform surgery in patients with distant melanoma metastasis:
    • Should be considered as part of a multidisciplinary approach to care
  • Overall, given the advances in systemic therapy, surgery as a sole component of the care of these patients is relatively uncommon
  • The role of metastasectomy in this setting:
    • Whether curative or palliative in intent:
      • Continues to evolve
  • Indeed, most previous trials and retrospective series that have evaluated the role of surgery for patients with distant melanoma metastasis have mostly been conducted prior to this era of more effective systemic therapy:
    • As such, if surgery is considered, the rationale, extent, timing, and decision to proceed should involve a multidisciplinary approach and thoughtful consideration of existing systemic treatment options
    • Common indications include:
      • Palliation of symptoms (e.g., gastrointestinal obstruction or hemorrhage, difficulty in managing cutaneous metastases, intractable pain)
      • Isolated metastases not responding to otherwise successful systemic therapy
      • Isolated stable oligometastatic disease
  • Complete metastasectomy may be considered in patients as part of a multidisciplinary approach to distant metastasis:
    • In at least one legacy study, such as the Canvaxin phase III trial, patients underwent complete metastasectomy for stage IV melanoma as part of an adjuvant stage IV clinical trial:
      • Despite the overall negative trial results related to the Canvaxin vaccine:
        • Patients had a 40% 5-year survival, even though this trial was conducted prior to the era of contemporary systemic therapy
    • Other nonrandomized trials of highly selected patients demonstrated similar results after complete resection of distant metastases
• Patient selection is critical for the strategy of complete surgical metastasectomy, whether for curative or palliative intent
• To aid in patient selection, a thorough imaging evaluation is indicated, including:
  • MRI of the brain and CT or PET/CT of the chest, abdomen, and pelvis to fully assess disease burden and the potential to offer either a complete or palliative resection
• Patient factors also play a role in patient selection:
  • Patients should not have comorbidities that would preclude a possible full recovery from surgery within 4 to 8 weeks:
    • To allow for the initiation of adjuvant or systemic therapies
  • Moreover, the biology of the melanoma itself should be considered:
    • Patients whose distant metastasis developed following a longer disease-free interval or who present with isolated or oligometastatic disease:
      • In general, more likely to be considered for surgical resection
  • Lastly, the systemic options available and their demonstrated efficacy should be considered:
    • This includes, but is not limited to, responsiveness and ability to tolerate immune checkpoint blockade, mutational status, and progression on other lines of therapy:
    • Ultimately, these decisions should be made in collaboration with a multidisciplinary team
  • Surgery may also offer effective palliation for isolated or oligometastatic accessible distant metastases
  • Examples of accessible lesions include isolated visceral metastases, isolated brain metastases, and occasionally isolated lung metastases
  • Palliative strategies may improve functional status and render patients more likely to tolerate systemic treatments
  • Importantly, surgery may also be considered to support consolidation of a mixed response to systemic therapy
  • Overall, the role of surgery in the context of the multidisciplinary management of the patient with distant metastases continues to evolve

• Given the high risk of recurrence for patients with clinical regional lymphadenopathy or resectable distant metastasis and the effectiveness of systemic therapies:
  • Neoadjuvant therapy is being actively pursued in several clinical trials and is increasingly employed in the clinical setting for patients who present with clinical regional lymphadenopathy
• Neoadjuvant therapy:
  • Provides the opportunity to examine disease biology in response to therapy, reduce the morbidity of surgical resection, and potentially tailor the need for and approach to adjuvant therapy based on extent of response
• For BRAF V600 mutant patients:
  • A single-center (MD Anderson), open-label phase II randomized neoadjuvant therapy trial with neoadjuvant BRAF / MEK combination inhibitor therapy dabrafenib + trametinib for 8 weeks followed by surgery versus surgery with adjuvant dabrafenib + trametinib (for patients in both study arms) in patients with resectable clinical stage IIIB / C or stage IV oligometastatic disease
  • The trial enrolled 14 patients to the neoadjuvant arm and 7 patients to the adjuvant arm
  • It was stopped early at a prespecified interim safety analysis after noting significantly longer event-free survival in the neoadjuvant arm:
    • 71% [10 of 14 patients] vs. 0% [0 of 7 patients]
  • Median event-free survival:
    • 19.7 vs. 2.9 months; HR 0.016; 95% CI, 0.00012 to 0.14; P < .0001
  • There were no grade 4 adverse events in the neoadjuvant group, and importantly, they observed a pathologic complete response (pCR) in 58% of patients treated on the neoadjuvant arm
