Recent advances in immunotherapy and in agents that target specific genetic mutations in the mitogen-activated protein kinase (MAPK) pathway have led to dramatic improvements in outcomes for patients with advanced cutaneous melanoma. However, compared to standard chemotherapy, the adverse events (AEs) associated with these agents (and combinations of agents) require precision treatment by a multidisciplinary team. This is particularly true for the immune-related AEs associated with ipilimumab.

Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4), a protein that exerts an inhibitory effect on cell proliferation. Ipilimumab binds to the CTLA-4 T-cell receptor and blocks this inhibitory effect.

The AEs associated with ipilimumab are mainly immuneresponse related. The phase III trials reported drugrelated AEs in 80% of patients; these events covered a broad range of systems, including dermatologic, gastrointestinal (including diarrhea in 30% of patients), hepatic, and endocrine.

Dermatologic toxicity is the most common AE (up to 43.5% overall, grades 3 or 4 in 1%-3%); this generally appears after 2 to 4 weeks of treatment. Symptomatic management with moisturizers, low-dose topical corticosteroids, or urea-based topical therapies is recommended.

The second most common toxicity is diarrhea, which affects almost one-third of patients. This toxicity can occur early (within days of treatment) but most commonly appears at 6 to 8 weeks and can progress to colitis. Grade 1 and 2 diarrhea can be managed symptomatically on an outpatient basis, but longer-term or higher-grade diarrhea may require more intensive management, such as intravenous corticosteroids.

Hepatotoxicity occurs in a significant proportion of patients and is typically seen between 6 to 8 weeks after initiation of therapy. Ipilimumab should be withheld for grade 2 changes in liver function tests, which should be measured daily for 3 days within initiation of oral steroid therapy if there is no improvement. More severe toxicity may occur, requiring close management.

Most of the immune-related AEs observed in clinical trials with ipilimumab occurred within 12 weeks of initial dosing and resolved within 1 to 2 months. Fewer than 10% of patients receiving ipilimumab treatment experienced an immune-related AE more than 70 days after their last dose; moreover, all of these events were grade 1 or 2 in severity.

Selective BRAF inhibitors are generally well tolerated with few grade 3/4 toxicities. The most common AEs associated with vemurafenib include grade 2/3 arthralgias (18% and 3%), rash (10% and 8%), photosensitivity (12% grade 2 or 3), fatigue (11% and 2%), cutaneous squamous cell carcinoma (12%), nausea (7% and 1%), and diarrhea (5% and <1%). Dose modification and/or interruption were required in more than one-third of patients to manage these AEs.

GSK2118436 is also well tolerated with similar AEs.

Fever (primarily associated with GSK2118436) can generally be managed with supportive care, although evaluation to exclude sepsis should be conducted. Squamous cell carcinoma typically develops between Weeks 2 and Weeks 14, and most of these are of the keratoacanthoma type, have no metastatic potential, and can be treated with surgical excision. Patients should be monitored for development of this AE regularly during treatment.

Early results from trials of the MEK inhibitors demonstrate that the most common AEs include an acneiform rash (all grade 85% for GSK1120212), diarrhea, fatigue, nausea, and vomiting. Prophylactic treatment is recommended to reduce the incidence of grade 3/4 skin rash. For grade 2 diarrhea, the drug should be withheld until symptoms have resolved to baseline or to grade 1.

Less common AEs include left ventricular systolic dysfunction, retinopathy, and retinal vein occlusion. Few cases of left ventricular systolic dysfunction were considered to be related to the MEK inhibitor. Retinal vein occlusion was not reversible but responded to treatment. Other early MEK inhibitor studies demonstrated ocular toxicity and visual disturbances.

Agents that block the programmed death (PD-1) receptor and its ligand (PD-L1) pathway have recently been shown to be effective in treatment of advancedstage melanoma. Encouraging results from phase I studies have resulted in fast-paced development of this class of drugs, as well as evaluation of their effect as combination therapy. Nivolumab, a fully human IgG4 PD-1 receptor blocking antibody, was associated with toxicities in approximately 41% of patients; most were suspected to be immune-related in etiology and included pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis. Most toxicities were reversible with discontinuation or interruption of treatment or with the administration of glucocorticoids.

MK-3475, or lambrolizumab, was studied in 135 patients with advanced melanoma. AEs included fatigue, fever, chills, myalgias, and headaches, almost all of which were grade 1 or 2. Grade 3 or 4 drug-related AEs were seen in 13% of patients. Six patients experienced treatment-related pneumonitis.

