Melanoma: Pharmacologic Management

Melanoma is a cancer that affects the melanocytes located in the skin (cutaneous) and neural crest cells located in the uveal tract of the eyes.¹ According to the National Cancer Institute Surveillance, Epidemiology, and End Results Program (NCI SEER), an estimated 97,610 cases of cutaneous melanoma will be diagnosed in the United States in 2023,² with the incidence of cutaneous melanoma increasing dramatically in recent years, particularly in men. 

Melanoma accounts for 5% of all new cancer cases and has a 5-year relative survival rate of 93.5%.² This is due to the fact that approximately 84% of patients present with localized disease, 9% with regional disease, and 4% with metastatic disease.^3,4 The prognosis is excellent in patients with localized melanoma, particularly those with tumors that measure 1.0 mm or less in thickness.³ 

The National Comprehensive Cancer Network (NCCN) provides treatment guidelines for cutaneous melanoma and uveal melanoma. This article will cover the pharmacologic management of both types.^5,6 

Treatment Recommendations for Cutaneous Melanoma

First-line treatment for localized and regional cutaneous melanoma includes surgery (wide excision) and radiation therapy.⁵ Adjuvant treatment with pharmacologic agents is suggested for patients at high risk for relapse to eliminate any remaining melanoma cells within surgical margins. Patients with distant metastases are treated with a combination of immunotherapy and/or targeted therapy to control the disease burden.

The 4 subtypes of cutaneous melanoma include superficial spreading melanoma, nodular melanoma, lentigo maligna, and acral lentiginous melanoma. The NCCN Panel specifies some treatments depending on the subtype. 

Topical Imiquimod for Primary Cutaneous Melanoma

Primary melanoma is treated with surgical excision and lymph node management.⁵ In cases for which excision is not feasible (due to the location of the tumor or comorbidity), off-label topical imiquimod is offered as a treatment option. Topical imiquimod is particularly effective for patients with lentigo maligna and is associated with high rates of clearance and low recurrence rates. Clinicians may also use topical imiquimod as an adjuvant treatment for patients who underwent excision for lentigo maligna with narrow margins.⁵ 

The NCCN does not provide any formal recommendations for the use of topical imiquimod. Results of studies have revealed that 5% imiquimod cream applied 5 days a week for 12 weeks is effective at eradicating cutaneous melanoma. Patients may use daily tazarotene 0.1% gel as a pretreatment for 2 weeks to induce an inflammatory response.⁷ 

Adjuvant Systemic Treatments for Stages I, II, and III Primary Melanoma

The NCCN states that adjuvant treatment for patients with stage I/II melanoma is not recommended outside the scope of clinical trials. There are currently no adjuvant treatments approved by the US Food and Drug Administration (FDA) for these purposes. However, recent studies have highlighted that there may be some benefits of treating patients with high-risk stage II and advanced resected cutaneous melanoma with adjuvant checkpoint inhibitor therapy or BRAF-targeted therapy.⁸ 

Immune Checkpoint Inhibitor Therapy

Immune checkpoint inhibitors block interactions between immune cells and tumor cells, sensitizing patients’ immune systems to their cancers. Blockade of programmed death-1 (PD-1) and CTLA-4 enhances T cell-mediated tumor cell killing and inflammatory responses to improve clinical responses and survival.⁹ 

The NCCN Panel recommends nivolumab as a postoperative adjuvant treatment for patients with stage III or IV cutaneous melanoma. The CheckMate 238 clinical trial (ClinicalTrials.gov Identifier: NCT02388906) demonstrated that nivolumab significantly improved relapse-free survival and distant metastasis-free survival among patients who underwent complete resection of stage IIIB, IIIC, or IV melanoma. Recommended dosing from the trial is a 3-mg/kg infusion of nivolumab every 2 weeks for 1 year or until disease progression.¹⁰ 

Pembrolizumab is also recommended for treating patients with stage III cutaneous melanoma at initial presentation or with recurrence. The recommended treatment based on the results of the KEYNOTE-054 study (ClinicalTrials.gov Identifier: NCT02362594) is a 200-mg infusion of pembrolizumab every 3 weeks for 1 year (18 doses) or until disease progression.¹¹ 

Although ipilimumab was shown to be less effective than nivolumab in the Checkmate 238 trial, the NCCN Panel recommends it be used as an adjuvant treatment in patients with nodal recurrence or those with resected stage IV disease.⁵ Specifically, ipilimumab is recommended for patients who were previously exposed to adjuvant pembrolizumab or nivolumab. Dosing recommendations vary: high-dose regimens use 10 mg/kg, although studies show the lower 3-mg/kg dose is safer and associated with less toxicity.¹² 

BRAF-Targeted Therapy

BRAF mutations are the most common genetic changes in cutaneous melanoma and are estimated to be found in half of all cases, with the BRAF V600E substitution mutation accounting for 90% of those.¹³ Small-molecule inhibitors are available that target this mutation and are widely used for treating cutaneous melanoma. 

