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• Localization studies for Primary Hyperparathyroidism (PHPT):
  • Are used for surgical planning
• Nuclear medicine parathyroid scan (Sestamibi scan):
  • Is the most commonly employed test
• There are a number of variations to how this is performed in different centers (e.g., subtraction scans with a second isotope or combined with SPECT [single photon emission CT])
• Meta-analyses suggest that the sensitivity of this test:
  • Is around 80%
• However, the range of sensitivities reported in the literature illustrate that the accuracy of this test may be influenced by patients and disease factors, as well as the experience of the practice.
• More info at:
  • https://collectedmed.com/index.php/directory/Coach_directory/articlelist/13076 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064437/

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #Hyperparathyroidism #PrimaryHyperparathyroidism #CancerSurgeon #EndocrineSurgery #Teacher #Surgeon #HeadandNeckSurgeon #SurgicalOncologist #ParathyroidAdenoma #Hypercalcemia #ElevatedCalciumLevels #Miami #MountSinaiMedicalCenter #MSMC #Mexico #Hialeah

• Merkel cell carcinoma
  • Is a neuroendocrine neoplasm of the
    skin
  • It is a rare, aggressive neuroendocrine skin cancer:
    • With a high risk of local recurrence, nodal involvement, and distant metastasis
• The incidence is rising:
  • Particularly among elderly and immunosuppressed patients, and prognosis remains poor, especially in those with advanced disease or immunosuppression
• A multidisciplinary approach:
  • Is essential for initial workup and staging
  • Histopathologic confirmation and microstaging of the primary lesion are required
• For patients with clinically node-negative disease:
  • Sentinel lymph node biopsy (SLNB) is recommended to assess occult nodal involvement:
    • As up to 40% of these patients may harbor microscopic nodal metastases
• Imaging (e.g., PET/CT):
  • Is indicated for patients with clinically apparent nodal or distant disease
• The majority of these tumors in North America (80%) are:
  • Caused by infections with Merkel cell polyomavirus (MCV):
    • A double-stranded DNA virus
• Nearly half of all Merkel cell car-
  cinoma lesions:
  • Occur in the head and neck region:
    • The cheek is the most common site:
      • Followed by the upper neck and nose
• These lesions typically occur in elderly white persons:
  • They appear as a red to violaceous, smooth, dome-shaped lesion with telangiectasias (Figure)
• These tumors have a high propensity
  for metastatic spread:
  • To regional lymph nodes as well as distant
    sites
• Histologically they are composed of:
  • Basophilic cells with scant cytoplasm and dark powdery chromatin:
    • They may be morphologically similar to other neuroendocrine carcinomas:
      • Hence metastatic small cell carcinoma, malignant melanoma, or primary neuroendocrine (or “small cell”) carcinoma of the parotid gland may be considerations in the differential diagnosis
  • Immunohistochemical stains:
    • For synaptophysin, chromogranin, and cytokeratin 20 (CK20) (demonstrating a characteristic “dotlike” pattern) or the Merkel cell polyoma virus large T antigen (recognized by the antibody CM2B4) are positive:
      • Whereas thyroid transcription factor-1 (TTF-1) is negative
• Surgical management:
  • Is the primary treatment for localized MCC
  • The National Comprehensive Cancer Network (NCCN) recommends:
    • Wide local excision (WLE) or Mohs micrographic surgery (MMS) with 1 to 2 cm surgical margins to the investing fascia of muscle when anatomically feasible
    • In anatomically challenging sites (e.g., head and neck):
      • Narrower margins may be acceptable, particularly if adjuvant radiotherapy is planned:
        • Studies indicate that local control is excellent with adjuvant radiotherapy, even when margins are ≤ 1 cm
  • The American Cancer Society aligns with these recommendations, emphasizing the importance of complete excision and individualized margin selection based on tumor location and patient factors
  • Elective neck dissection:
    • Is not routinely recommended for clinically node-negative patients:
      • Instead, SLNB is the preferred method for nodal staging:
        • If SLNB is positive, completion lymph node dissection or nodal radiotherapy may be considered
  • For clinically node-positive disease:
    • Fine needle aspiration or core biopsy is used for confirmation, and management includes lymph node dissection and / or nodal radiotherapy
• Radiation therapy:
  • Plays a central role in MCC management
  • Adjuvant radiotherapy is generally recommended for most patients:
    • Especially those with high-risk features such as:
      • Lymphovascular invasion
      • Immunosuppression
      • Positive or close margins
      • Large tumor size
  • The recommended dose is 50 to 66 Gy:
    • Tailored to the extent of residual disease and margin status
    • Radiotherapy alone is a definitive option for patients who are not surgical candidates