Of particular interest is the combination of PD-1 and CTLA-4 blockage, which has demonstrated impressive efficacy in early clinical trials. In one trial, 53 patients received concurrent treatment with nivolumab (antiPD-1) and ipilimumab (anti&ndash; CTLA-4) followed by nivolumab as a single agent and maintenance with nivolumab and ipilimumab. Fifty-three percent of patients had grade 3 or 4 treatment-related AEs, including elevated transaminases, diarrhea, rash, elevated lipase, and emesis. Frequently observed grade 1 and 2 AEs included rash, pruritus, fatigue, diarrhea, fever, nausea, and elevated transaminases. Most AEs were reversible and could be managed using standard algorithms.

Multidisciplinary management of a potentially wide array of AEs, particularly with the advent of combination therapy for treatment of late-stage melanoma, is critical to optimize patients&rsquo; treatment outcomes.

Jeffrey S. Weber, MD, PhD, at the H. Lee Moffitt Cancer Center, University of South Florida, Tampa, summarized these challenges as follows: &ldquo;There is a learning curve to managing AEs for immunologic agents. But in my opinion, it is no different than AEs of complex chemotherapy regimens that community oncologists currently manage all the time. It is just a matter of education, experience, and getting through the learning curve.&rdquo;

Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events.

Hodi FS, O&rsquo;Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.

Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.

Kahler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma.

Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.

Weber J. Anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events.

Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation.

Kefford R, Arkenau H, Brown MP, et al. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors.

Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma.

Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF.

Falchook G, Infante JR, Fecher LA, et al. The oral MEK 1/2 inhibitor GSK1120212 demonstrates early efficacy signals.

Lemech C, Arkenau HT. Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities.

Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.

Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA- 4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.

Articles

Clinical Articles

Recent advances in immunotherapy and in agents that target specific genetic mutations in the mitogen-activated protein kinase (MAPK) pathway have led to dramatic improvements in outcomes for patients with advanced cutaneous melanoma.

Managing Toxicities in Melanoma

Risk factors for contracting melanoma are complex and can include environmental exposure and an individual&rsquo;s genetic susceptibility,

but people at highest risk are those with a personal or family history of melanoma and those with large, atypical, and/or multiple (more than 50) nevi.

&ldquo;The people at greatest risk to develop melanoma epidemiologically are those with fair skin, light or red hair, light eyes, and extensive history of sun exposure or previous sunburn,&rdquo; said Christopher J. Miller, MD, director of dermatologic surgery at the Hospital of the University of Pennsylvania. &ldquo;All of these people should be monitored very closely,&rdquo; he cautioned.

Other risk factors include a tendency to freckle, sun sensitivity, use of tanning booths, and immunosuppression. The genetic susceptibility and environmental exposure risks are most prominently illustrated in individuals with fair skin and light eyes; however, melanoma can occur in any ethnic group and in areas of the body that have not had substantial sun exposure.

Individuals with few nevi tend to develop melanoma on areas of the body that are repeatedly exposed to sun, while individuals with large numbers of nevi have an increased risk of melanoma where nevi tend to be present, regardless of sun exposure (eg, the back).

According to Miller, both total cumulative ultraviolet (UV) exposure and intensity of individual exposures play a role in etiology and subtype of melanoma.

&ldquo;Intermittent, intensive sun exposure is a significant risk factor to develop the most common type of melanoma, called superficial spreading melanoma,&rdquo; Miller said. This type of melanoma is typically found on areas of the body that do not receive constant and continued UV exposure (eg, the trunk). &ldquo;There is another subtype of melanoma called a lentigo maligna melanoma that occurs more commonly on the head and neck or on the dorsal hands and forearmsareas that are more commonly exposed to regular, cumulative sun exposure,&rdquo; Miller explained.

The increasing incidence of melanoma appears consistent throughout the world, but varies when comparisons in latitude are noted. Melanoma is very rare in Africa, whereas Australia has among the highest incidence rates of melanoma worldwide.

Approximately 76,100 new cases of melanoma will be diagnosed in the United States in 2014.

Although melanoma accounts for less than 2% of skin cancer cases, it is responsible for most skin cancer deaths. An estimated 9710 persons will die from melanoma in 2014.

The median age at diagnosis of melanoma is 59 years.

