Metastatic Cutaneous Melanoma: Navigating the Evolving Treatment Landscape

Cutaneous melanoma is the fifth most frequently diagnosed cancer in men and women in the United States.^1,2 In 2023, it is estimated that 97,610 individuals will be diagnosed with melanoma, which is 5% of all new cases of cancer, and it is estimated that 7990 individuals will die from melanoma, which is 1.3% of cancer-related deaths.² The 5-year relative survival rate for melanoma is 93.5%, with the age-adjusted death rate decreasing on average 3.3% annually from 2011 to 2020.² However, the 5-year relative survival rate for patients diagnosed with metastatic disease is only 35.1%, highlighting a major practice gap that requires attention.²

Melanoma is characterized as localized (stage I-II), regional (stage III), or distant metastatic disease (stage IV).^3,4 Patient-specific factors, such as age and sex, and tumor-specific factors, such as Breslow tumor thickness, ulceration, and mitotic rate, are predictive of disease outcomes.^3-10 Treatment recommendations from the National Comprehensive Cancer Network (NCCN) guidelines for melanoma are grouped based on early-stage disease and advanced or metastatic disease.³ The treatment for early-stage disease typically involves surgery, radiation, and adjuvant immunotherapy or targeted therapy, whereas advanced or metastatic disease is solely treated with immunotherapy or targeted therapy.³

Historic Treatment Options for Metastatic Cutaneous Melanoma

Historically, cytotoxic agents for the treatment of metastatic melanoma included albumin-bound paclitaxel, carboplatin with paclitaxel, dacarbazine, or temozolomide.^11-15 The cytotoxic regimens have shown response rates of 13% to 26%. In addition, these regimens resulted in grade 3 and 4 adverse events.^11-14 High-dose interleukin-2 showed a modest overall response, 13% to 20%, but patients who had a complete response, 4% to 10%, were more likely to have more durable responses and longer OS.^16-19 Because of the significant risk for adverse events and the complexity of managing these patients, interleukin-2 should only be used in select patients.^16-19

Over the past decade, anti-PD1/cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) immune therapies and BRAF/MEK-targeted therapies have demonstrated improved survival and tolerability, which has altered the landscape of first-line therapies in metastatic cutaneous melanoma.

Review of Current Agents and Guideline Recommendations
MEK Pathway and Overcoming Resistance

In nearly 50% of patients with metastatic melanoma, tumors express BRAF V600 mutation.³ The BRIM-3 and BREAK-3 trials reported improvements in overall survival (OS) and more tolerable adverse events with the single-agent BRAF inhibitors vemurafenib and dabrafenib compared with traditional dacarbazine.^20-23 The primary end points of the BRIM-3 trial were OS and progression-free survival (PFS); when analyzed at 4 years, vemurafenib demonstrated benefit over dacarbazine in OS (17% vs 15.6%, respectively; P<.001) and PFS (5.3 months in the vemurafenib group vs 1.6 months in the dacarbazine group; P<.001).²⁴ The primary end point of the BREAK-3 trial was 5-year PFS for dabrafenib over dacarbazine (12% for dabrafenib vs the patients who received dacarbazine, all of whom had disease progression or were censored by 5 years; P<.001). A secondary end point of the BREAK-3 trial was the 5-year OS for dabrafenib versus dacarbazine (24% vs 22%, respectively; P<.001).²² The long term OS outcomes for the BRAF inhibitors in these trials were limited by the extent of crossover and subsequent treatment in certain patient populations.^20-22

However, monotherapy with BRAF inhibition provides a robust initial response of more than 50% that stops at approximately 6 months when disease progression occurs.²⁵ Trials that include BRAF inhibitors and MEK inhibitors were initiated with the intention of overcoming BRAF resistance, which typically results from mitogen-activated protein kinase downstream upregulation of MEK.^26-30 The pharmacologic activity of MEK inhibitors involves the complete inhibition of the mitogen-activated protein kinase pathway to induce cell death.²⁵ Overcoming the rapid recovery of the mitogen-activated protein kinase pathway leads to more durable responses with MEK inhibitors added to BRAF inhibitors.²⁵ Two large phase 3 trials combining dabrafenib with the MEK inhibitor trametinib (COMBI-v and COMBI-d), showed improved OS benefit and PFS compared with BRAF inhibitor monotherapy.^23,26 Pooled survival data from both trials showed a PFS rate at 5 years of 19% (95% confidence interval [CI], 15-22), and an OS rate at 5 years of 34% (95% CI, 30-38).²⁶

The coBRIM trial extended the 5-year PFS with cobimetinib plus vemurafenib versus vemurafenib plus placebo (14% vs 10%, respectively; P=.001).^27,28 The COLUMBUS trial compared treatment with encorafenib plus binimetinib versus monotherapy with vemurafenib or encorafenib.²⁹ The combination of encorafenib plus binimetinib demonstrated long-term benefit in the 5-year PFS rate versus monotherapy with encorafenib or vemurafenib (22.9% vs 19.3% and 10.2%, respectively).²⁹