Based on the results of the COMBI-AD clinical trial (ClinicalTrials.gov Identifier: NCT01682083), the NCCN Panel recommends adjuvant dabrafenib/trametinib for treating patients with resected stage III or recurrent cutaneous melanoma harboring BRAF V600E or V600K substitution mutations. Patients are treated with dabrafenib 150 mg twice daily and trametinib 2 mg once daily for 1 year or until disease progression occurs.¹⁴ 

Although the NCCN Panel recognizes there are some pilot trials studying neoadjuvant systemic treatment with BRAF-targeted therapies, they do not currently provide any recommendations. Instead, patients are encouraged to participate in clinical trials.

Treatment of Stage III In-Transit Disease

In-transit cutaneous melanoma refers to a type of metastasis that spreads at least 2 cm away from the primary tumor through a lymph vessel but does not reach nearby lymph nodes. In-transit melanoma lesions can be cutaneous or subcutaneous.^15,16  

The NCCN Panel recommends that isolated in-transit disease first be treated with excision therapy. However, there is a chance that the melanoma will spread to regional lymph nodes, meaning that other local pharmacologic treatments may be preferred. 

Talimogene Laherparepvec

Intralesional injections deliver pharmacologic therapies directly to pre-existing melanoma lesions. Talimogene laherparepvec (T-VEC) utilizes a modified herpes simplex virus type 1 (oncolytic virus) to directly deliver expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) to the tumor. This recruits dendritic cells and other immune cells preferentially into the melanoma tumor, inducing localized tumor cell lysis and generating tumor-derived antigens.¹⁶

Clinical trials in patients with unresectable stage IIIB-IV melanoma demonstrate that T-VEC induces significantly improved durable response rates and overall response rates compared with subcutaneous GM-CSF injections.¹⁷  

The initial dosing for intralesional T-VEC is 1 million plaque-forming units (PFU)/mL in a 1- to 4-mL injection. Subsequent doses are 100 million PFU/mL given in a 1- to 4-mL injection administered 3 weeks following the initial dose and continued once every 2 weeks.¹⁷ 

Interleukin-2

Interleukin-2 (IL-2) is a cytokine that activates and promotes the expansion of cytotoxic T cells to mediate tumor cell destruction. It also suppresses regulatory T cells within the melanoma tumor microenvironment.¹⁸ Several studies demonstrate the efficacy of intralesional IL-2 injections, with some showing a complete response rate as high as 70%. Intralesional IL-2 is also preferred because it minimizes the toxicity seen with high-dose intravenous (IV) IL-2 treatment. Patients may begin treatment with 3 million international units 3 times per week until clinical remission is achieved. The dose may be increased based on the patient’s tolerance.¹⁹ Treatment monitoring recommendations are reported below in Table 2. 

Isolated Limb Perfusion

The NCCN Panel recommends isolated limb perfusion or infusion for centers and staff with the expertise to manage both the treatment and potential side effects. This technique involves directly administering high doses of cytotoxic chemotherapy to the arm or leg affected by melanoma, often under hyperthermic conditions. The goal of isolated limb perfusion is to limit systemic toxicities.⁴ 

The agent most frequently used for isolated limb perfusion is melphalan, which is often used in combination with tumor necrosis factor (TNF)-α or actinomycin D. Patients with unresectable stage IIIB or locally metastatic melanoma respond well to isolated limb perfusion with melphalan, and the suggested dosing is 13 mg/L in the arm or 10 mg/L in the leg infused over 20 minutes.²⁰

Pharmacologic Treatment of Metastatic Melanoma

Recent research and advances in pharmacotherapy have led to the development of exciting novel agents that target activating mutations in melanoma. Immunotherapy has also become a preferred treatment option for unresectable and distant metastatic melanoma. Cytotoxic chemotherapy is assessed on a case-by-case basis for patients who are ineligible for targeted therapy/immunotherapy.⁵

First-line systemic therapy recommendations include BRAF-targeted therapies and immune checkpoint inhibitors. Patients should also be encouraged to enroll in clinical trials. Second-line therapies include IL-2, combination targeted therapy, and cytotoxic chemotherapy. 

Molecular testing is advised when staging disease to determine whether the patient’s tumor has any targetable mutations. Below are tables detailing the single-agent or combination therapies recommended by the NCCN Panel for treating metastatic cutaneous melanoma. 