Although the risk of melanoma increases with age, it is one of the most common cancers diagnosed in young adults, particularly young females.1,2 Melanoma is slightly more common in men than in women (1.2:1). Incidence of melanoma is higher in women before the age of 45 years, but rates in men are more than double and triple those in women by (&ldquo;Risk Factors and Trends&rdquo; continued) the ages of 60 and 80 years, respectively.

The incidence of melanoma also varies by race; it is approximately 20-fold higher among whites than among African Americans. Incidence rates of melanoma among whites increased by 2.7% per year from 2006 to 2010. Melanoma is rare in African Americans, with a lifetime risk of 0.1%, compared with a lifetime risk of 2.4% among whites. Whites also have a significantly higher incidence compared with Asians and Hispanics. Although incidence of melanoma is lower in the Hispanic and black populations, these groups are more likely to have metastatic disease and poorer outcomes.

The clinical outcome of melanoma initially depends on stage at diagnosis. About 82% to 85% of patients with melanoma present with localized disease, 10% to 13% present with regional disease, and the remaining 2% to 5% have distant metastatic disease at the time of diagnosis.

The 5-year relative survival rate for melanoma, regardless of stage at diagnosis, is 91%. When diagnosed at a local stage, the survival rate is 98%; but metastasis beyond the local site is associated with significantly reduced relative survival (62% and 16% for regional and distant metastases, respectively).

Five-year survival rates for melanoma have increased from 82% in the mid-1970s to 88% during the late 1980s and to 93% in 2009. However, survival rates remain substantially lower for African Americans, despite an increase in survival from 57% several decades ago to 77% in 2009 in this population.

Trends in mortality from melanoma are associated with age. In recent years, death rates from melanoma have been rapidly declining in whites younger than 50 years; however, among whites 50 years and older, melanoma death rates increased by 1.1% per year in men and 0.2% per year in women during the same period.

National Comprehensive Cancer Network. Melanoma (Version 3.2014). http://www.nccn.org/professionals/physician_ gls/pdf/melanoma.pdf. Accessed February 20, 2014.

American Cancer Society. Cancer Facts & Figures 2014. http:// www.cancer.org/acs/groups/content/@research/documents/ document/acspc-041770.pdf. Accessed February 20, 2014.

Erdei E, Torres SM. A new understanding in the epidemiology of melanoma.

Risk factors for contracting melanoma are complex and can include environmental exposure and an individualâ€™s genetic susceptibility, but people at highest risk are those with a personal or family history of melanoma and those with large, atypical, and/or multiple (more than 50) nevi.

Risk Factors and Trends in Melanoma

&ldquo;There&rsquo;s no question that there have been major advances made in the field over the last 5 years or so,&rdquo; Weber said.

Conventional chemotherapies include the use of alkylating agents that produce cytotoxic effects and block cell replication, but these agents exhibit minimal clinical response and do not increase overall survival. Also, these agents are limited to use in patients with non-BRAF mutations or in those who have developed resistance to other therapies.

Since the approval of the BRAF inhibitor vemurafenib in 2011, focus has been on subverting drug resistance to this agent. A BRAF inhibitor now under evaluation, dabrafenib (Tafinlar), received US Food and Drug Administration (FDA) approval in 2013 for treatment of unresectable or metastatic melanoma with the BRAF mutation.1 Although in the same class as vemurafenib, dabrafenib appears to exhibit more effectiveness in treatment of melanoma brain metastasis.

Another recently approved BRAF inhibitor, trametinib (Mekinist), is indicated for unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Trametinib is a highly specific, potent inhibitor of the mitogen-activated protein kinases 1 and 2 (MEK1 and MEK2) and BRAF downstream kinases, resulting in response rates of approximately 20% in patients with a BRAF mutation.

MEK kinases, located immediately downstream of the BRAF kinase, trigger activation of pathways that lead to tumor development. Several agents that block this pathway are under development. In a phase III trial, the forementioned trametinib demonstrated objective response rates (ORRs) in 22% of patients observed, and almost three-fourths of patients experienced tumor regression to some degree.

AZD6244, another MEK inhibitor that binds selectively to MEK1 and MEK2, is in phase II studies of patients with late-stage melanoma.

In early 2014, the FDA approved the combination of dabrafenib and trametinib for treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. In a phase I/II study, median progression-free survival in the combination full-dose group was 9.4 months compared with 5.8 months in the dabrafenib monotherapy group (hazard ratio, 0.39; 95% confidence interval, 0.25-0.62). In the combination group, 76% of patients experienced either complete or partial response compared with 54% in the monotherapy group.

