Melanoma Armamentarium Progresses Toward Precision Therapy

Of the various classifications of skin cancer, melanoma is one of the least common, accounting for approximately 1% of all skin cancers. Melanoma occurs when melanocytes, the skin cells responsible for producing pigment originating from the stratum basale in the epidermis, begin to proliferate outside normal cytostatic control mechanisms of the body. Risk factors for the occurrence of melanoma include UV light exposure, presence of moles, fair skin, light hair, freckling, male sex, and family history of melanoma.¹

Melanoma may be cutaneous (ie, uveal) or noncutaneous (ie, intraocular). Guidelines disseminated by the National Comprehensive Cancer Network refer specifically to the management of cutaneous melanoma.² Additionally, noncutaneous forms rarely involve proliferation via the lymphatic system, and treatment options are limited.

Treatment and Prognosis for Cutaneous Melanoma

Four major genomic subtypes of cutaneous melanoma have been identified by The Cancer Genome Atlas in a multiplatform analysis of 333 cutaneous melanomas that are used to direct targeted therapy and clinical trial designs. The BRAF mutation is the most common subtype, occurring in more than 50% of cases, and is the only subtype with targeted drug therapy approved by the FDA. The RAS mutation is the second most common subtype (28% of cases), followed by NF1 (14%), and triple wild-type mutation (14%). Targeted therapies directed at the RAS mutation, NF1 mutation, and cases that involve triple wild-type genes are under investigation.²

Among the standardized treatment options pertaining to the staging of cutaneous melanoma (Table^2-4), surgical excision is the mainstay and first-line option for cutaneous melanomas that have not metastasized from the primary site.² In stages involving further disease progression, sentinel lymph node biopsy or complete lymph node dissection prior to surgical excision is recommended. These procedures facilitate accurate “lymphatic mapping” and are useful for detecting metastatic melanomas. Results from sentinel lymph node biopsy may aid in clinical decision-making regarding appropriateness of adjuvant therapies. For patients with stage I and stage II disease, adjuvant therapy is generally not recommended outside a clinical trial setting.²

Treatment options for patients with resectable stage III melanoma include checkpoint inhibitors and combination signal transduction inhibitors. The combination signal transduction inhibitor therapy dabrafenib (Tafinlar; Novartis Pharmaceuticals Corporation) plus trametinib (Mekinist; Novartis Pharmaceuticals Corporation) has shown benefit regarding relapse-free survival in patients with BRAF V600–activating mutations (V600K and V600E) and is recommended for this subset of resectable stage III melanoma. However, it is not recommended to treat wild-type BRAF mutations with BRAF inhibitors because evidence growth in patients with both wild-type BRAF mutations and upstream RAS mutations.^3,4

For patients who have progressed to more severe stages despite PD-1 therapy, options include checkpoint inhibitor regimens with ipilimumab (Yervoy; Bristol Myers Squibb), high-dose IL-2 (an endogenous cytokine), and the novel biopharmaceutical viral product talimogene laherparepvec (Imlygic; Amgen, Inc) for patients with injectable lesions.^3,4 In general, immunotherapy and targeted therapy with signal transduction inhibitors are preferred for unresectable or distant metastatic disease, and cytotoxic therapy may be considered on a case-by-case basis.⁴

Select Novel Treatment Options

It is recommended that eligible patients enroll in clinical trials for adjuvant systemic therapies; updated and relevant clinical trial information involving chemotherapy, targeted therapy, immunotherapy, and surgical options is available on the National Cancer Institute’s website for review.

As of March 15, 2022, 683 clinical trials are in the recruitment phase, with 301 ongoing trials pertaining to melanoma.⁵ Since 2015, novel drug development has focused on biopharmaceuticals and medications that augment the T-lymphocyte response, whereas the focus of current randomized controlled trials is primarily investigating the comparison of BRAF/MEK targeted therapy and immunotherapy with checkpoint inhibitors.⁴

Talimogene laherparepvec (T-VEC)

T-VEC is a viral immunotherapeutic option for local treatment of unresectable metastatic stage IIIB/C-IVM1a melanoma. Derived from herpes simplex virus, T-VEC is used for direct injection into certain types of lesions that generate a systemic immune response directed against cancer. The virus invades both healthy host cells and cancer cells, but it cannot replicate in healthy tissue due to a lack of infected cell protein 34.5. T-VEC also helps to generate granulocyte macrophage colony-stimulating factor, which is released and secreted during tumor cell lysis; this then leads to the presentation of cancer cell contents to cytotoxic T lymphocytes and marks them for destruction.

