Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• The overproduction of parathyroid hormone (PTH):
  • Termed hyperparathyroidism (HPT):
    • Can be categorized as:
      • Primary
      • Secondary
      • Tertiary
• Primary hyperparathyroidism (PHPT) arises from:
  • An unregulated or autonoumous overproduction of PTH from an abnormal parathyroid gland or glands
• Increased PTH levels may also occur as a:
  • Compensatory response to hypocalcemic states:
    • Resulting from chronic renal failure or
    • Gastrointestinal (GI) malabsorption of calcium
  • This secondary HPT can be reversed by correction of the underlying problem:
    • Kidney transplantation for chronic renal failure
• However, chronically stimulated parathyroid glands may occasionally become autonomous:
  • Resulting in persistence or recurrence of the hypercalcemia after successful renal transplantation:
    • Resulting in tertiary HPT

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• Targeted BRAF and MEK dual inhibition (BRAFi /MEKi) in BRAF V600 mutant melanoma:
  • Has been associated with relatively rapid response, high disease control rates, and a survival benefit in stage IV melanoma
  • Unfortunately, this approach has also been associated with limited durability of response, leading some investigators to examine alternate stages of disease for this regimen
• Long et al. investigated the efficacy of these agents in the adjuvant stage III setting:
  • In a randomized, double-blind, placebo-controlled, phase III trial (COMBI-AD):
    • That randomly assigned patients with completely resected stage III melanoma and BRAF V600 mutations (n = 870) to receive:
      • Oral dabrafenib (150 mg BID) plus trametinib (2 mg once daily) versus placebo in a 1:1 fashion
    • At a median follow-up of 2.8 years:
      • The estimated 3-year RFS was 58% in the combination-therapy group and 39% in the placebo group (HR for relapse or death, 0.47; 95% CI, 0.39 to 0.58; P < .001)
      • In addition, the BRAFi / MEKi group had a significantly higher 3-year OS of 86% versus 77% in the placebo group (HR for death, 0.57; 95% CI, 0.42 to 0.79; P = .0006)
    • Authors noted that this level of improvement did not cross the prespecified interim analysis boundary of P = .000019
    • They concluded that combined dabrafenib plus trametinib in the adjuvant setting resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600 mutations and with an acceptable toxicity profile
• This trial led to the 2018 FDA approval of dabrafenib / trametinib:
  • For use in the adjuvant setting for those with stage III disease and BRAF V600E or V600K mutations