Overall, the use of BRAF inhibitors plus MEK inhibitors increases survival benefit compared with BRAF inhibitor monotherapy.²⁵ Considering other disadvantages in BRAF inhibitor monotherapy, MEK inhibitors can offer additional benefit in moderately decreasing the incidence of cutaneous adverse events. In a study of dabrafenib plus trametinib versus dabrafenib monotherapy, the combination treatment reduced cutaneous adverse events (7% vs 19%, respectively; P=.09); however pyrexia was more common in the combination group than in the monotherapy cohort (71% vs 26%, respectively).²⁵ Guidelines for the treatment of metastatic melanoma recommend the use of combination BRAF V600 and MEK therapies of dabrafenib plus trametinib, vemurafenib plus cobimetinib, or encorafenib plus binimetinib.³

Differences Between BRAF/MEK Combinations

The BRAF/MEK inhibitor combination therapies differ in adverse events and dose scheduling (Supplementary Table, available at Here). Some common adverse events include pyrexia associated with dabrafenib and photosensitivity and gastrointestinal adverse events (nausea and vomiting, and diarrhea) associated with vemurafenib.³⁰ Vemurafenib is associated with increased pill burden as a result of its dose of 960 mg (four 240-mg tablets) orally twice daily. Dabrafenib, vemurafenib, and cobimetinib are metabolized by the hepatic cytochrome P450 (CYP) system. Dabrafenib has an interaction with hormonal contraceptives and proton pump inhibitors, decreasing their concentrations through CYP3A4 induction.³¹ For MEK inhibitors, trametinib tablets must be refrigerated before use and must be stored in the original bottle.³² These medications and drug combinations are received on a continuous daily basis, and adherence should always be a consideration.

Pembrolizumab

Immune checkpoint inhibitors further improve melanoma pharmacotherapy regimens with benefit in objective response. Pembrolizumab is a highly selective and humanized monoclonal immunoglobin G4 antibody that binds to the PD-1 receptor on T cells to block PD-1 ligands (PD-L1 and PD-L2) from binding.³³ This process inhibits the negative immune regulation caused by PD-1 receptor signaling, leading to increased T-cell recognition and response.³³ In the KEYNOTE-001 trial, treatment with pembrolizumab in patients with advanced or metastatic melanoma resulted in a median OS of 23.8 months (95% CI, 20.2-30.4), with estimated 5-year OS rates of 34% in all patients and 41% in treatment-naïve patients.^34,35 A total of 86% of patients had treatment-related adverse events.³⁴ The most common adverse events were hypothyroidism, pneumonitis, and colitis, and 17% of patients had grade 3 or 4 adverse events.³⁴ Pembrolizumab offers a durable response for patients with advanced melanoma.

Ipilimumab

Ipilimumab is a fully human immunoglobulin G1 monoclonal antibody that acts as a CTLA-4 checkpoint inhibitor, strengthening the function and response of T cells.³⁶ In a pooled analysis of long-term survival data from clinical trials, the median OS in patients with metastatic or unresectable melanoma receiving ipilimumab was 11.4 months (95% CI, 10.7-12.1) with a 3-year survival rate of 22% (95% CI, 20-24).³⁶ The survival benefit was maintained for patients; the survival curve plateaued at approximately 3 years and remained at 20% to 26% for the duration of the follow-up. The limitations of these studies include a lack of a control group and variances in follow-up time.³⁶

In the KEYNOTE-006 trial, pembrolizumab and ipilimumab regimens were examined in patients with advanced melanoma, with the primary end points of PFS and OS.³⁷ The median estimates for PFS were 5.5 months with pembrolizumab every 2 weeks (95% CI, 3.4-6.9), 4.1 months with pembrolizumab every 3 weeks (95% CI, 2.9-6.9), and 2.8 months with ipilimumab (95% CI, 2.8-2.9). The OS for the pembrolizumab groups was superior at the prespecified one-sided alpha of 0.005, and the study ended early to allow patients in the ipilimumab group to receive pembrolizumab. Grades 3 to 5 adverse events were observed in 13.3% of the group receiving pembrolizumab every 2 weeks, 10.1% of the group receiving pembrolizumab every 3 weeks, and 19.9% of the patients receiving ipilimumab. Overall, treatment with pembrolizumab demonstrated less high-grade adverse events and prolonged PFS and OS than treatment with ipilimumab.³⁷ The use of ipilimumab as monotherapy is limited, but it may still be appropriate for some patients with advanced melanoma if they have previously received anti–PD-1 therapy.³

Pembrolizumab Plus Ipilimumab

In a prospective clinical trial, patients with melanoma whose disease progression after treatment with anti–PD-1 therapy received pembrolizumab plus 1 mg/kg of ipilimumab.³⁸ The primary end point of this study was response rate. The median length of the previous anti–PD-1 therapy was 4.8 months, and there was no association between the length of the previous anti–PD-1 therapy and response. Overall, 29% of the enrolled patients achieved a complete response (95% CI, 18.4-40.6). The median PFS was 5 months (95% CI, 2.8-8.3) and the median OS was 24.7 months (95% CI, 15.2-not reached). This study’s results showed that pembrolizumab plus ipilimumab was more likely to be effective than ipilimumab alone in this patient population.³⁸

