**The Modern Approach to Targeting Melanoma**

**The Modern Approach to Targeting Melanoma**

DOI: 10.5772/intechopen.73489

Jane O'Sullivan and Donal O'Connor Jane O'Sullivan and Donal O'Connor Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73489

#### **Abstract**

Melanoma treatment depends largely on the clinical stage of the disease. The preferred treatment is surgical resection of the disease. The surgical margins depend on the depth of the disease. Sentinel lymph node biopsy is generally advised for all lesions greater than 1 mm depth. Complete lymphadenopathy of surrounding lymph nodes is recommended in the presence of nodal disease. There are some controversies surrounding the timing and benefit of complete lymphadenopathy in clinically occult disease. There is evidence to support the role of adjuvant therapies in the form of immunotherapy in regionally advanced disease, and there has been a significant improvement in medical therapies for advanced melanoma. BRAF inhibitors have become mainstay treatment for patients with a BRAF mutation. Immunotherapy is another cornerstone of therapy for advanced melanoma. There is ongoing research to define the optimal therapeutic regimen. Future guidelines will likely incorporate this recent research. Chemotherapy has been relegated to second-line therapy in melanoma.

**Keywords:** melanoma, staging, therapeutic advances, immunotherapy, chemotherapy

#### **1. Introduction**

Melanoma is the deadliest of all the skin cancers. The incidence has been increasing in recent decades. There has been a significant development of therapies for melanoma. For the purpose of chapter, the staging of melanoma will be reviewed. There will be a brief overview of the current recommendations and ongoing research into the different therapeutic approaches.

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

## **2. Determining the appropriate therapy**

An important determinant of the appropriate treatment strategy is the clinical stage of the primary melanoma. Melanoma is staged by the TNM system. T refers to the primary tumour, N refers to the nodal status and M refers to the metastatic status. The AJCC released updated guidelines for the staging of melanoma in 2016. T1a tumours are less than 0.8 mm deep without ulceration, and T1b tumours are either less than 0.8 mm deep with ulceration or 0.8 mm to 1 mm deep with or without ulceration. T2a and T2b tumours are 1.0 mm to 2.0 mm without and with ulceration, respectively. T3a and T3b tumours are 2.0 mm to 4.0 mm without and with ulceration, respectively. Finally, T4a and T4b tumours are greater than 4.0 mm without and with ulceration, respectively. N1 refers to one-tumour involved or any number of in-transit satellite and/or microsatellite metastases with no tumour-involved lymph node. N1a and 1b refer to one clinically occult (detected by SLNB) and one clinically detected. N2 refers to two or three tumour-involved nodes or any number of in-transit, satellite, and/or microsatellite metastases with one tumourinvolved node. N2a and N2b refer to two or three clinically occult and at least one clinically and one clinically occult/clinically detected, respectively. N3 refers to four or more tumour-involved nodes or any number of in-transit, satellite, and/or microsatellite metastases with two or more tumour-involved nodes or any number of matted noes without or with in-transit, satellite and/or microsatellite metastases. N3a, N3b and N3c refer to four or more clinically occult, four or more, at least one of which was clinically detected or the presence of any number or matted nodes or two or more clinically occult or clinically detected and/or the presence of any number of matted nodes, respectively. Satellite metastases are clinically apparent cutaneous and/or subcutaneous metastases within 2 cm of the tumour. Microsatellites are microscopic cutaneous and/or subcutaneous metastases next to or below the melanoma on histological examination. In-transit metastases are clinically apparent cutaneous and/or subcutaneous metastases found greater than 2 cm from the primary melanoma. M0 refers to no distant disease, and M1 refers to distant disease. M1a refers to distant metastases in the skin, soft tissue including muscle, M1b refers to distant metastasis to lung, M1c refers to distant metastasis to non-CNS visceral sites and M1d refers to distant metastasis to the CNS. M can be further risk stratified based on the LDH level [1].