The programmed death (PD)-1 receptor is expressed on activated T cells and impacts T-cell function during the effector phase of tumor rejection. The PD-1 ligand (PD-L1) is expressed on epithelial and endothelial cells, as well as other types of immune cells, such as dendritic cells, macrophages, and B cells. PD-L1 may be upregulated when inflammation is present; some researchers hypothesize that tumors may exploit this function in efforts to avoid a tumor-directed T-cell response.

Expression of PD-L1 in tumors has characteristically been associated with poor prognosis; however, in patients with melanoma, recent reports have challenged this idea. An &ldquo;adaptive resistance&rdquo; mechanism, in which PD-L1 expression is a reflection for the melanoma being attacked by T cells, is the explanation for the improved prognosis. Positive results from phase I studies have led to fast-paced development of agents to target both PD-1 and PD-L1, and research is ongoing. To date, data have been reported for PD-1-specific antibodies nivolumab (MDX-1106; ONO-4538) and lambrolizumab (MK-3475), as well as PD-L1specific antibodies BMS936559 (MDX-1105) and MPDL3280A.

Lambrolizumab received the FDA Breakthrough Therapy designation for promising new drugs in April 2013. In a recent phase IB trial in patients with advanced and unresectable melanoma, 135 patients with advanced melanoma were treated with lambrolizumab at 3 different dosages. A significant proportion of patients had visceral metastases, including brain metastases. The ORR for the highest dosage cohorts were reported to be 38% and 52%; no difference in response rate was observed between patients who had received prior treatment with ipilimumab versus those with no prior treatment. Most responses were seen at the time of the first tumor assessment (12 weeks). Durability of response was suggested by the fact that the median duration of response and median overall survival had not been reached after 11 months of follow-up. Phase II and III studies are under way.

A second PD-1 inhibitor, nivolumab, has also demonstrated favorable results in patients with melanoma. In a recent phase I study, 61% and 44% of patients survived to 1 and 2 years, respectively, according to data presented at the American Society of Clinical Oncology 2013 meeting. The median overall survival was reported to be 16.8 months, and the objective response rate was 31%. Median duration of response was 104 weeks.

Cytotoxic T-Lymphocyte Antigen and PD-1/PD-L1 Combination

BMS936559, a fully human antiPD-L1 monoclonal antibody, was associated with objective tumor responses in 17% of patients with advanced melanoma. MPDL-3280A, a fully human monoclonal PD-L1&ndash;specific antibody of the IgG4 isotype, is undergoing early-phase studies in patients with advanced melanoma

Some evidence suggests that synergy exists between cytotoxic T-lymphocyte antigen (CTLA-4) and PD-1/PD-L1, providing a rationale for combination treatment for patients with advanced-stage melanoma. A phase I trial evaluated treatment with the antiPD-1 agent nivolumab and the anti&ndash;CTLA-4 agent ipilimumab in 53 patients with advanced melanoma. Combination treatment was followed by single-agent nivolumab administerd every 3 weeks for 4 doses, then maintenance with nivolumab and ipilimumab every 12 weeks for up to 8 doses. Twenty-one of 52 (40%) patients experienced a confirmed response. Importantly, most of these responses were rapid in onset and deep (&ge;80% tumor reduction at 12 weeks). Responses were observed in patients with extensive and bulky disease.

According to Weber, &ldquo;The combination, despite a fair amount of toxicity, has a very impressive response rate. Many patients become complete responders, which is very encouraging.&rdquo; This impressive tumor activity has led to rapidly expanding clinical trial programs in many solid tumor types.9,10 Studies evaluating other combinations are being done, such as checkpoint blockade with novel vaccines, angiogenesis inhibition, inhibition of the mitogenactivating protein kinase (MAPK) pathway, and other directly targeted immunosuppressive pathways.

Bertolotto C. Melanoma: from melanocyte to genetic alterations and clinical options. published online December 12, 2013.

. 2013;2013:635203. doi: 10.1155/2013/635203.

Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.

Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study.

Pretto F, Neri D. Pharmacotherapy of metastatic melanoma: emerging trends and opportunities for a cure.

ClinicalTrials.gov. MEK inhibitor AZD6244 in treating patients with stage III or IV melanoma. http://clinicaltrials.gov/ ct2/show/study/NCT00866177. Accessed February 20, 2014.

Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.

