Melanoma medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]; Serge Korjian M.D.; Yazan Daaboul, M.D.

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Overview

Surgery is the primary treatment for melanoma. Advances in systemic therapies have substantially reduced melanoma-related mortality in the past 15 years. Immunotherapy with immune checkpoint inhibitors is now recommended by all current guidelines as adjuvant treatment for melanoma, given their superior safety profile and improved survival compared with interferon. [1]

Medical Therapy

The table below outlines the recommended immunotherapy regimens by melanoma stage.

Melanoma Stage Recommended Medical Therapy Safety Profile of Medical Therapy
Melanoma in Situ (Stage 0) and Stage ⅠA-ⅡA Melanoma Wide local excision with margins determined by Breslow thickness (5 mm for in situ to 2 cm for ≥2 mm) [2]
  • Dual immune checkpoint therapy carries a moderate-to-severe risk of immune-related adverse events (dermatitis, hypothyroidism, colitis, arthritis, pneumonitis) as compared to monotherapy. [3]; [4]
  • Immune-related adverse events correlate with improved tumor response. [5] and longer survival. [6]
  • Nivolumab or pembrolizumab monotherapy may be preferred in patients with autoimmune disease [7] or those wishing to minimize treatment-related toxicity.
Stage ⅡB-C Melanoma As per NCCN and ESMO guidelines: [8]
  • Adjuvant Nivolumab or pembrolizumab for 12 months improves recurrence-free survival.
  • Observation after surgery is also an option, as overall survival benefit has not been shown.
Stage ⅢA-D Melanoma As per NCCN and ESMO guidelines, adjuvant therapy for 12 months with the following regimens is recommended: [8],
As per NCCN and ASCO, the following neoadjuvant regimens may be considered for clinically node-positive, non-metastatic melanoma, especially bulky or difficult-to-resect tumors. [9]
Unresectable StageⅢ/StageIV Melanoma First-line therapy as per ASCO guidelines: [9]

•Nivolumab + Ipilimumab (4 cycles, every 3 weeks), followed by maintenance Nivolumab every 4 weeks for up to 2 years or until disease progression/ dose-limiting toxicity.

Second-line therapies approved by the FDA (These therapies require further studies and are not routinely recommended in current guidelines
  • Tumor-infiltrating lymphocyte therapy (lifileucel). [10] ; [8]
  • Talimogene laherparepvec ( Intralesional oncolytic herpes virus). [11]
  • BRAF V600E/K variant:

Dabrafenib + Trametinib [12] Encorafenib + Binimetinib, [13] or Vemurafenib + Cobimetinib (sequentially after immunotherapy if disease progresses) [14]

* ASCO= The American Society of Clinical Oncology; NCCN= The National Comprehensive Cancer Network; ESMO= European Society for Medical Oncology; FDA= Food and Drug Administration.

Other FDA-Approved Chemotherapy Agents available for Metastatic or Unresectable Melanoma
Single Chemotherapy Agent
  1. Dacarbazine (DTIC)
  2. Docetaxel (Taxotere)
  3. Imatinib (Gleevec)
  4. Ipilimumab (Yervoy)
  5. Paclitaxel (Taxol)
  6. Temozolomide (Temodar)
Combination Therapy
  1. Paclitaxel nanoparticle albumin-bound + Bevacizumab + Carboplatin (ABC)
  2. Carboplatin + Paclitaxel
  3. Carboplatin + Paclitaxel + nanoparticle albumin-bound
  4. Carboplatin + Paclitaxel +, Sorafenib
  5. Cisplatin + Dacarbazine ± Carmustine
  6. Cisplatin + Dacarbazine + IL-2 + IFN alfa-2b ± Carmustine
  7. Cisplatin + Paclitaxel + Dacarbazine
  8. Cisplatin + Vinblastine + Dacarbazine
  9. Cisplatin + Vinblastine + Dacarbazine + IL-2 + IFN alfa-2b (sequential biochemotherapy)
  10. Temozolomide + Bevacizumab
  11. Dabrafenib + Trametinib
  12. Ipilimumab + Dacarbazine
  13. Ipilimumab + Nivolumab
  14. Binimetinib + Encorafenib

[15]

To review the 2019 AAD Guidelines on use of Imiquimod therapy in Primary Cutaneous Melanoma, click here

2019 AAD Guidelines for Surveillance for Dermatologic Toxicities of patients taking Novel Immunotherapy Agents

According to the American Academy of Dermatology (AAD), dermatologists should collaborate with oncologists for the management of cutaneous toxicity during BRAF/MEK kinase or immune checkpoint inhibitor therapy because appropriate recognition and control of skin side effects may improve the quality of life of patients with Cutaneous Melanoma (CM) and avoid unnecessary interruption of medication.