Table 1. Single-Agent or Combination Biologic Treatment Recommendations for Metastatic Cutaneous Melanoma

Treatment	Dosing and Treatment Schedule	Additional Testing Required
Ipilimumab	3 mg/kg infused IV over 30 min every 3 wk for a total of 4 doses	FDA-approved test for PD-L1 expression
Ipilimumab/intralesional T-VEC	T-VEC: Injection on day 1 with 1 million PFU/mL; subsequent doses given on day 1 of week 4 followed by every 2 wk thereafter with 100 million PFU/mL  Ipilimumab: 3 mg/kg infused IV every 3 wk starting on day 1 of week 6 for up to 4 total doses
Nivolumab	240 mg every 2 wk or 480 mg every 4 wk, infused IV over 30 minutes; treat until disease progresses or unacceptable toxicity develops
Nivolumab/ipilimumab	Nivolumab 1 mg/kg and  ipilimumab 3 mg/kg infused IV every 3 wk for a maximum of 4 doses or until unacceptable toxicity occurs
Nivolumab and relatlimab-rmbw	Nivolumab 480 mg and relatlimab-rmbw 160 mg infused IV every 4 wk; treat until disease progresses or unacceptable toxicity occurs
Pembrolizumab	200 mg every 3 wk or 400 mg every 6 wk infused IV over 30 min; treat until disease progresses or unacceptable toxicity occurs
Pembrolizumab/low-dose ipilimumab	Pembrolizumab 2 mg/kg with ipilimumab 1 mg/kg every 3 wk infused IV over 30 min for 4 total doses; follow up with pembrolizumab 2 mg/kg every 3 wk for up to 2 y or until disease progresses or unacceptable toxicity occurs	FDA-approved test for PD-L1 expression

FDA = Food & Drug Administration; IV = intravenous; PD-L1 =  programmed death-ligand 1; PFU = plaque-forming units.

From clinical trials and FDA-approved prescribing information.^21-26

Table 2. Single-Agent Small Molecule Inhibitor Treatment Recommendations for Metastatic Cutaneous Melanoma

Treatment	Dosing and Treatment Schedule	Indication
Binimetinib	45 mg orally twice daily 12 h apart, with or without food; treat until disease progresses or unacceptable toxicity occurs	NRAS mutations
Dabrafenib	150 mg orally twice daily 12 h apart, with ≥1 h prior to or 2 h following a meal	BRAF mutations
Entrectinib	600 mg once daily, with or without food; treat until disease progresses or unacceptable toxicity occurs
Imatinib	400 mg once daily; treat until disease progresses or unacceptable toxicity occurs	KIT mutations
Larotrectinib	100 mg twice daily, with or without food; treat until disease progresses or unacceptable toxicity occurs	NTRK mutations
Vemurafenib	960 mg orally twice daily, with or without food; treat until disease progresses or unacceptable toxicity occurs	BRAF mutations

From clinical trials and FDA-approved prescribing information.^27-32

Table 3. Combination Small Molecule Inhibitor Treatment Recommendations for Metastatic Cutaneous Melanoma

Treatment	Dosing and Treatment Schedule	Indication
Dabrafenib/trametinib	Dabrafenib 150 mg orally twice daily with trametinib 2 mg orally once daily; treat until disease progresses or unacceptable toxicity occurs	BRAF V600E or V600K mutations
Encorafenib/binimetinib	Encorafenib 450 mg orally once daily with binimetinib 45 mg orally twice daily; treat until disease progresses or unacceptable toxicity occurs	BRAF V600E or V600K mutations
Pembrolizumab/lenvatinib	Lenvatinib 20 mg orally once daily with pembrolizumab 200 mg IV infusion every 21 d; treat until disease progresses or unacceptable toxicity occurs
Vemurafenib/cobimetinib	Vemurafenib 960 mg orally twice daily, cobimetinib 60 mg orally once daily for 21 d followed by 7 d off; treat until disease progresses or unacceptable toxicity occurs	BRAF V600E or V600K mutations
Vemurafenib/cobimetinib plus atezolizumab	Initial treatment: Vemurafenib 960 mg orally twice daily, cobimetinib 60 mg orally once daily for 21 d followed by 7 d off (first 28 d) Subsequent treatment with triple combination: Atezolizumab 840 infused on days 1 and 15; cobimetinib 60 mg once daily on days 1-21, vemurafenib 960 mg twice daily on days 1-28; cycle every 28 d until disease progresses or unacceptable toxicity occurs	BRAF V600E or V600K mutations

IV = intravenous.

From clinical trial data.^33-37

Table 4. Cytotoxic Chemotherapy Recommendations for Metastatic Cutaneous Melanoma

Treatment	Dosing and Treatment Schedule
Cisplatin/vinblastine/dacarbazine (CVD)	Cisplatin 30 mg/m2 infusion on days 1-3, vinblastine 2.5 mg/m2 infusion on day 1, and dacarbazine 250 mg/m2 infusion on days 1-3; cycle every 21 d
Dacarbazine	250 mg/m2/d IV infusion for 5 d; cycle every 21 d
Paclitaxel	250 mg/m2 24-h infusion; cycle every 21 d
Paclitaxel/carboplatin	Paclitaxel 100 mg/m2 weekly IV infusion with carboplatin targeting an AUC of 2 on days 1, 8, and 15 of a 28-d cycle; treat until disease progresses
Temozolomide	200 mg/m2/d orally for 5 d; cycle every 28 d

AUC = area under the curve; IV = intravenous.