*2.1.1. Surgical*

Surgical excision forms the cornerstone of treatment in primary cutaneous melanoma. Following the initial histological diagnosis and microstaging of the tumour, a wider and often deeper excision of the melanoma is performed. The surgical management of melanoma depends primarily on the Breslow thickness, the presence or absence of ulceration, and positivity of sentinel lymph node biopsy [3]. The ultimate aim of surgical therapy irrespective of depth is to obtain clear margins. The extent of the surgical margins is determined by three factors: (1) Wide margins result in a reduced risk of local recurrence. (2) There is no benefit to excising margins beyond 1 cm in thin melanoma. (3) There is no demonstrated benefit to excising margins beyond 2 cm in any thickness melanoma. The guidelines suggest a margin between 1 cm and 2 cm for primary cutaneous melanoma. Furthermore, the guidelines state that an excision should be performed to the level of muscle fascia or depending on tumour location at least to the level of the deep adipose tissue. However, in the case of stage 0 melanoma, an excision margin between 0.5 and 1.0 cm margin is acceptable. In the case of stage 0 lentigo maligna, margins may need to be extended to >0.5 cm, due to characteristically widespread subclinical extension. Permanent section total peripheral margin control and Moh's micrographic surgery have been used to achieve histological control of the margins.

The Modern Approach to Targeting Melanoma http://dx.doi.org/10.5772/intechopen.73489 89

There are several trials performed to determine the optimal extent of the margins when excising melanoma. In thin melanomas, an international, randomised prospective study examined 1 cm margins in the context of primary cutaneous melanomas less than 2 mm depth. A total of 612 patients were included in the trial, with 305 randomised to 1 cm margins and 307 randomised to wide margins less than 3 cm. The disease-free and overall survival was similar in the two groups [5]. In the case of intermediate-thickness tumours (1 to 4 mm depth), a large, multicentre randomised trial demonstrated that margins of 2 cm were acceptable with respect to 5-year survival. Reducing the margins from 4 to 2 cm led to a significant reduction in skin grafting and total length of hospital stay [6]. In another multicentre trial, they investigated the optimal excision margins in high-risk melanoma. High-risk melanoma was defined as localised melanoma 2 mm or greater in thickness on the trunk or limbs. Elective lymph-node dissection, sentinel biopsy and adjuvant therapies were not permitted. Patients were either randomised to 1 cm or 3 cm margins. The trial demonstrated that a 1 cm margin in high-risk melanoma is associated with a significant increase in regional recurrence vs. a 3 cm margin, but both patient populations had a similar overall survival rate [3]. A Cochrane review examined the different excision margins in melanoma. A narrow margin was defined as 1–2 cm, and a wide margin was defined as 3–5 cm. The systematic review included data from randomised trials for 1633 participants in the narrow excision margin group and 1664 in the wide excision margin group. There was no statistically significant difference in terms of overall survival and recurrence free survival between wide and narrow margins. However, there was a trend toward improved overall survival and recurrence free survival. The review concluded that there was inadequate evidence to determine the optimal excision margins for primary cutaneous melanoma [7].

Sentinel lymph node biopsy should be considered in patients with a primary cutaneous melanoma of 1 mm or greater depth. Sentinel lymph node biopsy is generally not advised in

However, there is a paucity of evidence to support their use [4].

Stage 1 and 2 are defined by tumour size. Stage 3 is defined by positive nodal disease. Stage 4 is defined by the presence of metastases. Based on the TNM staging, stage 0 refers to T1sNoMo, stage 1a refers to T1a/N0/M0, stage 1b refers to T1b or T2a/N0/M0, stage 2A refers to T2b or T3a/N0/M0, stage 2B refers to T3B or T4a/N0/M0, stage 2C refers to T4b/N0/M0, stage 3 refers to any T/N1 or higher/M0 and stage 4 refers to any T/any N/M1 [1].