Recommendations for Dermatologic Toxicities of Immunotherapy Agents for advanced CM (Stage Ⅲ and IV)

Class A
1. Dermatologic assessment every 2-4 wk for the first three months of BRAF inhibitor monotherapy is recommended for patients with numerous squamoproliferative neoplasms, although combination BRAF/MEK inhibition is standard and associated with less skin toxicity.(Level Ⅰ/Ⅱ )
2. Dermatologic assessment of patients undergoing therapy with immune checkpoint inhibitors should occur within the first month of therapy and continue as needed for management of skin side effects. Patients with atopic dermatitis, psoriasis, or other autoimmune dermatoses should be seen before initiation of therapy by a dermatologist for pre-emptive counseling and treatment. (Level Ⅰ/Ⅱ )
Class C
1. The frequency of dermatologic assessment for cutaneous toxicity diagnosis and management depends on the agent(s) being used, age of the patient, underlying skin cancer risk factors (eg, history of actinic damage and/or skin cancer), and/or the potential role of skin findings as a biomarker for response.(Level Ⅲ, Expert Opinion )

[16]


References

  1. ↑ Coit DG, Thompson JA, Albertini MR, Barker C, Carson WE, Contreras C, Daniels GA, DiMaio D, Fields RC, Fleming MD, Freeman M, Galan A, Gastman B, Guild V, Johnson D, Joseph RW, Lange JR, Nath S, Olszanski AJ, Ott P, Gupta AP, Ross MI, Salama AK, Skitzki J, Sosman J, Swetter SM, Tanabe KK, Wuthrick E, McMillian NR, Engh AM (April 2019). "Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology". J Natl Compr Canc Netw. 17 (4): 367–402. doi:10.6004/jnccn.2019.0018. PMID 30959471.
  2. ↑ Orme SE, Moncrieff MD (February 2024). "A Review of Contemporary Guidelines and Evidence for Wide Local Excision in Primary Cutaneous Melanoma Management". Cancers (Basel). 16 (5). doi:10.3390/cancers16050895. PMC 10930506 Check |pmc= value (help). PMID 38473257 Check |pmid= value (help).
  3. ↑ Wolchok JD, Chiarion-Sileni V, Rutkowski P, Cowey CL, Schadendorf D, Wagstaff J, Queirolo P, Dummer R, Butler MO, Hill AG, Postow MA, Gaudy-Marqueste C, Medina T, Lao CD, Walker J, Márquez-Rodas I, Haanen JB, Guidoboni M, Maio M, Schöffski P, Carlino MS, Sandhu S, Lebbé C, Ascierto PA, Long GV, Ritchings C, Nassar A, Askelson M, Benito MP, Wang W, Hodi FS, Larkin J (January 2025). "Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma". N Engl J Med. 392 (1): 11–22. doi:10.1056/NEJMoa2407417. PMC 12080919 Check |pmc= value (help). PMID 39282897 Check |pmid= value (help).
  4. ↑ Tawbi HA, Hodi FS, Lipson EJ, Schadendorf D, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas H, Lao CD, Janoski De Menezes J, Dalle S, Arance AM, Grob JJ, Ratto B, Rodriguez S, Mazzei A, Dolfi S, Long GV (May 2025). "Three-Year Overall Survival With Nivolumab Plus Relatlimab in Advanced Melanoma From RELATIVITY-047". J Clin Oncol. 43 (13): 1546–1552. doi:10.1200/JCO.24.01124. PMC 12054981 Check |pmc= value (help). PMID 39671533 Check |pmid= value (help).
  5. ↑ Xing P, Zhang F, Wang G, Xu Y, Li C, Wang S, Guo Y, Cai S, Wang Y, Li J (December 2019). "Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis". J Immunother Cancer. 7 (1): 341. doi:10.1186/s40425-019-0779-6. PMC 6894272 Check |pmc= value (help). PMID 31801636.
  6. ↑ Watson AS, Goutam S, Stukalin I, Ewanchuk BW, Sander M, Meyers DE, Pabani A, Cheung WY, Heng DY, Cheng T, Monzon JG, Navani V (December 2022). "Association of Immune-Related Adverse Events, Hospitalization, and Therapy Resumption With Survival Among Patients With Metastatic Melanoma Receiving Single-Agent or Combination Immunotherapy". JAMA Netw Open. 5 (12): e2245596. doi:10.1001/jamanetworkopen.2022.45596. PMC 9856439 Check |pmc= value (help). PMID 36480204 Check |pmid= value (help).