From clinical trial data.^38-41

Treatment Recommendations for Uveal Melanoma

Although uncommon in the general population, uveal melanoma is the most common type of cancer affecting the eye. Nearly all cases are diagnosed as local disease, with less than 3% of patients presenting with metastases at the time of diagnosis. The 5-year disease-specific survival rate for uveal melanoma is between 70% and 81%. Common symptoms that lead to an early diagnosis include blurred or double vision, partial or complete loss of vision, and visual disturbances.⁴² 

The NCCN Panel provides treatment recommendations for uveal melanoma arising from the ciliary body or choroid (not including the iris). This type of melanoma also tends to have different mutations compared with cutaneous and conjunctival melanomas. Commonly seen mutations in uveal melanoma include chromosomal aberrations affecting chromosomes 3 and 8, in addition to mutations in GNA11 and GNAQ.⁶ 

In recent years, clinicians have gravitated away from treating primary uveal melanoma with surgery, instead preferring radiation therapy, laser therapy, photodynamic therapy, or cryotherapy.⁶ There are currently no pharmacologic recommendations made for early-stage uveal melanoma. 

Treatment of Metastatic Uveal Melanoma

Pharmacotherapy is only recommended for treating the rare case of metastatic uveal melanoma. Treatment recommendations from the NCCN Panel depend on where the disease has spread and to what extent. 

Tebentafusp

Tebentafusp is currently the only FDA-approved treatment for metastatic uveal melanoma. It is a bispecific protein containing an anti-CD3 effector and a T-cell receptor that activates T cell-mediated immunity against uveal melanoma cells. Clinical trial (ClinicalTrials.gov Identifier: NCT03070392) results demonstrate that tebentafusp significantly improves overall survival compared with single-agent dacarbazine, pembrolizumab, or ipilimumab.^6,43 

Tebentafusp is administered as 20 µg IV infusion on day 1, 30 µg on day 8, and 68 µg for all subsequent weekly doses. Treatment should be continued until unacceptable toxicity occurs or the patient’s disease progresses. 

Targeting Liver Metastases

The NCCN Panel notes that current data from several meta-analyses suggest that systemic therapy may result in worse outcomes compared with localized treatments. The Panel does not make any formal recommendations for systemic therapy. In addition to tebentafusp treatment, patients with metastatic uveal melanoma may receive treatments targeted at liver metastases.⁶ 

Many of these treatment options — including isolated hepatic infusion, percutaneous hepatic infusion, and hepatic arterial infusion — deliver chemotherapy directly to the liver tissue.⁶ 

Monitoring Side Effects, Adverse Events, and Drug-Drug Interactions Associated With Treatment for Melanoma

Chemotherapy agents often exhibit several off-target effects. Although their mechanism of action of targeting rapidly dividing cells is ideal for treating cancer, it can also result in unwanted toxicities. Patients should be monitored for any new adverse events, and treatment modification or discontinuation considered based on severity. 

Table 5. Side Effect Profiles of Chemotherapy Drugs

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Carboplatin	Abdominal pain, back pain, constipation, cough, decreased appetite, diarrhea, fatigue and weakness, pyrexia, headache, joint pain, musculoskeletal pain, nausea, rash, upper respiratory tract infection, vomiting Warnings: Infusion reaction	None indicated	May be harmful to fetus; avoid using in breastfeeding patients
Cisplatin	Infections, myelosuppression, nausea, peripheral neuropathy, pyrexia, vomiting Warnings: Infection reaction, nephrotoxicity, ocular toxicity, ototoxicity, secondary leukemia	Nephrotoxic and ototoxic drugs	May be harmful to fetus; avoid using in breastfeeding patients; use with caution in patients with renal impairment
Dacarbazine	Anorexia, nausea, vomiting Warnings: Hematopoietic depression, cytopenia, hepatotoxicity	None indicated	May be harmful to fetus; avoid using in breastfeeding patients
Melphalan	Cytopenia, diarrhea, nausea, vomiting, skin complications, vasculitis, alopecia, pulmonary fibrosis, hemolytic anemia Warnings: Tissue extravasation, hypersensitivity reaction, secondary malignancies, bone marrow suppression, mutagenesis	None indicated	May be harmful to fetus; avoid using in breastfeeding patients
Paclitaxel	Arthralgia, cytopenias, diarrhea, elevated liver enzyme levels, infections, myalgia, nausea, vomiting Warnings: Bradycardia, hypersensitivity, hypotension	CYP2C8 and CPY3A4 inhibitors and inducers	May be harmful to fetus; avoid using in breastfeeding patients; use with caution in geriatric patients
Temozolomide	Alopecia, fatigue, nausea, vomiting Warnings: Hepatotoxicty, myelosuppression, pneumocystis pneumonia, secondary MDS/AML	None indicated	May be harmful to fetus; avoid using in breastfeeding patients; use with caution in geriatric patients, as they may develop serious thrombocytopenia or neutropenia during the first treatment cycle
Vinblastine	Cytopenia, alopecia, nausea, vomiting, abdominal pain, constipation, anorexia, diarrhea, paresthesias, peripheral neuritis, hypertension, bone pain, jaw pain	Avoid concomitant use with phenytoin and strong CYP3A inhibitors	May be harmful to fetus; avoid using in breastfeeding patients

MDS/AML = myelodysplastic syndrome/acute myeloid leukemia.