• Immune checkpoint blockade:
  • Has fundamentally changed the management of cutaneous melanoma:
    • Including in the adjuvant setting and for local recurrence after prior therapies
  • These agents, primarily anti–PD-1 antibodies (pembrolizumab, nivolumab) and anti–CTLA-4 (ipilimumab):
    • Work by releasing inhibitory signals on T cells:
      • Thereby enhancing antitumor immunity
    • This mechanism is particularly effective in melanoma:
      • A tumor type with high immunogenicity
• Historically, adjuvant therapy for resected high-risk melanoma was limited to interferon-α:
  • Which provided only modest benefit and significant toxicity
• The introduction of immune checkpoint inhibitors:
  • Especially anti–PD-1 agents:
    • Has led to substantial improvements in recurrence-free survival (RFS) and overall survival (OS):
      • With a more favorable toxicity profile compared to ipilimumab or interferon
• The American Academy of Dermatology and major clinical trials:
  • Have established anti–PD-1 therapy as the standard adjuvant approach for:
    • Resected stage III and select stage IV melanoma
• Key randomized trials (KEYNOTE-054, CheckMate 238):
  • Demonstrated that adjuvant pembrolizumab or nivolumab significantly improves RFS compared to placebo or ipilimumab:
    • With 3-year RFS rates of 63% to 70% in stage III disease and a reduction in the risk of recurrence or death by 40% to 50%
  • These benefits are observed in both BRAF-mutant and wild-type melanoma:
    • The choice between immunotherapy and BRAF / MEK inhibitors in BRAF-mutant cases:
      • Is individualized based on toxicity profiles and patient preference
• Despite these advances, local recurrence remains a clinical challenge:
  • Approximately 25% to 30% of patients recur within 1 year of adjuvant anti–PD-1 therapy:
    • With a substantial proportion presenting with locoregional disease
• Management of local recurrence after prior surgery or intralesional therapy is multidisciplinary:
  • For resectable local recurrences:
    • Surgery remains the mainstay:
      • But systemic therapy is considered for unresectable, multifocal, or high-risk recurrences
  • The effectiveness of immune checkpoint blockade in the setting of local recurrence depends on prior treatment history:
    • Patients who recur during or shortly after adjuvant anti–PD-1 therapy:
      • Have a low likelihood of response to further PD-1 monotherapy:
        • In these cases, escalation to combination immunotherapy (anti–PD-1 plus anti–CTLA-4) or switch to BRAF / MEK inhibitors (for BRAF-mutant melanoma) is recommended, as these approaches have demonstrated higher response rates
    • For patients who recur after a significant interval off adjuvant therapy:
      • Rechallenge with anti–PD-1 may be considered, as some may still respond
      • Retreatment and escalation strategies, including novel combinations, are under investigation, and clinical trial enrollment is encouraged for resistant or recurrent disease
  • Toxicity remains a consideration, with immune-related adverse events:
    • Affecting skin, GI tract, endocrine organs, and other systems:
      • These are generally manageable but require prompt recognition and intervention:
    • Quality of life and patient selection are important, especially in the adjuvant and recurrent settings
• In summary:
  • Immune checkpoint blockade is the standard of care for adjuvant therapy in high-risk resected cutaneous melanoma and plays a central role in the management of local recurrence, particularly when escalation or combination strategies are employed after prior anti–PD-1 exposure
  • Prospective data on optimal sequencing after adjuvant therapy and in local recurrence are limited, and management should be individualized within a multidisciplinary framework
• References:
  • Immune Checkpoint Inhibitors in Melanoma. Carlino MS, Larkin J, Long GV. Lancet (London, England). 2021;398(10304):1002-1014. doi:10.1016/S0140-6736(21)01206-X.
  • Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. Patel SP, Othus M, Chen Y, et al. The New England Journal of Medicine. 2023;388(9):813-823. doi:10.1056/NEJMoa2211437.
  • 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.
  • Guidelines of Care for the Management of Primary Cutaneous Melanoma. Swetter SM, Tsao H, Bichakjian CK, et al. Journal of the American Academy of Dermatology. 2019;80(1):208-250. doi:10.1016/j.jaad.2018.08.055.
  • 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.
  • Novel Adjuvant Options for Cutaneous Melanoma. Dimitriou F, Long GV, Menzies AM. Annals of Oncology : Official Journal of the European Society for Medical Oncology. 2021;32(7):854-865. doi:10.1016/j.annonc.2021.03.198.
  • Monoclonal Antibodies as Adjuvant Therapies for Resected Melanoma. Eljilany I, Garcia JR, Jamal B, Tarhini AA. Expert Opinion on Biological Therapy. 2025;25(5):1-14. doi:10.1080/14712598.2025.2484305.
  • Management of Early Melanoma Recurrence Despite Adjuvant Anti-Pd-1 Antibody Therapy. Owen CN, Shoushtari AN, Chauhan D, et al. Annals of Oncology : Official Journal of the European Society for Medical Oncology. 2020;31(8):1075-1082. doi:10.1016/j.annonc.2020.04.471.
  • Nature and Management of Melanoma Recurrences Following Adjuvant Anti-Pd-1 Based Therapy. Woodford R, McKeown J, Hoeijmakers LL, et al. European Journal of Cancer (Oxford, England : 1990). 2024;212:115055. doi:10.1016/j.ejca.2024.115055.
  • Treatment of Recurrent Melanoma Following Adjuvant Therapy. Malissen N, Grob JJ. American Journal of Clinical Dermatology. 2023;24(3):333-341. doi:10.1007/s40257-023-00762-y.
  • The Concepts of Rechallenge and Retreatment With Immune Checkpoint Blockade in Melanoma Patients. Zaremba A, Eggermont AMM, Robert C, et al. European Journal of Cancer (Oxford, England : 1990). 2021;155:268-280. doi:10.1016/j.ejca.2021.07.002.