  7. ↑ Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F, Guminski A, Puzanov I, Lawrence DP, Buchbinder EI, Mudigonda T, Spencer K, Bender C, Lee J, Kaufman HL, Menzies AM, Hassel JC, Mehnert JM, Sosman JA, Long GV, Clark JI (February 2016). "Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders". JAMA Oncol. 2 (2): 234–40. doi:10.1001/jamaoncol.2015.4368. PMID 26633184.
  8. ↑ 8.0 8.1 8.2 Amaral T, Ottaviano M, Arance A, Blank C, Chiarion-Sileni V, Donia M, Dummer R, Garbe C, Gershenwald JE, Gogas H, Guckenberger M, Haanen J, Hamid O, Hauschild A, Höller C, Lebbé C, Lee RJ, Long GV, Lorigan P, Muñoz Couselo E, Nathan P, Robert C, Romano E, Schadendorf D, Sondak V, Suijkerbuijk KP, van Akkooi AC, Michielin O, Ascierto PA (January 2025). "Cutaneous melanoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up". Ann Oncol. 36 (1): 10–30. doi:10.1016/j.annonc.2024.11.006. PMID 39550033 Check |pmid= value (help).
  9. ↑ 9.0 9.1 Seth R, Agarwala SS, Messersmith H, Alluri KC, Ascierto PA, Atkins MB, Bollin K, Chacon M, Davis N, Faries MB, Funchain P, Gold JS, Guild S, Gyorki DE, Kaur V, Khushalani NI, Kirkwood JM, McQuade JL, Meyers MO, Provenzano A, Robert C, Santinami M, Sehdev A, Sondak VK, Spurrier G, Swami U, Truong TG, Tsai KK, van Akkooi A, Weber J (October 2023). "Systemic Therapy for Melanoma: ASCO Guideline Update". J Clin Oncol. 41 (30): 4794–4820. doi:10.1200/JCO.23.01136. PMID 37579248 Check |pmid= value (help).
  10. ↑ Chesney J, Lewis KD, Kluger H, Hamid O, Whitman E, Thomas S, Wermke M, Cusnir M, Domingo-Musibay E, Phan GQ, Kirkwood JM, Hassel JC, Orloff M, Larkin J, Weber J, Furness AJ, Khushalani NI, Medina T, Egger ME, Graf Finckenstein F, Jagasia M, Hari P, Sulur G, Shi W, Wu X, Sarnaik A (December 2022). "Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study". J Immunother Cancer. 10 (12). doi:10.1136/jitc-2022-005755. PMC 9748991 Check |pmc= value (help). PMID 36600653 Check |pmid= value (help).
  11. ↑ Andtbacka RH, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL (June 2019). "Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma". J Immunother Cancer. 7 (1): 145. doi:10.1186/s40425-019-0623-z. PMC 6554874 Check |pmc= value (help). PMID 31171039. Vancouver style error: non-Latin character (help)
  12. ↑ Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandalá M, Haanen JB, Lebbé C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV (August 2019). "Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma". N Engl J Med. 381 (7): 626–636. doi:10.1056/NEJMoa1904059. PMID 31166680.
  13. ↑ Schadendorf D, Dummer R, Flaherty KT, Robert C, Arance A, de Groot JW, Garbe C, Gogas HJ, Gutzmer R, Krajsová I, Liszkay G, Loquai C, Mandalà M, Yamazaki N, Queirolo P, Guenzel C, Polli A, Thakur M, di Pietro A, Ascierto PA (June 2024). "COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma". Eur J Cancer. 204: 114073. doi:10.1016/j.ejca.2024.114073. PMID 38723373 Check |pmid= value (help).
  14. ↑ Ascierto PA, Dréno B, Larkin J, Ribas A, Liszkay G, Maio M, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Atkinson V, Dutriaux C, Garbe C, Hsu J, Jones S, Li H, McKenna E, Voulgari A, McArthur GA (October 2021). "5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study". Clin Cancer Res. 27 (19): 5225–5235. doi:10.1158/1078-0432.CCR-21-0809. PMC 9401485 Check |pmc= value (help). PMID 34158360 Check |pmid= value (help).
  15. ↑ Peter Yang and Jeremy Warner. Melanoma. Hemonc.org. Accessed on August 21, 2015. http://hemonc.org/wiki/Melanoma
  16. ↑ Swetter SM, Tsao H, Bichakjian CK, Curiel-Lewandrowski C, Elder DE, Gershenwald JE, Guild V, Grant-Kels JM, Halpern AC, Johnson TM, Sober AJ, Thompson JA, Wisco OJ, Wyatt S, Hu S, Lamina T (January 2019). "Guidelines of care for the management of primary cutaneous melanoma". J Am Acad Dermatol. 80 (1): 208–250. doi:10.1016/j.jaad.2018.08.055. PMID 30392755.
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