Nivolumab With or Without Ipilimumab

Similar to pembrolizumab, nivolumab is a human immunoglobin G4 monoclonal antibody that acts through binding to the PD-1 receptor and blocking the interaction with PD-L1 and PD-L2, leading to increased antitumor immune response.³⁹ In the CheckMate 067 trial, ipilimumab monotherapy was compared with nivolumab monotherapy or nivolumab plus ipilimumab. The PFS rate at 3 years was highest in the nivolumab plus ipilimumab group versus nivolumab or ipilimumab alone (39% vs 32% and 10%, respectively).³⁹ The OS at 5 years was highest in the combination group versus nivolumab or ipilimumab alone (52% vs 44% and 26%, respectively).⁴⁰ The most frequent adverse events in the nivolumab plus ipilimumab group were diarrhea, rash, and fatigue.³⁹ Treatment-related grade 3 or 4 adverse events were significantly higher in the ipilimumab plus nivolumab arm than in the nivolumab or ipilimumab monotherapy groups (59% vs 21% and 28%, respectively).³⁸ Patients had longer OS in the nivolumab plus ipilimumab cohort than in the ipilimumab monotherapy group, which supports the use of the combination treatment in patients with advanced melanoma.^39,40

Nivolumab With or Without Relatlimab

The dual immunotherapy of nivolumab plus relatlimab was approved for the treatment of unresectable or advanced melanoma in 2022.⁴¹ Relatlimab is a novel human immunoglobin G4 blocking antibody that binds to the lymphocyte activation gene-3 (LAG-3) immune checkpoint inhibitor leading to blocked interaction between LAG-3 and its ligands (including MHC II) to reduce LAG-3 pathway immune response inhibition thus improving the effector function of T cells.⁴¹ The RELATIVITY-047 trial evaluated the use of the fixed-dose combination of nivolumab plus relatlimab versus nivolumab alone in patients with treatment-naïve metastatic or unresectable melanoma.⁴² In adults, the dosing for relatlimab was 160 mg plus nivolumab 480 mg. The trial enrolled patients who previously received adjuvant BRAF/MEK inhibition. The combination therapy doubled the median PFS versus nivolumab monotherapy (10.1 months vs 4.6 months, respectively; P=.0055).^41,42 At 12 months, the PFS was 47.7% with nivolumab plus relatlimab (95% CI, 41.8-53.2) and 36% for nivolumab monotherapy (95% CI, 30.5-41.6).⁴² The overall response rate (ORR) was 43% for nivolumab plus relatlimab and 33% for nivolumab monotherapy.⁴¹ In both treatment groups, patients with LAG-3 expression of ≥1% had longer PFS survival estimates.⁴² The median PFS was similar between the 2 groups when PD-L1 expression was ≥1%. The median PFS in the relatlimab plus nivolumab group was 15.7 months (95% CI, 10.1-25.8) and 14.7 months in the nivolumab group (95% CI, 5.1-not reached) The expression of LAG-3 and PD-L1 status were not associated with direct PFS benefit.⁴²

Future evaluation and clinical trials will be needed to further explore biomarker utility for LAG-3. Although the adverse-effect profiles were similar for both arms, 18.9% of patients in the nivolumab plus relatlimab arm versus 9.7% in the nivolumab arm had grades 3 and 4 adverse events.^41,42 Guidelines from the NCCN have listed nivolumab plus relatlimab as a category 1 preferred regimen for the treatment of front-line metastatic melanoma, adding another strong immunotherapy option for patients with an improved safety profile compared with anti–PD-1 and CTLA-4 immunotherapy combination therapy (nivolumab plus ipilimumab).³ Providers should still be aware of potential serious immune-mediated reactions and infusion-related reactions with nivolumab plus relatlimab.^41,42

Guideline Recommendations for Metastatic or Unresectable Melanoma

In patients with metastatic or unresectable melanoma, the first-line therapies include anti–PD-1 monotherapy or combination therapy or combination targeted BRAF V600 therapy for patients with BRAF mutations (category 1 recommendation).^3-5 The anti–PD-1 monotherapy options include pembrolizumab or nivolumab. The anti–PD-1 combination therapies include nivolumab plus ipilimumab or nivolumab plus relatlimab-rmbw. The BRAF/MEK therapy options include dabrafenib plus trametinib, vemurafenib plus cobimetinib, or encorafenib plus binimetinib. In addition, vemurafenib plus cobimetinib and atezolizumab (category 2A recommendation) and pembrolizumab with low-dose ipilimumab (category 2B recommendation) can be use in the first-line setting for metastatic melanoma. When melanoma progresses or maximum clinical benefit is observed, other treatment options that were not previously attempted should be explored.^3-5

Sequencing Considerations for BRAF-Positive Metastatic or Unresectable Melanoma

For patients with BRAF-positive metastatic or unresectable melanoma, front-line treatment selection between targeted therapy (BRAF/MEK inhibitors) and immunotherapy can be a challenge and is individualized based on patients’ goals and the therapy’s adverse-event profile.³ Clinical trials are currently ongoing to address the sequencing considerations between targeted therapy and checkpoint inhibitors.^43,44