• The KEYNOTE-716 trial:
  • Was a randomized, double-blind, phase 3 study:
    • Evaluating adjuvant pembrolizumab (200 mg IV every 3 weeks for up to 1 year) versus placebo:
      • In patients aged ≥ 12 years with completely resected, high-risk stage IIB or IIC cutaneous melanoma (T3b / T4, node-negative)
    • The primary endpoint was:
      • Recurrence-free survival (RFS)
    • Secondary endpoints:
      • Distant metastasis-free survival (DMFS)
      • Safety
  • Patients with recurrence after placebo could cross over to pembrolizumab
• Key findings:
  • Pembrolizumab significantly reduced the risk of recurrence or death compared to placebo
  • At a median follow-up of 39.4 months, the hazard ratio for RFS was:
    • 0.62 (95% CI, 0.49–0.79)
    • The estimated 36-month RFS was 76.2% for pembrolizumab vs 63.4% for placebo
  • DMFS was also improved:
    • 36-month DMFS:
      • 84.4% vs 74.7%; HR 0.59, 95% CI 0.44–0.79
  • The benefit was consistent across subgroups:
    • Including tumor location and histopathologic features
  • Grade ≥ 3 treatment-related adverse events occurred in 16% of pembrolizumab-treated patients, with no new safety signals on long-term follow-up
  • Overall survival data remain immature, and immune-related toxicity remains a consideration
• Clinical implications:
  • The KEYNOTE-716 trial established adjuvant pembrolizumab as a standard of care for resected stage IIB / IIC melanoma:
    • Extending the benefit of immune checkpoint blockade to node-negative, high-risk stage II disease
  • The American Society of Clinical Oncology now recommends:
    • Adjuvant pembrolizumab for these patients, with the caveat that the risk of immune-related toxicity must be weighed against the lack of mature overall survival data
      
• In context, KEYNOTE-716 complements prior major adjuvant trials:
  • EORTC 18071:
    • Ipilimumab vs placebo, stage III:
      • Improved RFS / OS but high toxicity
  • CheckMate 238:
    • Nivolumab vs ipilimumab, stage III / IV):
      • Superior RFS and safety for nivolumab
  • KEYNOTE-054:
    • Pembrolizumab vs placebo, stage III:
      • improved RFS / DMFS with favorable safety
  • KEYNOTE-716:
    • Is the first to show a significant benefit for adjuvant anti–PD-1 therapy in stage II melanoma:
      • Expanding the population eligible for effective adjuvant immunotherapy
• References:
  • Pembrolizumab Versus Placebo as Adjuvant Therapy in Completely Resected Stage IIB or IIC Melanoma (KEYNOTE-716): A Randomised, Double-Blind, Phase 3 Trial. Luke JJ, Rutkowski P, Queirolo P, et al. Lancet (London, England). 2022;399(10336):1718-1729. doi:10.1016/S0140-6736(22)00562-1.
  • Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma (KEYNOTE-716): Distant Metastasis-Free Survival Results of a Multicentre, Double-Blind, Randomised, Phase 3 Trial. Long GV, Luke JJ, Khattak MA, et al. The Lancet. Oncology. 2022;23(11):1378-1388. doi:10.1016/S1470-2045(22)00559-9.
  • Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. Luke JJ, Ascierto PA, Khattak MA, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2024;42(14):1619-1624. doi:10.1200/JCO.23.02355.
  • Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Long-Term Follow-Up, Crossover, and Rechallenge With Pembrolizumab in the Phase III KEYNOTE-716 Study. Luke JJ, Ascierto PA, Khattak MA, et al. European Journal of Cancer (Oxford, England : 1990). 2025;220:115381. doi:10.1016/j.ejca.2025.115381.
  • 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 Pembrolizumab in Stage II Melanoma: Outcomes by Primary Tumor Location in the Randomized, Double-Blind, Phase III KEYNOTE-716 Trial. Yoon CH, Ross MI, Gastman BR, et al. Annals of Surgical Oncology. 2025;32(4):2756-2764. doi:10.1245/s10434-024-16642-6.
  • Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Outcomes in Histopathologic Subgroups From the Randomized, Double-Blind, Phase 3 KEYNOTE-716 Trial. Schadendorf D, Luke JJ, Ascierto PA, et al. Journal for Immunotherapy of Cancer. 2024;12(3):e007501. doi:10.1136/jitc-2023-007501.

• 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.