From FDA-approved prescribing information.^44-50

Immune checkpoint inhibitors have the ability to trigger immune-related reactions and infusion-related reactions. Grades 3 and 4 adverse events are also fairly common in patients treated with these therapies, ranging from 20% to 60%, depending on the treatment.⁵ Patients should be closely monitored when undergoing treatment with immune checkpoint inhibitors. Thyroid function, liver enzymes, and creatinine should be monitored before and throughout treatment to look for any signs of adverse reactions.

Table 6. Side Effect Profiles of Monoclonal Antibody/Biologic Agents for Melanoma

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Atezolizumab	Alopecia, cough, decreased appetite, dyspnea, fatigue Warnings: Immune-related reactions, infusion-related reaction	None indicated	May be harmful to fetus; avoid using in breastfeeding patients
Aldesleukin	Abdominal pain, chills, diarrhea, headache, injection-related reactions, nausea, pyrexia, vomiting Warnings: Exacerbation of previous immune-related diseases (Crohn disease, inflammatory arthritis, scleroderma, myasthenia gravis, IgA glomerulonephritis, diabetes mellitus, thyroiditis, cholecystitis, cerebral vasculitis, bullous pemphigoid, Stevens-Johnson syndrome), severe eosinophilia	Avoid use of concomitant hepatotoxic and nephrotoxic drugs, as liver and kidney function are impaired during treatment	Patients should have normal cardiac, CNS, hepatic, and pulmonary function before therapy begins; patients typically experience drop in mean arterial blood pressure within 12 hours of beginning therapy due to capillary leak syndrome, so careful monitoring (complete blood count with differential, platelet count, chest radiograph, blood chemistries) is recommended to maintain ideal blood pressure and organ perfusion
Ipilimumab	Colitis, decreased appetite, diarrhea, fatigue, headache, insomnia, nausea, pruritus, pyrexia, rash, vomiting, weight loss Warnings: Severe or fatal immune-mediated reactions, severe infusion-related reactions	None indicated	May be harmful to fetus; avoid using in breastfeeding patients
Nivolumab	Abdominal pain, back pain, decreased appetite, diarrhea, nausea, fatigue and weakness, pyrexia, headache, musculoskeletal pain, skin itching and rash, upper respiratory tract infection, urinary tract infection, vomiting Warnings: Anaphylaxis, immune-mediated reactions, infusion-related reaction	None indicated	May be harmful to fetus; avoid using in breastfeeding patients
Nivolumab and relatlimab-rmbw	Diarrhea, fatigue, musculoskeletal pain, pruritus, rash, cytopenia, increased liver enzyme levels, hyponatremia Warnings: Severe infusion-related reactions, complications when undergoing allogeneic HSCT, severe or fatal immune-mediated reactions	None indicated	May be harmful to fetus; avoid using in breastfeeding patients
Pembrolizumab	Abdominal pain, alopecia, arthralgia, cough, decreased appetite, fatigue, headache, insomnia, myalgia, peripheral neuropathy, pyrexia, skin rash, stomatitis  Warnings: Severe immune-related reactions, infusion reactions	None indicated	May be harmful to fetus; avoid using in breastfeeding patients
Talimogene laherparepvec	Chills, fatigue, flu-like symptoms, injection site reactions, nausea, pyrexia, vomiting Warnings: Severe injection site reactions, herpetic infection	Acyclovir or other antiviral drugs used to treat herpesvirus infections	No formal studies indicate any risk to embryo-fetal development, but pregnant women should be counseled on the potential hazards
Tebentafusp	Abdominal pain, chills, dry skin, edema, fatigue, headache, hypotension, nausea, pruritus, pyrexia, vomiting Warnings: Elevated liver enzymes, cytokine release syndrome, skin reactions	None indicated	May be harmful to fetus; avoid using in breastfeeding patients

CNS = central nervous system; HSCT = hematopoietic stem cell transplantation; IgA = immunoglobulin A.

From FDA-approved prescribing information.^{21,23-25,51-54}

The most commonly reported side effects of targeted therapies (particularly BRAF therapies) are pyrexia and flu-like symptoms. Patients may be treated with antipyretics (eg, acetaminophen and nonsteroidal anti-inflammatory drugs [NSAIDs]). These symptoms tend to resolve within 2 to 4 weeks of initiating treatment. In some cases, patients may also develop dermatologic complications; referral to a dermatologist for further monitoring and treatment may be necessary.⁵ 

