Associations of Cutaneous Immune-Related Adverse Effects of Immunotherapy With Treatment Response in Patients With Metastatic Melanoma
Main Article Content
Keywords
checkpoint inhibitors, immunology, ipilimumab, melanoma, nivolumab, oncology, pembrolizumab
Abstract
Background: Dermatologic toxicity is the most common immune-related adverse effect of cancer immunotherapy.
Methods: We retrospectively reviewed the health records of adult (≥18 years) melanoma patients who received ipilimumab, nivolumab, or pembrolizumab from January 1, 2011, through September 15, 2017, at Mayo Clinic. The χ2 test was used to assess the association between development of a cutaneous immune-related adverse effect and antitumoral response to the immune checkpoint inhibitors. Odds ratios were calculated with logistic regression models and were adjusted for sex and immunotherapeutic drugs. We described the various cutaneous immune-related adverse effects and assessed the response to immunotherapy (each patient’s objective clinical response was categorized as favorable [complete or partial response] or unfavorable). We then determined whether development of a cutaneous immune-related adverse effect was associated with the clinical response.
Results: Of 690 melanoma patients, 232 (33.6%) had a cutaneous immune-related adverse effect. The most common effects were dermatitis (21.4%), pruritus (5.5%), and vitiligo (4.2%). Median (range) time to onset of dermatitis was 3 (0-7) weeks; lichenoid dermatitis, 12 (6-18) weeks; and vitiligo, 40 (12-96) weeks. Development of a cutaneous immune-related adverse effect was significantly associated with favorable clinical response.
Conclusions: Development of cutaneous immune-related adverse effects is associated with favorable responses to nivolumab, ipilimumab, pembrolizumab, and ipilimumab plus nivolumab therapy in patients with metastatic melanoma.
References
2. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-2532.
3. Weber JS, Hodi FS, Wolchok JD, et al. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol. 2017;35(7):785-792.
4. Hua C, Boussemart L, Mateus C, et al. Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab. JAMA Dermatol. 2016;152(1):45-51.
5. Teulings HE, Limpens J, Jansen SN, et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015;33(7):773-781.
6. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 2009. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009-05-29_QuickReference_8.5x11.pdf.
7. Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12-25.
8. Minkis K, Garden BC, Wu S, Pulitzer MP, Lacouture ME. The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis. J Am Acad Dermatol. 2013;69(3):e121-128.
9. Hwang S. Difference in skin toxicities observed in patients with metastatic melanoma treated with combined pembrolizumab and ipilimumab vs. pembrolizumab alone. 50th Annual Scientific Meeting of the Australasian College of Dermatologist; 2017; Sydney, Australia.
10. Curry JL, Tetzlaff MT, Nagarajan P, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017;44(2):158-176.
11. Collins LK, Chapman MS, Carter JB, Samie FH. Cutaneous adverse effects of the immune checkpoint inhibitors. Curr Probl Cancer. 2017;41(2):125-128.
12. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330.
13. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol. 2015;33(13):1430-1437.
14. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018-2028.
15. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109-1117.
16. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-135.
17. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.
18. Troyanova-Slavkova S, Eickenscheidt L, Dumann K, Kowalzick L. [Initially undetected de novo psoriasis triggered by nivolumab for metastatic base of the tongue carcinoma]. Hautarzt. 2018;69(8):674-680.
19. Om A, Cardon B, Cohen G. Psoriasiform eruption on the face and extremities associated with nivolumab therapy. JAAD Case Rep. 2018;4(4):373-375.
20. Bonigen J, Raynaud-Donzel C, Hureaux J, et al. Anti-PD1-induced psoriasis: a study of 21 patients. J Eur Acad Dermatol Venereol. 2017;31(5):e254-e257.
21. Lomax AJ, Ge L, Anand S, McNeil C, Lowe P. Bullous pemphigoid-like reaction in a patient with metastatic melanoma receiving pembrolizumab and previously treated with ipilimumab. Australas J Dermatol. 2016;57(4):333-335.
22. Tanita K, Fujimura T, Kambayashi Y, et al. Intensity-Modulated Radiotherapy Triggers Onset of Bullous Pemphigoid in a Patient with Advanced Melanoma Treated with Nivolumab. Case Rep Oncol. 2018;11(1):114-118.
23. Matsumoto Y, Kadono T, Matsuoka M, et al. Disseminated erythema with intense and selective inflammation of sweat gland and lichenoid drug eruption during nivolumab therapy. J Dermatol. 2018;45(2):e33-e34.
24. Shao K, McGettigan S, Elenitsas R, Chu EY. Lupus-like cutaneous reaction following pembrolizumab: An immune-related adverse event associated with anti-PD-1 therapy. J Cutan Pathol. 2018;45(1):74-77.
25. Barbosa NS, Wetter DA, Wieland CN, Shenoy NK, Markovic SN, Thanarajasingam U. Scleroderma Induced by Pembrolizumab: A Case Series. Mayo Clin Proc. 2017;92(7):1158-1163.
26. Burillo-Martinez S, Morales-Raya C, Prieto-Barrios M, Rodriguez-Peralto JL, Ortiz-Romero PL. Pembrolizumab-Induced Extensive Panniculitis and Nevus Regression: Two Novel Cutaneous Manifestations of the Post-immunotherapy Granulomatous Reactions Spectrum. JAMA Dermatol. 2017;153(7):721-722.
27. Tetzlaff MT, Jazaeri AA, Torres-Cabala CA, et al. Erythema nodosum-like panniculitis mimicking disease recurrence: A novel toxicity from immune checkpoint blockade therapy-Report of 2 patients. J Cutan Pathol. 2017;44(12):1080-1086.