The phase 3 DREAMseq clinical trial evaluated the efficacy and safety of immunotherapy with nivolumab plus ipilimumab followed by combination targeted therapy with dabrafenib plus trametinib after disease progression compared with the reverse sequence in treatment-naïve patients who had BRAF V600 mutation–positive advanced melanoma.⁴³ Patients with active brain metastasis were excluded from the study. The trial was stopped early because of a significant 20% survival benefit with immunotherapy combination in the front-line setting at 2 years (72% vs 52%, respectively; P=.0095). The median PFS between the 2 arms also favored front-line immunotherapy; in the front-line nivolumab plus ipilimumab arm, the PFS was 11.8 months versus 8.5 months in the front-line dabrafenib plus trametinib arm (P=.054). There was an improved duration of response with front-line nivolumab plus ipilimumab compared with front-line dabrafenib plus trametinib (median duration of response, not reached vs 12.7 months, respectively; P<.001). The second-line response rates were substantially lower with the immunotherapy combination of nivolumab plus ipilimumab than dabrafenib plus trametinib (30% vs 46%, respectively), whereas the response rates for targeted therapy with dabrafenib plus trametinib were similar between the lines of therapy (43% for front-line therapy vs 48% for second-line therapy), highlighting the benefit of front-line immunotherapy.⁴³

The phase 2 SECOMBIT clinical trial was a similarly designed study that evaluated the impact of sequencing on OS of patients who received immunotherapy with ipilimumab plus nivolumab compared with the BRAF V600/MEK inhibitor combination of encorafenib plus binimetinib.⁴⁴ This trial also included a third treatment arm as a “sandwich” approach, in which patients initiated treatment with encorafenib plus binimetinib for 8 weeks followed by ipilimumab plus nivolumab and on disease progression, patients would reinitiate therapy with encorafenib plus binimetinib. Data continue to be collected for this trial, but survival outcomes are trending towards favorability with upfront treatment with ipilimumab plus nivolumab. The 3-year OS rates were 62% with ipilimumab plus nivolumab and 54% for encorafenib plus binimetinib. The sandwich approach also had strong survival results, with a 60% OS rate at 3 years.⁴⁴

A third sequencing clinical trial, the phase 2 EBIN study, is evaluating nivolumab plus ipilimumab followed by encorafenib plus binimetinib versus the reverse sequence.⁴⁵ Treatment sequencing considerations still do not address if these data can be applied to single-agent immunotherapy, which will likely impact many clinical decisions for patients who may not be suitable for combination immunotherapy because of increased adverse events.

Other sequencing considerations in this patient population include the impact of triplet therapy in the front-line setting and determining if adding immunotherapy to targeted BRAF V600/MEK inhibitors provides more long-lasting responses. Tumor microenvironment data have implicated that immunotherapy and BRAF V600/MEK inhibitor triplet combination therapy increases antigen presentation, T-cell infiltration, and T-cell activation leading to suppression of tumor growth and improved tumor immunogenicity.^46-48 The phase 3 IMspire150 trial evaluated the safety and efficacy of first-line treatment with the triplet combination of atezolizumab plus vemurafenib and cobimetinib in patients with unresectable, metastatic BRAF V600 mutation–positive melanoma.⁴⁹ Patients started treatment with vemurafenib plus cobimetinib with cycle 1 and then atezolizumab was added in cycle 2 in the experimental arm. The results of the IMspire150 trial showed significant improvement in median PFS with the triplet therapy versus with vemurafenib plus cobimetinib alone (15.1 months vs 10.6 months, respectively; hazard ratio [HR], 0.78; P=.025). The safety results from the IMspire150 trial showed a similar incidence of overall adverse events (99% in each group) as well as similar grades 3 and 4 adverse events between groups (79% in the atezolizumab group vs 73% in the control group).⁴⁹

The phase 2 KEYNOTE-022 trial evaluated pembrolizumab as first-line immunotherapy in combination with dabrafenib and trametinib versus dabrafenib plus trametinib alone in patients with metastatic BRAF V600 mutation–positive melanoma.⁵⁰ The duration of response was significantly prolonged in the pembrolizumab triplet group versus with dabrafenib plus trametinib (25.1 months vs 12.1 months, respectively; HR, 0.32). The OS trended towards benefit with the triplet arm, but was not statistically significant at 24 months (63% for the triplet group vs 52% for the doublet group; HR, 0.64; 95% CI, 0.38-1.06). In contrast to the IMspire150 trial,⁴⁹ the results of the KEYNOTE-022 trial showed higher grade 3 to 5 adverse events with the pembrolizumab triplet than with the doublet (58.3% vs 25%, respectively), as well as more patients in the triplet group discontinuing therapy as a result of adverse events (47% in the triplet group vs 20% in the doublet group).⁵⁰

Part 3 of the phase 3 COMBI-i trial evaluated the immunotherapy agent spartalizumab in combination with dabrafenib and trametinib as a triplet combination treatment versus dabrafenib plus trametinib alone in treatment-naïve patients with metastatic melanoma.⁵¹ Unfortunately, the PFS was not significant (16.2 months vs 12 months, respectively) and the ORRs were similar between the groups (69% vs 64%, respectively). The adverse events were significantly higher in the triplet arm, with 55% of patients having grade 3 to 5 adverse events after receiving spartalizumab plus dabrafenib and trametinib versus 33% of the patients who received dabrafenib plus trametinib; therapy discontinuation as a result of adverse events was higher with spartalizumab (32% vs 14%, respectively).

