Cutaneous melanoma is a disease in which neoplastic (cancer) cells form in the melanocytic cells, arising in the epidermis of our largest organ, the skin. The American Cancer Society estimates that about 99,780 new melanomas will be diagnosed in 2022 (57,180 in men and 42,600 in women).1,2
While the rates of melanoma have been increasing over the last few decades, this has varied considerably by age. Melanoma is more common in men, among individuals of fair complexion and those who have been exposed to natural and artificial sunlight over long periods of time3,4,, particularly when exposed during childhood and early adolescence.
Immune and cellular therapies have emerged in the last two decades as remarkable treatment options for patients with both hematologic and solid tumor malignancies. The development and efficacy of these new drugs in the modern era came to light in the treatment of patients with metastatic melanoma and has made its way recently into the treatment of earlier stages of the disease.
Role of Systemic Therapies in Advanced and Metastatic Melanoma
Most melanoma cases are diagnosed at an early, localized stage where adequate surgical excision is often curative, with a survival rate of roughly 98%.2 However, more advanced disease, including regional nodal involvement and metastatic/distant disease, represents approximately 13% of all cases and often requires systemic therapy, which is given in an effort to decrease risk of recurrence in regional disease or palliatively reduce and control disease burden in the metastatic setting.2
Prior to 2011, therapies used to treat patients with metastatic melanoma were largely ineffective. The emergence of many new therapies to treat locally advanced and metastatic melanoma in the last decade have dramatically altered the landscape in the treatment and outcomes of these patients. Now, these therapies have made their mark in the adjuvant space, after melanoma resection in certain populations, and have been used prior to melanoma resections, but usually when patients are enrolled in clinical trials.
Immunotherapy Background
One way to conceptualize some of the new immunotherapy agents used in the treatment of malignancies is to think about these drugs as “unleashing the brakes” on the normally quiescent immune system to then go and attack the cancer cells.
The activation of cellular immunity begins when T cells recognize peptide fragments composed of intracellular proteins expressed on the surface of antigen-presenting cells (APCs) bound to specific mixed histocompatibility complex (MHC) molecules.5 This very precise interaction requires the presence of a costimulatory molecule called B7, which, once activated, up-regulates the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) receptor on T-cells. The normal function of CTLA-4 is a “negative regulator” of T cell activation, thereby normally serving as a “physiologic brake” on an activated immune system.5
In 2011, based upon survival gains in a randomized phase 3 clinical trial6, the FDA approved ipilimumab, a fully human monoclonal antibody targeting the CTLA-4 immune checkpoint, for the treatment of patients with metastatic melanoma. Ipilimumab was a breakthrough drug that became the first immune checkpoint inhibitor approved in this setting.
A second co-inhibitory pathway of cancer immunotherapy utilizes the programmed cell death receptor (PD-1), which normally is an inhibitory receptor present on activated T-cells.5 Normally, when PD-1 binds to its ligand PD-L1, present on active tumor cells, the T-cell’s ability to produce an effective immune response is blunted.5 However, when antibodies directed against PD-1 (nivolumab, pembrolizumab and cemiplimab) or PD-L1 (durvalumab, atezolizumab and avelumab) the anti-tumor response is restored and often quite enhanced, producing tumor regressions in patients with certain malignancies.
The use of these novel agents in combination or alone are the mainstay of therapy now in advanced and metastatic melanoma treatment. Updated long-term data from the CheckMate-067 phase 3 trial were recently presented at the American Society of Clinical Oncology (ASCO) Conference in Chicago in June 2022 and revealed that 48% of patients with newly diagnosed previously untreated advanced melanoma treated with nivolumab/ipilimumab remain alive at 7.5 years as compared to 42% of patients treated with nivolumab alone and 22% of patients treated with ipilimumab alone.7 This data reinforces the long-term benefits for immune checkpoint inhibition in this patient population.
Who Responds Best to Immunotherapy?
Immunotherapy has revolutionized the care of patients with melanoma, in some cases allowing patients to survive 
years longer than ever thought possible. Many patients with metastatic melanoma derive benefit from immune therapy drugs; however, these drugs are nonspecific and not akin to “targeted therapy,” which targets specific cancer genes or mutations in cancer cells.
In light of this, it can be difficult to determine which patients with metastatic melanoma will have the most robust response to immunotherapy.
Interestingly, however, tissue studies from patients with melanoma are frequency associated with a large number of somatic mutations, which is likely due to ultraviolet (UV) damage from sun exposure.2,5 These mutations may result in the presentation of cancer-specific antigens that serve as targets for the checkpoint inhibitor-reactivated tumor cells. It is postulated that the number of such somatic mutations, among other factors, may be able to predict which patients will have a more robust response to immunotherapy.5
This is an idea that is also shared in patients with small cell lung cancer, another malignancy where because of a direct toxin (i.e. cigarette smoke), immunotherapy drugs have shown tremendous potential.
Dr. Samantha Shams
Dr. Shams is a board-certified hematologist and medical oncologist currently practicing at Piedmont Cancer Institute’s Atlanta office. After graduating with high honors from the University of Georgia, she earned her medical degree at Mercer University. he completed her internship and residency at Emory University and formalized her training with a fellowship in hematology/medical oncology at Moffitt Cancer Center/The University of South Florida. As an Atlanta native, she dreamed of coming back to her hometown to provide exceptional oncologic care for Georgia residents.
References
- The American Cancer Society . Retrieved June 14, 2022 from cancer.org.
- Surveillance, Epidemiology, and End Results Program. (n.d.). Retrieved June 14, 2022, from https://seer.cancer.gov/
- Colantonio S, Bracken MB, Beecker J. The association of indoor tanning and melanoma in adults: systematic review and meta-analysis. J Am Acad Dermatol 2014;70:847-857 e841-818.
- Ivry GB, Ogle CA, Shim EK. Role of sun exposure in melanoma. Dermatol Surg 2006;32:481-492.
- Sosman, J. A., & Atkins, M. B. (2019, December 7). Immunotherapy of advanced melanoma with immune checkpoint inhibition. Retrieved June 12, 2022, from https://www.uptodate.com/home.
- Hodi, FD, O’Day SJ, McDermott DF, Weber, RW, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Eng J Med 2010; 363:711-723
- Wolchok JD, Chiarion-Sileni V, Gonzales R, et al. Efficacy and safety results from a phase III trial of nivolumab alone or combined with ipilimumab versus ipilimumab alone in treatment-naive patients with advanced melanoma (CheckMate 067). J Clin Oncol. 2015;33:18s (suppl; abstr LBA1).