• National Comprehensive Cancer Network guidelines for HNMCC recommend treatment for localized tumors to include:
  • Surgical excision followed by adjuvant radiotherapy or observation, favoring the use of radiotherapy for patients with HNMCC for its potentially limited ability to achieve 1- to 2-cm margins and the risk of false-negative sentinel lymph node biopsy results
  • Furthermore, MCC is a radiosensitive malignant neoplasm, and postoperative radiotherapy has shown improved outcomes, including increased OS and disease-free survival, compared with surgery alone
• Chemotherapy is not recommended as adjuvant therapy for localized MCC:
  • As it has not demonstrated a survival benefit and is associated with significant toxicity
  • Its use is generally reserved for select patients with advanced or metastatic disease:
    • Often in the palliative setting
• Immunotherapy has become the standard of care for advanced or metastatic MCC:
  • Immune checkpoint inhibitors such as avelumab and pembrolizumab are first-line agents:
    • Offering durable responses and improved outcomes compared to traditional chemotheraphy
• There remain areas of ongoing controversy and research, including the optimal surgical margin size, the precise indications for adjuvant radiotherapy, and the management of high-risk or immunosuppressed patients:
  • The rarity of MCC and lack of prospective randomized trials contribute to variability in practice patterns
• References:
  • Association Between Surgical Margins Larger Than 1 cm and Overall Survival in Patients With Merkel Cell Carcinoma. Andruska N, Fischer-Valuck BW, Mahapatra L, et al. JAMA Dermatology. 2021;157(5):540-548. doi:10.1001/jamadermatol.2021.0247.
  • Merkel Cell Carcinoma. Lewis DJ, Sobanko JF, Etzkorn JR, et al. Dermatologic Clinics. 2023;41(1):101-115. doi:10.1016/j.det.2022.07.015.
  • Survival of Patients With Head and Neck Merkel Cell Cancer: Findings From the Pan-Canadian Merkel Cell Cancer Collaborative. Nayak AL, Pickett AT, Delisle M, et al. JAMA Network Open. 2023;6(11):e2344127. doi:10.1001/jamanetworkopen.2023.44127.
  • Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology. Bichakjian CK, Olencki T, Aasi SZ, et al. Journal of the National Comprehensive Cancer Network : JNCCN. 2018;16(6):742-774. doi:10.6004/jnccn.2018.0055.
  • Best Practices in Surgical and Nonsurgical Management of Head and Neck Merkel Cell Carcinoma: An Update. Duarte-Bateman D, Shen A, Bullock T, et al. Molecular Carcinogenesis. 2023;62(1):101-112. doi:10.1002/mc.23483.
  • Overall Survival After Mohs Surgery for Early-Stage Merkel Cell Carcinoma. Cheraghlou S, Doudican NA, Criscito MC, Stevenson ML, Carucci JA. JAMA Dermatology. 2023;159(10):1068-1075. doi:10.1001/jamadermatol.2023.2822.
  • Merkel Cell Carcinoma of the Head and Neck: Epidemiology, Pathogenesis, Current State of Treatment and Future Directions. Yusuf MB, McKenzie G, Rattani A, et al. Cancers. 2021;13(14):3506. doi:10.3390/cancers13143506.
  • Narrow Excision Margins Are Appropriate for Merkel Cell Carcinoma When Combined With Adjuvant Radiation: Analysis of 188 Cases of Localized Disease and Proposed Management Algorithm. Tarabadkar ES, Fu T, Lachance K, et al. Journal of the American Academy of Dermatology. 2021;84(2):340-347. doi:10.1016/j.jaad.2020.07.079.
  • Identifying an Optimal Adjuvant Radiotherapy Dose for Extremity and Trunk Merkel Cell Carcinoma Following Resection: An Analysis of the National Cancer Database. Patel SA, Qureshi MM, Sahni D, Truong MT. JAMA Dermatology. 2017;153(10):1007-1014. doi:10.1001/jamadermatol.2017.2176.
  • Merkel Cell Carcinoma – Current Controversies and Future Directions. Steven N, Lawton P, Poulsen M. Clinical Oncology (Royal College of Radiologists (Great Britain)). 2019;31(11):789-796. doi:10.1016/j.clon.2019.08.012.

• 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

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #Hyperparathyroidism #PrimaryHyperparathyroidism #CancerSurgeon #EndocrineSurgery #Teacher #Surgeon #HeadandNeckSurgeon #SurgicalOncologist #ParathyroidAdenoma #Hypercalcemia #ElevatedCalciumLevels #Miami #MountSinaiMedicalCenter #MSMC #Mexico #Hialeah

• 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.