T-VEC has been approved for unresectable metastatic cancer since 2015. A study in 2021 evaluated T-VEC plus surgical resection vs resection alone and showed an improved recurrence-free survival of 72.4% vs 79.7% (HR, 0.75; 80% CI, 0.58-0.96).⁶ The most common adverse events (AEs) included fatigue (50.3%), chills (48.6%), and pyrexia (42.8%), and the most common serious AE was cellulitis (2.1%). For some patients who are amenable to injections more than once monthly and can tolerate the AEs, T-VEC therapy may address slight disease progression regardless of candidacy for resection.^6,7

Pembrolizumab (Keytruda; Merck & Co, Inc)

The intravenous immune checkpoint inhibitor, pembrolizumab, is well known since its FDA approval in 2014 for the treatment of unresectable melanoma. Since its approval, pembrolizumab has been used in the treatment of 16 different types of cancer, including lung cancer, head and neck cancers, and Hodgkin lymphoma.

In December 2021, the FDA approved pembrolizumab as an adjuvant treatment in patients with stage IIB or IIC melanoma following complete resection.⁸ The KEYNOTE-716 study (NCT03553836), a multicenter, randomized, double-blind, placebo-controlled trial in patients with completely resected stage IIB or IIC melanoma, showed statistically significant improvement in recurrence-free survival (HR, 0.65; 95% CI, 0.46-0.92; P = .0132).9 Within 2 years, 11% of patients in the pembrolizumab group vs 17% of patients in the placebo group experienced disease progression or death.⁹

The safety data from the KEYNOTE-716 trial were similar to data from KEYNOTE-054 (NCT02362594), which targeted therapy for resected, stage III melanoma. In the KEYNOTE-054 trial, 28% of patients experienced diarrhea, 19% had skin rash, 16% had arthralgia, and 14% developed a cough.9 Based on trial results, investigators found that pembrolizumab was a medication with a robust clinical experience that may offer some patients with resected, high-risk melanoma a chance to live longer without disease progression.

Tebentafusp-tebn (Kimmtrak; Immunocore Ltd)

Patients with noncutaneous melanoma have limited pharmacologic options aside from radiation and surgery. However, there is now a pharmacologic treatment option for metastatic uveal melanoma for HLA-A*02:01–positive patients. Available as a weekly injection, tebentafusp-tebn is a bispecific glycoprotein 100 peptide/human leukocyte antigen–directed CD3 T-cell engager used in the treatment of unresectable or metastatic uveal melanoma. Novel bispecific T-cell engager therapy augments cytotoxic T-cell activity by release of cytokines and cytolytic proteins, which leads to lysis of melanoma tumor cells.¹⁰

A phase 2 trial (NCT03070392) of adults with metastatic uveal melanoma improved overall survival vs the investigator’s choice of pembrolizumab, ipilimumab, or dacarbazine (73% vs 59%; HR, 0.51; 95% CI, 0.37-0.71; P < .0001).10 The most common AEs were cytokine-related events such as chills (47.76%), hypotension (37.14%), and pyrexia (2.45%), as well as skin-related events such as rash (53.88%), erythema (24.49%), and pruritus (0.41%). The prescribing information warns of risk of cytokine release syndrome.¹⁰

HLA-A*02:01 is not an oncologic phenotype, but rather an inflammatory phenotype that confers risk of metastases but also therapy response. In patients with this phenotype, tebentafusp-tebn may improve overall survival, depending on the patient’s history of melanoma treatment and tolerability of the agent.¹¹

Ipilimumab and nivolumab (Opdivo; Bristol Myers Squibb) plus sargramostim (Leukine; Partner Therapeutics, Inc)

The combination of ipilimumab, a CTLA-4 inhibitor, and nivolumab, an intravenous PD-1 inhibitor, is an immunotherapeutic option for patients with advanced melanoma as well as other types of cancers. A phase 2/3 clinical trial (NCT02339571) assessing the efficacy and safety of this dual drug therapy, alongside sargramostim, was completed on October 20, 2021; patients enrolled in the study had been diagnosed with unresectable stage III to IV melanoma.