  • The trial was continued as a single-arm neoadjuvant study
• The results were replicated in the phase II, single-arm NeoCombi study conducted in Australia:
  • Which found a 49% pCR in the cohort of 35 patients receiving neoadjuvant dabrafenib + trametinib
• Leveraging advances in the immunotherapy arena:
  • Several trials (OpACIN, OpACIN-Neo, Amaria et al., 2018) have investigated various regimens of nivolumab with or without ipilimumab, and one trial from the University of Pennsylvania investigated neoadjuvant single-dose pembrolizumab (Huang et al.):
    • A recent meta-analysis of these four studies by Menzies et al. found that 38% (n = 51) of patients had a pCR:
      • Which correlated with improved RFS (100% vs. 72%, P < .001):
        • No patients with a pCR had thus far died
    • In addition, in patients with pCR, near pCR, or partial pathologic response following neoadjuvant immunotherapy:
      • The 2-year RFS was 96%, with very few relapses observed
    • Of note, the optimal dose from OpACIN-Neo appeared to be ipilimumab 1 mg/kg and nivolumab 3 mg/kg, which was also better tolerated than the ipilimumab 3 mg/kg and nivolumab 1 mg/kg employed in the metastatic setting
• The ongoing PRADO trial (NCT02977052), based on an expansion cohort from OpACIN-Neo, is investigating whether CLND can be safely omitted in patients with a major pathologic response in the excised index lymph node after two cycles of neoadjuvant ipilimumab + nivolumab
• The role of neoadjuvant therapy in patients with melanoma continues to rapidly evolve
• When considered, this approach should be discussed in the context of a multidisciplinary care team, preferably in the context of a clinical trial

• True local recurrence:
  • Is defined as recurrence at the site of the primary tumor, within or continuous with the scar:
    • It is most likely the result of incomplete excision of the primary tumor
    • It represents a relatively rare pattern of recurrence
• In many cases, such “local recurrences”:
  • May more appropriately be considered persistence of the primary tumor
• A local recurrence consisting of a single lesion in a patient whose primary melanoma had favorable prognostic features:
  • May be appropriately treated with wide excision similar to a primary melanoma lesion
• Patients with local recurrences consisting of multiple, small, and superficial lesions may be treated in a fashion similar to that used to treat patients with in-transit disease
• Definition of Local Recurrence:
  • Local recurrence in cutaneous melanoma refers to the reappearance of melanoma at or near the site of the original primary tumor:
    • Typically within 2 cm of the initial surgical scar, in the absence of regional or distant metastasis
• Evaluation and Staging:
  • Before initiating treatment:
    • Clinical examination:
      • Thorough skin and lymph node examination
    • Imaging:
      • PET-CT or CT/MRI to rule out regional or distant metastases
    • Biopsy:
      • Confirm recurrence histologically
    • Restaging:
      • Based on AJCC 8th Edition Melanoma Staging System
• Surgical Management:
  • Surgery remains the cornerstone of treatment:
    • Wide Local Excision (WLE):
      • Excision with clear margins:
        • Typically 1 to 2 cm based on Breslow depth
      • May include re-excision if margins were inadequate in prior surgery
  • Reconstruction:
    • May be required depending on the anatomical location and size of excision
  • Sentinel Lymph Node Biopsy (SLNB):
    • Consider SLNB in recurrent lesions if not performed previously:
      • Particularly in patients with intermediate or thick lesions:
        • Offers prognostic information and can alter staging
• Adjuvant Therapy:
  • Based on risk of recurrence, pathological findings, and prior treatments:
    • Immunotherapy:
      • Anti-PD-1 agents like nivolumab or pembrolizumab
    • Targeted therapy:
      • For BRAF V600-mutant melanoma:
        • Dabrafenib + trametinib
    • Radiotherapy:
      • May be used postoperatively for high-risk features:
        • Positive margins, perineural invasion, multiple recurrences
    • Regional and Systemic Therapy for Unresectable Recurrence
    • If the recurrence is not surgically resectable or has multiple in-transit metastases:
      • Intralesional therapy:
        • T-VEC – talimogene laherparepvec
      • Systemic immunotherapy or targeted therapy:
        • Clinical trials may offer novel therapies
• Surveillance:
  • Regular follow-up is essential due to the risk of further recurrences or metastasis
  • Typical schedule:
    • Every 3 to 6 months for the first 2 to 3 years
    • Annually thereafter
    • Includes skin checks, lymph node exams, and imaging when indicated
• Prognostic Factors:
  • Breslow thickness of recurrence
  • Ulceration
  • Time to recurrence
  • Prior sentinel node involvement
  • Genetic mutations (BRAF, NRAS)
• Multidisciplinary Management:
  • Patients with recurrent melanoma should ideally be managed in a melanoma or skin cancer multidisciplinary team (MDT) setting involving:
    • Dermatology
    • Surgical oncology
    • Medical oncology
    • Radiation oncology
    • Pathology and radiology