A meta-analysis evaluated 5 randomized controlled trials and more than 1200 patients who received front-line triplet therapy.⁴⁸ Based on the analysis, triple combination therapy significantly improved PFS (HR, 0.71; P=.0005) and the 2-year OS based on risk ratio (RR, 1.12; P=.01); however, triplet therapy did not have an impact on ORR (RR, 1.09; P=.37). Adverse events were a concern with the triplet arm based on the meta-analysis and included an increased risk for hypothyroidism, arthralgias/myalgias, hepatotoxicity, and pyrexia in the triplet group compared with the control group.⁴⁸

The sequencing data available are promising, and the durable responses and potential survival benefit of combination immunotherapy is intriguing. However, front-line BRAF V600/MEK inhibitor combination therapy may still have a place in therapy for specific patient populations. With the lack of consistent survival benefit across various triplet therapy clinical trials and the concern for increased adverse events, currently triplet combination therapy is not recommended outside of a clinical trial. More research related to triplet therapy’s efficacy benefits and safety risks is required, as well as further insight into the specific patient populations who may benefit in the front-line setting with triplet therapy compared with standard sequencing approaches.

Until more robust clinical data are available related to sequencing, treatment decisions should be individualized based on patient presentation, burden of disease, and the patient’s potential tolerance of the therapy.^43-45 Patients with BRAF mutation–positive metastatic melanoma who have rapidly progressing or symptomatic disease and are in need of a fast response may benefit from upfront targeted therapy or a potential sandwich approach, as in the EBIN trial.⁴⁵ Patients with good performance status and goals of extended response and survival, regardless of the adverse-event risk, would likely benefit most from front-line immunotherapy combination with nivolumab plus ipilimumab based on the results from the DREAMseq and SECOMBIT studies.^43,44 In patients with BRAF-positive metastatic melanoma for which immunotherapy combination is not appropriate (ie, significant comorbidities, performance status score of >2, autoimmune disease), a decision between targeted therapy and single-agent immunotherapy is required. Patients without strong support at home, those at risk for poor adherence, or other patient factors that would impact the benefit of targeted BRAF/MEK therapy (ie, cardiovascular disease, drug interactions; Supplementary Table) may benefit from receiving single-agent immunotherapy in the front-line setting. See the algorithm in the Supplementary Figure (available at Here) for front-line treatment considerations for metastatic melanoma.

Future Horizon for Treatment of Metastatic Melanoma

Although the current treatment landscape in metastatic melanoma has shifted greatly in the past decade, continued focus on clinical trials and dedication to patient care are required for patients with this malignancy. Questions still remain about the best treatment approach for BRAF-positive metastatic melanoma, whether upfront triplet therapy versus combination targeted therapy or immunotherapy in the front line or a potential sandwich approach.^45-51 How will long-term efficacy (OS) data on nivolumab plus relatlimab⁴¹ compare with data on ipilimumab plus nivolumab?^39,52,53 More robust data and long-term OS outcomes will help answer these concerns along with others, such as the optimal duration of therapy in those patients who achieve a complete response. Other areas of interest include identifying potential biomarkers (anti–CTLA-4 resistance–associated MAGE-A, CD8, human leukocyte antigen (HLA)-I diversity, HLA loss of heterozygosity, IFNGR1/2, lactate dehydrogenase, neutrophil-to-lymphocyte ratio, tumor burden) for selecting ideal patients or identifying the potential risk for resistance to combination immunotherapy to enhance our ability to optimize response and limit adverse events.^52,53

The use of clinical trials in patients with metastatic melanoma continues to be of most importance, and currently there are nearly 100 phase 3 and more than 800 ongoing phase 2 clinical trials that aim to address existing treatment gaps and overcome treatment resistance.⁵⁴ Immunotherapy combinations continue to be of strong interest, and multiple new immunotherapy combinations are being studied. Nivolumab is being studied in combination with HBI-8000, a class I selective oral histone deacetylase inhibitor with immunomodulatory effects, in the front-line metastatic melanoma setting.^55,56 Other anti–LAG-3/PD-1 combinations are also being evaluated in phase 3 clinical trials in metastatic melanoma with fianlimab plus cemiplimab versus pembrolizumab monotherapy.⁵⁷ Nivolumab subcutaneous injection, for improved patient convenience, is also being evaluated in patients with metastatic melanoma after complete resection.⁵⁸