28. Helm MF, Bax MJ, Bogner PN, Chung CG. Metastatic melanoma with features of blue nevus and tumoral melanosis identified during pembrolizumab therapy. JAAD Case Rep. 2017;3(2):135-137.
29. Bari O, Cohen PR. Tumoral Melanosis Associated with Pembrolizumab-Treated Metastatic Melanoma. Cureus. 2017;9(2):e1026.
30. Imafuku K, Yoshino K, Ymaguchi K, Tsuboi S, Ohara K, Hata H. Nivolumab therapy before vemurafenib administration induces a severe skin rash. J Eur Acad Dermatol Venereol. 2017;31(3):e169-e171.
31. Saw S, Lee HY, Ng QS. Pembrolizumab-induced Stevens-Johnson syndrome in non-melanoma patients. Eur J Cancer. 2017;81:237-239.
32. Nayar N, Briscoe K, Fernandez Penas P. Toxic Epidermal Necrolysis-like Reaction With Severe Satellite Cell Necrosis Associated With Nivolumab in a Patient With Ipilimumab Refractory Metastatic Melanoma. J Immunother. 2016;39(3):149-152.
33. Gillis NK, Hicks JK, Bell GC, Daly AJ, Kanetsky PA, McLeod HL. Incidence and Triggers of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in a Large Cancer Patient Cohort. J Invest Dermatol. 2017;137(9):2021-2023.
34. Mirza S, Hill E, Ludlow SP, Nanjappa S. Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome. Melanoma Res. 2017;27(3):271-273.
35. Reule RB, North JP. Cutaneous and pulmonary sarcoidosis-like reaction associated with ipilimumab. J Am Acad Dermatol. 2013;69(5):e272-e273.
36. Cho M, Nonomura Y, Kaku Y, Dainichi T, Otsuka A, Kabashima K. Generalized Lichen Nitidus Following Anti-PD-1 Antibody Treatment. JAMA Dermatol. 2018;154(3):367-369.
37. Velasco-Tamariz V, Burillo-Martinez S, Prieto-Barrios M, Calleja-Algarra A, Rodriguez-Peralto JL, Ortiz-Romero PL. Widespread biphasic amyloidosis related to ipilimumab treatment for metastatic melanoma. Int J Dermatol. 2017;56(9):e189-e191.
38. Kyllo RL, Parker MK, Rosman I, Musiek AC. Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma. J Am Acad Dermatol. 2014;70(4):e85-e86.
39. Hwang SJ, Carlos G, Wakade D, Sharma R, Fernandez-Penas P. Ipilimumab-induced acute generalized exanthematous pustulosis in a patient with metastatic melanoma. Melanoma Res. 2016;26(4):417-420.
40. Kang A, Yuen M, Lee DJ. Nivolumab-induced systemic vasculitis. JAAD Case Rep. 2018;4(6):606-608.
41. Kottschade L. Management of immune-related adverse events from immune checkpoint inhibitor therapy. In: Dong H, Markovic SN, eds. The Basics of Cancer Immunotherapy. Springer International Publishing; 2018:143-152.
42. Wang LL, Patel G, Chiesa-Fuxench ZC, et al. Timing of Onset of Adverse Cutaneous Reactions Associated With Programmed Cell Death Protein 1 Inhibitor Therapy. JAMA Dermatol. 2018;154(9):1057-1061.
43. Brahmer JR, Lacchetti C, Thompson JA. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. 2018;14(4):247-249.
44. Perret RE, Josselin N, Knol AC, et al. Histopathological aspects of cutaneous erythematous-papular eruptions induced by immune checkpoint inhibitors for the treatment of metastatic melanoma. Int J Dermatol. 2017;56(5):527-533.
45. Callahan MK, Postow MA, Wolchok JD. Immunomodulatory therapy for melanoma: ipilimumab and beyond. Clin Dermatol. 2013;31(2):191-199.
46. Tanaka R, Okiyama N, Okune M, et al. Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-alpha is a biomarker of nivolumab recativity. J Dermatol Sci. 2017;86(1):71-73.
47. Lo JA, Fisher DE, Flaherty KT. Prognostic Significance of Cutaneous Adverse Events Associated With Pembrolizumab Therapy. JAMA Oncol. 2015;1(9):1340-1341.
48. Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression. JAMA Dermatol. 2015;151(11):1206-1212.
Article Sidebar
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
Creative Commons Attribution (CC BY): lets others distribute and copy the article, to create extracts, abstracts, and other revised versions, adaptations or derivative works of or from an article (such as a translation), to include in a collective work (such as an anthology), to text or data mine the article, even for commercial purposes, as long as they credit the author(s), do not represent the author as endorsing their adaptation of the article, and do not modify the article in such a way as to damage the author's honor or reputation.
Authors retain copyright in their work and license the publisher to publish the content. The publisher is the National Society for Cutaneous Medicine, with production and publishing support provided by OJS, Open Journal Systems,see https://pkp.sfu.
Prior to January 2022, authors transferred copyright to the National Society for Cutaneous Medicine. However, all articles are freely available to anyone in the world. There are no subscription fees, page charges, or article processing charges.
Alan Bryce, Mayo Clinic, Rochester, MN, USA
Chair, Division of Hematology/Oncology, Department of Internal Medicine
Prakash Vishnu, Mayo Clinic, Florida, USA
Department of Medical Oncology
Svetomir Markovic, Mayo Clinic, Rochester, MN, USA
Professor,
Department of Medical Oncology
Marian McEvoy, Mayo Clinic, Rochester, MN, USA
Professor,
Department of Dermatology