Table 7. Side Effect Profiles for Targeted Therapies for Melanoma

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Binimetinib	Abdominal pain, nausea, vomiting, diarrhea, fatigue Warnings: Cardiomyopathy, ocular toxicity, venous thromboembolism, hepatotoxicity, hemorrhage, rhabdomyolysis	None indicated	May be harmful to fetus; avoid using in breastfeeding patients; reduce dose in patients with moderate or severe hepatic impairment
Cobimetinib	Nausea, vomiting, diarrhea, stomatitis, pyrexia, chills, eye disorders, acneiform dermatitis, photosensitivity Warnings: New primary malignancies, cardiomyopathy, severe skin reactions and photosensitivity, hemorrhage, hepatotoxicity, ocular toxicity, rhabdomyolysis	Moderate or strong CYP3A inhibitors and inducers (carbamazepine, phenytoin, rifampin, and efavirenz)	May be harmful to fetus; avoid using in breastfeeding patients
Dabrafenib	Headache, pyrexia, alopecia, PPE, papilloma, arthralgia, hyperkeratosis  Warnings: New primary malignancies, cardiomyopathy, hyperglycemia, uveitis, hemorrhage, serious febrile reactions and skin toxicities, G6PD deficiency	Strong CYP2C8 and CYP3A4 inhibitors, warfarin, hormonal contraceptives, dexamethasone	May be harmful to fetus; avoid using in breastfeeding patients; closely monitor patients with moderate or severe hepatic impairment
Encorafenib	Abdominal pain, constipation, vomiting, nausea, pyrexia, fatigue, headache, myopathy, arthralgia, dry skin and rashes, alopecia, pruritus, peripheral neuropathy, hemorrhage, dizziness Warnings: Prolonged QT interval, new primary malignancies, uveitis, hemorrhage	Drugs that prolong the QT interval; moderate or strong CYP3A4 inhibitors or inducers; sensitive CYP3A4 substrates; BCRP, OATP1B1, or OATP1B3 substrates	May be harmful to fetus; avoid using in breastfeeding patients
Entrectinib	Arthralgia, cognitive impairment, constipation, cough, diarrhea, dizziness, dysgeusia, dyspnea, edema, fatigue, nausea, pyrexia, weight loss Warnings: Hyperuricemia, prolonged QT interval, CNS effects, hepatotoxicity, bone fractures, CHF, vision problems	Drugs that prolong the QT interval, moderate or strong CYP3A inhibitors or inducers	May be harmful to fetus; avoid using in breastfeeding patients
Imatinib	Abdominal pain, vomiting, dyspepsia, diarrhea, skin rash, fatigue, nausea, muscle cramps and musculoskeletal pain, fluid retention, cough, upper respiratory tract infection, pyrexia, dizziness, insomnia, bone pain, depression, weight gain Warnings: Hematologic, dermatologic, hypereosinophilic cardiac, and hepatic toxicities; hypothyroidism; TLS; gastrointestinal disorders; hemorrhage; CHF and left ventricular disease; fluid retention and edema	Strong CYP3A4 inhibitors and inducers, dihydropyridine calcium channel blockers, triazolobenzodiazepines, warfarin, HMG-CoA reductase inhibitors	May be harmful to fetus; avoid using in breastfeeding patients; reduce dose by 25% in patients with severe hepatic impairment; reduce dose in patients with moderate or severe renal impairment
Larotrectinib	Constipation, cytopenia, diarrhea, dizziness, elevated liver enzymes, fatigue, musculoskeletal pain, nausea, pyrexia, vomiting Warnings: CNS effects, hepatotoxicity, skeletal fractures	Sensitive CYP3A4 substrates, moderate or strong CYP3A4 inhibitors and inducers	May be harmful to fetus; avoid using in breastfeeding patients
Lenvatinib	Fatigue, diarrhea, hypertension, decreased appetite, arthralgia, headache, stomatitis, nausea, weight loss, abdominal pain, dysphonia, PPES, proteinuria Warnings: Renal failure, hypertension, arterial thromboembolic events, proteinuria, prolonged QT interval, hypocalcemia, impaired wound healing, ONJ, gastrointestinal perforation, fistula formation, thyroid dysfunction, proteinuria, hepatotoxicity	Drugs that prolong the QT interval	May be harmful to fetus; avoid using in breastfeeding patients; reduce dose in patients with severe renal impairment or severe hepatic impairment
Trametinib	Pyrexia, peripheral edema, chills, nausea, abdominal pain, vomiting, diarrhea, hypertension, rash, hemorrhage, dizziness Warnings: Hyperglycemia, ILD, serious febrile reactions, new primary malignancies, hemorrhage, cardiomyopathy, gastrointestinal perforation, colitis, ocular toxicities, venous thromboembolism, serious skin toxicities	Trametinib is approved in combination with dabrafenib; see drug interactions with dabrafenib	May be harmful to fetus; avoid using in breastfeeding patients
Vemurafenib	Alopecia, dry skin, rash, photosensitivity reaction, pruritus, hyperkeratosis, erythema, pyrexia, fatigue, peripheral edema, nausea, vomiting, constipation, diarrhea, dysgeusia, headache, benign or malignant cutaneous neoplasms, decreased appetite, cough Warnings: Hepatotoxicity, ophthalmologic reactions, renal failure, new primary malignancies, hypersensitivity reaction, prolonged QT interval, dermatologic reactions, photosensitivity, radiation sensitivity, plantar fascial fibromatosis, Dupuytren contracture	Strong CYP3A4 inhibitors and inducers, CYP1A2 substrates (tizanidine), concurrent ipilimumab may raise liver enzymes, P-gp substrates (digoxin)	May be harmful to fetus; avoid using in breastfeeding patients

BCRP = breast cancer resistance protein; CHF = congestive heart failure; CNS = central nervous system; G6PD = glucose-6-phosphate dehydrogenase; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; ILD = interstitial lung disease; ONJ = osteonecrosis of the jaw; P-gp = P-glycoprotein; PPE = palmar-plantar erythrodysesthesia; TLS = tumor lysis syndrome.