The combination of pembrolizumab and lenvatinib is currently being evaluated in the phase 3 LEAP-003 clinical trial in the front-line setting.⁵⁹ Pembrolizumab is also being studied in combination with IO102-IO103, a first-in-class dual-antigen immunomodulatory agent that targets immune resistance pathways mediated by indoleamine 2,3-dehydrogenase and PD-L1, in patients with treatment-naïve advanced melanoma in the phase 3 IOB-012/KN-D18 trial.⁶⁰ The phase 2 MASTERKEY-115/KEYNOTE-A07 clinical trial is evaluating pembrolizumab in combination with talimogene laherparepvec in patients with metastatic or unresectable melanoma who had disease progression after receiving anti–PD-1 therapy.⁶¹ Tebentafusp, a bispecific glycoprotein 100–targeted monoclonal antibody consisting of an affinity-enhanced T-cell receptor attached to an anti-CD3 effector, was approved in 2022 for unresectable or metastatic uveal melanoma based on the OS improvements shown in a phase 3 clinical trial.⁶² Currently, multiple clinical trials are underway in metastatic cutaneous melanoma to evaluate treatment with tebentafusp as monotherapy or in combination with immunotherapy.^62-64

Pharmacists’ Role in an Evolving Treatment Landscape

As melanoma treatments continues to develop and evolve, pharmacists remain essential to the multidisciplinary healthcare team. The availability of various melanoma treatments brings to question the management and sequencing of regimens. Real-world patient demographics do not always align with the clinical trial population parameters. Other challenges arise with deciphering the clinical impact of and place in therapy for various regimens because head-to-head comparisons are typically not readily available, which adds to the complexities related to individualized treatment selection. Pharmacists are uniquely positioned to work with real-world evidence to design individual sequencing regimens, counsel patients, and monitor and manage immune-related adverse events (irAEs). Multiple publications have highlighted the benefits of pharmacist-led programs involving education, and the assessment of adverse events within a multidisciplinary team can lead to improved patient knowledge, early recognition of irAEs, and improved patient outcomes (ie, optimized treatment of irAEs, prevention of severe irAEs, reduction in immunotherapy discontinuation).^65-69 The education of the healthcare team on biomarkers and real-world clinical trial applications can also be part of pharmacists’ roles.

Patient education on adherence is vital in a treatment landscape that involves more complex oral therapies. Associated adverse events and the subsequent management of those events are services that pharmacists are uniquely positioned to provide with the goal of identifying adverse events early and initiating the appropriate interventions to maximize treatment outcomes. Optimization of the selection of medications by pharmacists can lead to significant overall cost-savings to the healthcare system. Pharmacists enhance medication utilization through follow-up, therapeutic interventions, and timing the appropriate discontinuation of therapy, and they must continue to be an integral part of the multidisciplinary team through expanded services and practice models to improve patients’ outcomes.^69,70

Conclusion

The growing body of evidence and rapid drug approvals in melanoma make for a complicated treatment selection process. Additional research is needed regarding real-world evidence and clinical trial application to community oncology practices to answer questions about the best sequencing approach and place in therapy for new combination treatment regimens. Pharmacists offer strong clinical and pharmacologic expertise in medication regimen management, including treatment individualization, patient selection, monitoring, counseling, financial support, and the management of adverse events, which can lead to better outcomes for patients with metastatic cutaneous melanoma.

Author Disclosure Statement
Dr Elder is on the Advisory Boards of Bristol Myers Squibb, Genentech, and Pfizer; Dr Simon and Dr Gyori have no conflict of interest to report.