Onclive 2014. http://www.onclive.com/publications/contemporary- oncology/2014/february-2014/immune-checkpointblockade- in-cancer-inhibiting-ctla-4-and-pd-1pd-l1-withmonoclonal- antibodies/3#sthash.udDXKdvy.dpuf. Accessed March 1, 2014.

Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.

Many patients with melanoma are diagnosed with unresectable stage III or IV disease that requires systemic treatment. Treatment of melanoma depends largely on the stage at diagnosis.

Targeted Treatments for Melanoma

Table 1. Phase III Melanoma Trials (Currently Recruiting)

The NRAS Melanoma and MEK Inhibitor (NEMO) trial1 is a randomized, phase III, open-label, multicenter, dual-arm study to compare the efficacy of MEK162 45 mg twice daily versus dacarbazine 1000 mg/m2 IV every 3 weeks in patients with advanced unresectable (stage IIIc) or metastatic (stage IV) NRAS mutationpositive melanoma. This study, funded by Novartis, is enrolling approximately 393 patients who will be randomized in a 2:1 ratio to receive either MEK162 or dacarbazine. Patients will be stratified according to criteria from: the American Joint Committee on Cancer stage (IIIC, IVM1a, and IVM1b vs IVM1c), the Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1), and prior first-line therapy (ipilimumab vs none).

The primary end point of the study is progressionfree survival (PFS) and a key secondary end point is overall survival (OS). Other secondary end points include overall response rate; time to objective response; duration of response; disease control rate (defined as the proportion of patients with a best overall response rate of complete response, partial response, or stable disease); number of patients with adverse events (AEs) and with serious AEs; time to definitive 10% deterioration in the global health status score (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30]); and change from baseline in the EuroQol Group standardized instrument for use as a measure of health outcome (EQ-5D-5L).

The study began in July 2013 and will be completed in May 2016. The final data collection date for the primary outcome measure will occur in December 2014.

A second Novartis-sponsored phase III trial2 (COLUMBUS) began in September 2013 and is scheduled to end in June 2017. This study compares the combination of LGX818 (a highly potent RAF inhibitor) plus MEK162 and LGX818 monotherapy versus vemurafenib in BRAF-mutant melanoma. This prospective, randomized, open-label, multicenter, parallel group, 3-arm study aims to enroll approximately 900 patients with locally advanced unresectable or metastatic melanoma with BRAF V600 mutation. Patients will be randomized 1:1:1 to one of 3 treatment arms: (1) LGX818 plus MEK162 (combination arm), (2) LGX818 monotherapy (LGX818 arm), or (3) vemurafenib.

The primary outcome measure is PFS. Secondary outcome measures include OS; objective response rate; time to response; disease control rate; duration of objective response; number of patients with AEs and serious AEs; ECOG Performance status; time to definitive 10-point deterioration in ECOG performance status; pharmacokinetics of LGX818 and MEK162; time to definitive 10% deterioration in global health status (EORTC QLQ-C-30); time to definitive 10% deterioration in the FACT-M melanoma subscale; and global health status (EQ-5D).

The doses of the experimental treatments are as follows: arm 1, LGX818 300 mg orally once daily in a fasting state; arm 2, LGX818 450 mg orally once daily in a fasting state and MEK162 45 mg orally twice daily in a fasting state; and arm 3, vemurafenib 960 mg orally twice daily.

Other phase III trials now enrolling subjects are listed in Table 1. Trial protocols under development include targeted therapies and combinations of therapies, including CDK 4/6 inhibitors, BRAF or MEK inhibitors combined with murine double minute 2 (MDM2) inhibitors, and BRAF plus MEK inhibitors plus PD-1 antibodies.

ClinicalTrials.gov. Study comparing the efficacy of MEK162 versus dacarbazine in unresectable or metastatic NRAS mutation- positive melanoma. http://clinicaltrials.gov/ct2/show/ study/NCT01763164. Accessed March 2, 2014.

ClinicalTrials.gov. Study comparing combination of LGX818 plus MEK162 and LGX818 monotherapy versus vemurafenib in BRAF mutant melanoma (COLUMBUS). http://clinicaltrials .gov/ct2/show/study/NCT01909453. Accessed March 2, 2014.

This article provides an overview of clinical trials in melanoma.

Melanoma (May 2014) | Targeted Therapies: Melanoma

Managing Toxicities in Melanoma

Risk Factors and Trends in Melanoma

Targeted Treatments for Melanoma

Clinical Trials of Note