From FDA-approved prescribing information.^{27-29,31,32,55-59}

References

1. Melanoma Treatment (PDQ^®)–Health Professional Version. National Cancer Institute. Updated January 31, 2023. Accessed May 31, 2023. https://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq 
2. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: melanoma of the skin. National Cancer Institute. Accessed May 31, 2023. https://seer.cancer.gov/statfacts/html/melan.html 
3. Balch CM, Gershenwald JE, Soong S-J, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-6206. doi:10.1200/JCO.2009.23.4799
4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29. doi:10.3322/caac.21254
5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Melanoma: Cutaneous. National Comprehensive Cancer Network. Updated March 10, 2023. Accessed May 31, 2023. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf 
6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Melanoma: Uveal. National Comprehensive Cancer Network. Updated May 4, 2023. Accessed May 31, 2023. https://www.nccn.org/professionals/physician_gls/pdf/uveal.pdf 
7. Chambers M, Swetter SM, Baker C, Saunders E, Chapman MS. Topical imiquimod for lentigo maligna: survival analysis of 103 cases with 17 years follow-up. J Drugs Dermatol. 2021;20(3):346-348. doi:10.36849/JDD.2021.5660
8. Kobeissi I, Tarhini AA. Systemic adjuvant therapy for high-risk cutaneous melanoma. Ther Adv Med Oncol. Published online October 28, 2022. doi:10.1177%2F17588359221134087
9. Rausch MP, Hastings KT. Chapter 9: Immune checkpoint inhibitors in the treatment of melanoma: from basic science to clinical application. In: Ward WH, Farma JM, eds. Cutaneous Melanoma: Etiology and Therapy [Internet]. Codon Publications; 2017. 
10. Weber J, Mandala M, Del Vecchio M, et al; the CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824-1835. doi:10.1056/NEJMoa1709030
11. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789-1801. doi:10.1056/NEJMoa1802357
12. Tarhini AA, Lee SJ, Hodi FS, et al. A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): preliminary safety and efficacy of the ipilimumab arms [ASCO abstract 9500]. J Clin Oncol. 2017;35(suppl):15. doi:10.1200/JCO.2017.35.15_suppl.9500
13. Ascierto PA, Kirkwood JM, Grob J-J, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85. doi:10.1186/1479-5876-10-85
14. Dummer R, Hauschild A, Santinami M, et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma. N Engl J Med. 2020;383:1139-1148. doi:10.1056/NEJMoa2005493
15. In-transit metastasis. National Cancer Institute. Accessed June 7, 2023. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/in-transit-metastasis
16. Ferrucci PF, Pala L, Conforti F, Cocorocchio E. Talimogene laherparepvec (T-VEC): an intralesional cancer immunotherapy for advanced melanoma. Cancers (Basel). 2021;13(6):1383. doi:10.3390/cancers13061383
17. Andtbacka RHI, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780-2788. doi:10.1200/JCO.2014.58.3377
18. Amaria RN, Reuben A, Cooper ZA, Wargo JA. Update on use of aldesleukin for treatment of high-risk metastatic melanoma. Immunotargets Ther. 2015;4:79-89. doi:10.2147/ITT.S61590
19. Weide B, Derhovanessian E, Pflugfelder A, et al. High response rate after intratumoral treatment with interleukin-2: results from a phase 2 study in 51 patients with metastasized melanoma. Cancer. 2010;116(17):4139-4146. doi:10.1002/cncr.25156
20. Johansson J, Kiffin R, Andersson A, et al. Isolated limb perfusion with melphalan triggers immune activation in melanoma patients. Front Oncol. 2018;8:570. doi:10.3389/fonc.2018.00570
21. Yervoy. Drug Label Information. DailyMed. Updated February 15, 2023. Accessed June 7, 2023. 
22. Chesney J, Puzanov I, Collichio F, et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol. 2018;36(17):1658-1667. doi:10.1200/JCO.2017.73.7379
23. Opdivo. Drug Label Information. DailyMed. Updated February 15, 2023. Accessed June 7, 2023. 
24. Opdualag. Drug Label Information. DailyMed. Updated March 18, 2022. Accessed June 7, 2023. 
25. Keytruda. Drug Label Information. DailyMed. Updated April 3, 2023. Accessed June 7, 2023. 
26. Carlino MS, Menzies AM, Atkinson V, et al. Long-term follow-up of standard-dose pembrolizumab plus reduced-dose ipilimumab in patients with advanced melanoma: KEYNOTE-029 part 1B. Clin Cancer Res. 2020;26(19):5086-5091. doi:10.1158/1078-0432.CCR-20-0177