References

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7-33.
2. National Cancer Institute SEER Program. Cancer stat facts: melanoma of the skin. Accessed July 8, 2022. www.seer.cancer.gov/statfacts/html/melan.html
3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Melanoma: Cutaneous. Version 3.2023. October 27, 2023. Accessed February 1, 2024. www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf
4. Keung EZ, Gershenwald JE. The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care. Expert Rev Anticancer Ther. 2018;18:775-784.
5. Balch CM, Gershenwald JE, Soong SJ, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28:2452-2459.
6. Thompson JF, Soong SJ, Balch CM, et al. Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol. 2011;29:2199-2205. Erratum in: J Clin Oncol. 2011;29:2949.
7. Balch CM, Soong SJ, Gershenwald JE, et al. Age as a prognostic factor in patients with localized melanoma and regional metastases. Ann Surg Oncol. 2013;20:3961-3968.
8. Maurichi A, Miceli R, Camerini T, et al. Prediction of survival in patients with thin melanoma: results fromsupa multi-institution study. J Clin Oncol. 2014;32:2479-2485.
9. Eriksson H, Frohm-Nilsson M, Järås J, et al. Prognostic factors in localized invasive primary cutaneous malignant melanoma: results of a large population-based study. Br J Dermatol. 2015;172:175-186.
10. in ‘t Hout FEM, Haydu LE, Murali R, et al. Prognostic importance of the extent of ulceration in patients with clinically localized cutaneous melanoma. Ann Surg. 2012;255:1165-1170.
11. Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. 2000;19:21-34.
12. 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;18:158-166. Erratum in: J Clin Oncol. 2000;18:2351.
13. Hersh EM, O’Day SJ, Ribas A, et al. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010;116:155-163.
14. Kottschade LA, Suman VJ, Amatruda T III, et al. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage iv melanoma: a north central cancer treatment group study, N057E(1). Cancer. 2011;117:1704-1710.
15. Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006;106:375-382.
16. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271:907-913.
17. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105-2116.
18. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(suppl 1):S11-S14.
19. Smith FO, Downey SG, Klapper JA, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14:5610-5618.
20. Chapman PB, Robert C, Larkin J, et al. Vemurafenib in patients with BRAFv600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann Oncol. 2017;28:2581-2587.
21. Gazzé G. Pharmacist’s role in optimizing therapy of the newer agents for the management of metastatic melanoma. Melanoma Manag. 2015;2:75-82.
22. Hauschild A, Ascierto PA, Schadendorf D, et al. Long-term outcomes in patients with BRAFV600-mutant metastatic melanoma receiving dabrafenib monotherapy: analysis from phase 2 and phase 3 clinical trials. Eur J Cancer. 2020;125:114-120.
23. Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28:1631-1639. Erratum in: Ann Oncol. 2019;30:1848.
24. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-2516.
25. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAFV600 mutations. N Engl J Med. 2012;367:1694-1703.
26. Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381:626-636.
27. Ascierto PA, Dréno B, Larkin J, et al. 5-year outcomes with cobimetinib plus vemurafenib in BRAF V600 mutation-positive advanced melanoma: extended follow-up of the coBRIM Study. Clin Cancer Res. 2021;27:5225-5235.
28. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867-1876.
29. Dummer R, Flaherty K, Robert C, et al. Five-year overall survival (OS) in COLUMBUS: A randomized phase 3 trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients (pts) with BRAF V600-mutant melanoma; J Clin Oncol. 2021;39(suppl 15):Abstract 9507. Erratum in: J Clin Oncol. 2023;41:2301.
30. Heinzerling L, Eigentler TK, Fluck M, et al. Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management. ESMO Open. 2019;4:e000491.
31. Czupryn M, Cisneros J. BRAF/MEK inhibitor therapy: consensus statement from the faculty of the melanoma nursing initiative on managing adverse events and potential drug interactions. Clin J Oncol Nurs. 2017;21:11-29.
32. Mekinist (trametinib) tablets, for oral use [prescribing information]. Novartis; June 2022. Accessed February 6, 2024. www.accessdata.fda.gov/drugsatfda_docs/label/2022/204114s024lbl.pdf
33. Ribas A, Hamid O, Daud A, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315:1600-1609. Erratum in: JAMA. 2016;315:2472.
34. Hamid O, Robert C, Daud A, et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019;30:582-588.
35. A Study of Pembrolizumab in Participants With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma (KEYNOTE-001). NLM identifier: NCT01295827. Updated July 12, 2022. Accessed July 20, 2022. www.clinicaltrials.gov/ct2/show/results/NCT01295827
36. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33:1889-1894.
37. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521-2532.
38. Olson DJ, Eroglu Z, Brockstein B, et al. Pembrolizumab plus ipilimumab following anti-PD/L1 failure in melanoma. J Clin Oncol. 2021;39:2647-2655.
39. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345-1356. Erratum in: N Engl J Med. 2018;379:2185.
40. Larkin J, Chairion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535-1546.
41. Opdualag (nivolumab and relatlimab-rmbw) injection, for intravenous use [prescribing information]. Bristol Myers Squibb. March 2022. Accessed February 6, 2024. www.accessdata.fda.gov/drugsatfda_docs/label/2022/761234s000lbl.pdf
42. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386:24-34.
43. Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing): A phase III trial–ECOG-ACRIN EA6134. J Clin Oncol. 2022;41:186-197.
44. Ascierto PA, Mandala M, Ferrucci PF, et al. SECOMBIT: The best sequential approach with combo immunotherapy [ipilimumab (I)/nivolumab (N)] and combo target therapy [encorafenib (E)/binimetinib (B)] in patients with BRAF mutated metastatic melanoma: a phase II randomized study. Ann Oncol. 2021;32(suppl 5):S1316-S1317.
45. Immunotherapy With Ipilimumab and Nivolumab Preceded or Not by a Targeted Therapy With Encorafenib and Binimetinib (EBIN). NLM identifier: NCT03235245. Updated April 21, 2021. Accessed July 20, 2022. www.clinicaltrials.gov/ct2/show/NCT03235245
46. Sullivan RJ, Hamid O, Gonzalez R, et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med. 2019;25:929-935.
47. Dixon-Douglas JR, Patel RP, Somasundram PM, McArthur GA. Triplet therapy in melanoma-combined BRAF/MEK inhibitors and anti-PD-(L)1 antibodies. Curr Oncol Rep. 2022;24:1071-1079.
48. Liu Y, Zhang X, Wang G, Cui X. Triple combination therapy with PD-1/PD-L1, BRAF, and MEK inhibitor for stage III-IV melanoma: a systematic review and meta-analysis. Front Oncol. 2021;11:693655.
49. 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;395:1835-1844. Erratum in: Lancet. 2020;396:446.
50. Ferrucci PF, Di Giacomo AM, Del Vecchio M, et al. KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma. J Immunother Cancer. 2020;8:e001806. Erratum in:  J Immunother Cancer. 2021;9:e001806corr1.
51. Dummer R, Long GV, Robert C, et al. Randomized phase III trial evaluating spartalizumab plus dabrafenib and trametinib for BRAF V600-mutant unresectable or metastatic melanoma. J Clin Oncol. 2022;40:1428-1438.
52. Bai R, Lv Z, Xu D, Cui J.  Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. Biomark Res. 2020;8:34.
53. Weiss SA, Wolchok JD, Sznol M. Immunotherapy of melanoma: facts and hopes. Clin Cancer Res. 2019;25:5191-5201.
54. Clinical Trials.gov - Metastatic Melanoma - Clinical Trials [Internet]. Bethesda, MD. 2024. Accessed February 13, 2024. https://clinicaltrials.gov/search?cond=melanoma,%20skin
55. Dong M, Ning ZQ, Xing PY, et al. Phase I study of chidamide (CS055/HBI-8000), a new histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas. Cancer Chemother Pharmacol. 2012;69:1413-1422.
56. Study Comparing Investigational Drug HBI-8000 Combined With Nivolumab vs. Nivolumab in Patients with Advanced Melanoma. NLM identifier: NCT04674683. Updated August 31, 2022. Accessed September 1, 2022. www.clinicaltrials.gov/ct2/show/NCT04674683
57. Clinical Study of Fianlimab in Combination with Cemiplimab in Adolescent and Adult Patients With Previously Untreated Unresectable Locally Advanced or Metastatic Melanoma. NLM identifier: NCT05352672. Updated July 7, 2022. Accessed August 21, 2022. www.clinicaltrials.gov/ct2/show/NCT05352672
58. A Study to Compare Nivolumab Administered Subcutaneously vs Intravenous in Melanoma Participants Following Complete Resection (CheckMate-6GE). NLM identifier: NCT05297565. Updated September 1, 2022. Accessed September 2, 2022. https://clinicaltrials.gov/ct2/show/NCT05297565
59. Safety and Efficacy Study of Pembrolizumab (MK-3475) Combined With Lenvatinib (MK-7902/E7080) as First-line Intervention in Adults With Advanced Melanoma (MK-7902-003/E7080-G000-312/LEAP-003). NLM identifier: NCT03820986. Updated August 23, 2022. Accessed August 25, 2022. https://clinicaltrials.gov/ct2/show/NCT03820986
60. IO102-IO103 in Combination With Pembrolizumab Versus Pembrolizumab Alone in Advanced Melanoma (IOB-012/KN-D18). NLM identifier: NCT05155254. Updated September 6, 2022. Accessed September 9, 2022. https://clinicaltrials.gov/ct2/show/NCT05155254
61. Talimogene Laherparepvec With Pembrolizumab in Melanoma Following Progression on Prior Anti-PD-1 Based Therapy (MASTERKEY-115). NLM identifier: NCT04068181. Updated September 9, 2022. Accessed September 27, 2022. https://clinicaltrials.gov/ct2/show/NCT04068181
62. Nathan P, Hassel JC, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385:1196-1206.
63. Phase 1b/2 Study of the Combination of IMCgp100 with Durvalumab and/or Tremelimumab in Cutaneous Melanoma. NLM identifier: NCT02535078. Updated June 30, 2022. Accessed August 27, 2022. www.clinicaltrials.gov/ct2/show/NCT02535078
64. Tebentafusp in Molecular Relapsed Disease (MRD) Melanoma (TebeMRD). NLM identifier: NCT05315258. Updated August 2, 2022. Accessed August 27, 2022. www.clinicaltrials.gov/ct2/show/NCT05315258
65. Linger CM, Trinh VA, Ma J, et al. Impact of pharmacists on identification of immune checkpoint inhibitor toxicities. J Am Coll Clin Pharm. 2021;4:1540-1547.
66. Medina P, Jeffers KD, Trinh VA, Harvey RD. The role of pharmacists in managing adverse events related to immune checkpoint inhibitor therapy. J Pharm Pract. 2020;33:338-349.
67. Myers G, Stevens J, Flewelling A, et al. Evaluation and clinical impact of a pharmacist-led, interdisciplinary service focusing on education, monitoring and toxicity management of immune checkpoint inhibitors. J Oncol Pharm Pract. 2023;29:145-154.
68. Renna CE, Dow EN, Bergsbaken JJ, Leal TA. Expansion of pharmacist clinical services to optimize the management of immune checkpoint inhibitor toxicities. J Oncol Pharm Pract. 2019;25:954-960.
69. Meleis L, Patel M, DeCoske M, et al. Evaluation of the role and impact of ambulatory clinical pharmacists in an academic comprehensive cancer center. J Adv Pract Oncol. 2020;11:817-824.
70. Lankford C, Dura J, Tran A, et al. Effect of clinical pharmacist interventions on cost in an integrated health system specialty pharmacy. J Manag Care Spec Pharm. 2021;27:379-384.