Ipilimumab and nivolumab are designed to support the ability of the immune system to fight off cancer cells via reduced inhibition of cytotoxic T lymphocytes, whose function is “turned off” by cancer cells in many cancers. For this reason, ipilimumab combined with nivolumab is used in the treatment of stage IIB to stage IV melanoma, as well as gastric cancer and mesothelioma.¹²

Sargramostim is a granulocyte-macrophage colony-stimulating factor designed to increase the production of white blood cells. This combination of preexisting treatment options in the ipilimumab/nivolumab/sargramostim regimen is thought to lead to a more pronounced immune reaction in the treatment of melanoma. The efficacy and safety results of this study are pending.

Conclusion

Pharmacists across the continuum of care are positioned to provide education to patients and providers on the optimal treatment options for patients with melanoma at all stages. Armed with specialized training pertaining to medication regimens and experiential wisdom on diverse oncological presentations, pharmacists are vital in providing recommendations on curative, palliative, and supportive treatment to patients with cancer.

Pharmacists may also provide insight by analyzing clinical trials for novel treatment options and their subsequent pathway to the market. From helping guide oncologists in selecting the most appropriate chemotherapeutic regimen to providing feedback on clinical trial data in interprofessional settings to optimizing patient quality of life with pharmacologic AE management, pharmacists continue to stand out as integral parts of the treatment team for patients with cancer.

As new and more targeted treatment options surface for melanoma, pharmacists will be crucial in the selection,implementation, monitoring, and optimization of anticancer treatment therapies; they will also have a chance to showcase their ability to interpret the results of clinical trials as they relate to patient care.

Reference

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2. Coit DG, Thompson JA, Albertini MR, et al. Cutaneous melanoma, version 2. 2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019;17(4):367-402. doi:10.6004/jnccn.2019.0018

3. Seth R, Messersmith H, Kaur V, et al. Systemic therapy for melanoma: ASCO guideline. J Clin Oncol. 2020;38(33):3947-3970. doi:10.1200/JCO.20.00198

4. Melanoma Treatment (PDQ)–Health Professional Version. National Cancer Institute. Updated October 14, 2022. Accessed March 1, 2022. https://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq

5. Rilonacept to improve artery function in patients with atherosclerosis. ClinicalTrials.gov. Updated April 30, 2012. Accessed March 1, 2022. http://clinicaltrials.gov/show/NCT00417417ClinicalTrials.gov

6. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7-17. doi:10.1200/JCO.1996.14.1.7

7. Dummer R, Gyorki DE, Hyngstrom J, et al. Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial. Nat Med. 2021;27(10):1789-1796. doi:10.1038/s41591-021-01510-7

8. FDA approves pembrolizumab for adjuvant treatment of stage IIB or IIC melanoma. FDA. Updated December 6, 2021. Accessed April 1, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-stage-iib-or-iic-melanoma

9. Pembrolizumab. Package insert. Merck & Co Inc; 2022. Accessed October 1, 2022. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf

10. Safety and efficacy of IMCgp100 versus investigator choice in advanced uveal melanoma. ClinicalTrials.gov. Updated March 21, 2022. Accessed November 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03070392

11. Souri Z, Wierenga APA, Mulder A, Jochemsen AG, Jager MJ. HLA expression in uveal melanoma: an indicator of malignancy and a modifiable immunological target. Cancers (Basel). 2019;11(8):1132. doi:10.3390/cancers11081132

12. Nivolumab: depth answers. IBM Micromedex. March 15, 2022. Accessed October 1, 2022. www.micromedexsolutions.com

About the Authors

Ada Griffin is a class of 2022 PharmD candidate at Auburn University Harrison School of Pharmacy in Alabama.

John Parker is a class of 2022 PharmD candidate at the Auburn University Harrison School of Pharmacy in Alabama.

Marilyn N. Bulloch, PharmD, BCPS, FCCM is an associate clinical professor in the Department of Pharmacy Practice at the Auburn University Harrison School of Pharmacy in Alabama.