27. Mektovi. Drug Label Information. DailyMed. Updated June 10, 2022. Accessed June 7, 2023. 
28. Tafinlar. Drug Label Information. DailyMed. Updated May 26, 2023. Accessed June 7, 2023. 
29. Rozlytrek. Drug Label Information. DailyMed. Updated June 8, 2020. Accessed June 7, 2023. 
30. Wei X, Mao L, Chi Z, et al. Efficacy evaluation of imatinib for the treatment of melanoma: evidence from a retrospective study. Oncol Res. 2019;27(4):495-501. doi:10.3727%2F096504018X15331163433914
31. Vitrakvi. Drug Label Information. DailyMed. Updated December 6, 2022. Accessed June 7, 2023. 
32. Zelboraf. Drug Label Information. DailyMed. Updated April 5, 2023. Accessed June 7, 2023. 
33. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30-39. doi:10.1056/NEJMoa1412690
34. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603-615. doi:10.1016/S1470-2045(18)30142-6
35. Arance A, de la Cruz-Merino L, Petrella TM, et al. Phase II LEAP-004 study of lenvatinib plus pembrolizumab for melanoma with confirmed progression on a programmed cell death protein-1 or programmed death ligand 1 inhibitor given as monotherapy or in combination. J Clin Oncol. 2023;41(1):75-85. doi:10.1200/JCO.22.00221
36. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867-1876. doi:10.1056/NEJMoa1408868
37. Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF^V600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;395(10240):1835-1844. doi:10.1016/S0140-6736(20)30934-X 
38. Bajetta E, Del Vecchio M, Nova P, et al. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann Oncol. 2006;17(4):571-577. doi:10.1093/annonc/mdl007
39. Einzig AI, Höchster H, Wiernik PH, et al. A phase II study of taxol in patients with malignant melanoma. Invest New Drugs. 1991;9(1):59-64. doi:10.1007/BF00194546
40. Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006;106(2):375-382. doi:10.1002/cncr.21611
41. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18(1):158-166. doi:10.1200/JCO.2000.18.1.158
42. Krantz BA, Dave N, Komatsubara KM, Marr BP, Carvajal RD. Uveal melanoma: epidemiology, etiology, and treatment of primary disease. Clin Ophthalmol. 2017;11:279-289. doi:10.2147/OPTH.S89591
43. Nathan P, Hassel JC, Rutkowski P, et al; IMCgp100-202 Investigators. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385:1196-1206. doi:10.1056/NEJMoa2103485
44. Carboplatin. Drug Label Information.  DailyMed. Updated July 7, 2021. Accessed June 7, 2023. 
45. Cisplatin. Drug Label Information. DailyMed. Updated December 31, 2019. Accessed June 7, 2023. 
46. Dacarbazine. Drug Label Information. DailyMed. Updated February 29, 2020. Accessed June 7, 2023. 
47. Alkeran. Drug Label Information. DailyMed. Updated December 5, 2022. Accessed June 7, 2023. 
48. Paclitaxel. Drug Label Information. DailyMed. Updated October 27, 2022. Accessed June 7, 2023. 
49. Temozolomide. Drug Label Information. DailyMed. Updated January 1, 2022. Accessed June 7, 2023. 
50. Vinblastine Sulfate. Drug Label Information. DailyMed. Updated December 31, 2019. Accessed June 7, 2023. 
51. Tecentriq. Drug Label Information. DailyMed. Updated May 19, 2023. Accessed June 7, 2023. 
52. Proleukin. Drug Label Information. DailyMed. Updated May 23, 2019. Accessed June 7, 2023. 
53. Imlygic. Drug Label Information. DailyMed. Updated February 15, 2023. Accessed June 7, 2023. 
54. Kimmtrak. Drug Label Information. DailyMed. Updated November 30, 2022. Accessed June 7, 2023. 
55. Cotellic. Drug Label Information. DailyMed. Updated October 1, 2022. Accessed June 7, 2023. 
56. Braftovi. Drug Label Information. DailyMed. Updated June 10, 2022. Accessed June 7, 2023. 
57. Gleevec. Drug Label Information. DailyMed. Updated August 19, 2022. Accessed June 7, 2023. 
58. Lenvima. Drug Label Information. DailyMed. Updated November 1, 2022. Accessed June 7, 2023. 
59. Mekinist. Drug Label Information. DailyMed. Updated May 26, 2023. Accessed June 7, 2023. 

Author Bio

Emily Wagner, MS, earned a Bachelor of Science degree in biotechnology from the Rochester Institute of Technology in 2018 and a Master of Science degree in biomedical sciences with a focus in pharmacology from the University of Colorado Anschutz Medical Campus in 2020. During her thesis work, she studied non-small cell lung cancer and how the immune system plays a role in response to different treatments. Emily currently lives in Colorado where she enjoys the mountains, spending time with her dog, baking, and reading a good book.