#### **2.1. Stages 0, 1 and 2**

The ESMO guidelines recommend surgical therapy as the primary management strategy in localised melanoma. The guideline recommends against performing routine lymphadenectomy or irradiation to the surrounding lymph nodes. The guideline recommends radiotherapy for local disease control where there are positive margins in lentigo maligna melanoma, in cases of metastases resection where there are positive histological margins or after the removal of bulky disease [2].

#### *2.1.1. Surgical*

**2. Determining the appropriate therapy**

88 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

An important determinant of the appropriate treatment strategy is the clinical stage of the primary melanoma. Melanoma is staged by the TNM system. T refers to the primary tumour, N refers to the nodal status and M refers to the metastatic status. The AJCC released updated guidelines for the staging of melanoma in 2016. T1a tumours are less than 0.8 mm deep without ulceration, and T1b tumours are either less than 0.8 mm deep with ulceration or 0.8 mm to 1 mm deep with or without ulceration. T2a and T2b tumours are 1.0 mm to 2.0 mm without and with ulceration, respectively. T3a and T3b tumours are 2.0 mm to 4.0 mm without and with ulceration, respectively. Finally, T4a and T4b tumours are greater than 4.0 mm without and with ulceration, respectively. N1 refers to one-tumour involved or any number of in-transit satellite and/or microsatellite metastases with no tumour-involved lymph node. N1a and 1b refer to one clinically occult (detected by SLNB) and one clinically detected. N2 refers to two or three tumour-involved nodes or any number of in-transit, satellite, and/or microsatellite metastases with one tumourinvolved node. N2a and N2b refer to two or three clinically occult and at least one clinically and one clinically occult/clinically detected, respectively. N3 refers to four or more tumour-involved nodes or any number of in-transit, satellite, and/or microsatellite metastases with two or more tumour-involved nodes or any number of matted noes without or with in-transit, satellite and/or microsatellite metastases. N3a, N3b and N3c refer to four or more clinically occult, four or more, at least one of which was clinically detected or the presence of any number or matted nodes or two or more clinically occult or clinically detected and/or the presence of any number of matted nodes, respectively. Satellite metastases are clinically apparent cutaneous and/or subcutaneous metastases within 2 cm of the tumour. Microsatellites are microscopic cutaneous and/or subcutaneous metastases next to or below the melanoma on histological examination. In-transit metastases are clinically apparent cutaneous and/or subcutaneous metastases found greater than 2 cm from the primary melanoma. M0 refers to no distant disease, and M1 refers to distant disease. M1a refers to distant metastases in the skin, soft tissue including muscle, M1b refers to distant metastasis to lung, M1c refers to distant metastasis to non-CNS visceral sites and M1d refers to distant metastasis to the CNS. M can be further risk stratified based on the LDH level [1].

Stage 1 and 2 are defined by tumour size. Stage 3 is defined by positive nodal disease. Stage 4 is defined by the presence of metastases. Based on the TNM staging, stage 0 refers to T1sNoMo, stage 1a refers to T1a/N0/M0, stage 1b refers to T1b or T2a/N0/M0, stage 2A refers to T2b or T3a/N0/M0, stage 2B refers to T3B or T4a/N0/M0, stage 2C refers to T4b/N0/M0, stage 3 refers

The ESMO guidelines recommend surgical therapy as the primary management strategy in localised melanoma. The guideline recommends against performing routine lymphadenectomy or irradiation to the surrounding lymph nodes. The guideline recommends radiotherapy for local disease control where there are positive margins in lentigo maligna melanoma, in cases of metastases resection where there are positive histological margins or after the

to any T/N1 or higher/M0 and stage 4 refers to any T/any N/M1 [1].

**2.1. Stages 0, 1 and 2**

removal of bulky disease [2].

Surgical excision forms the cornerstone of treatment in primary cutaneous melanoma. Following the initial histological diagnosis and microstaging of the tumour, a wider and often deeper excision of the melanoma is performed. The surgical management of melanoma depends primarily on the Breslow thickness, the presence or absence of ulceration, and positivity of sentinel lymph node biopsy [3]. The ultimate aim of surgical therapy irrespective of depth is to obtain clear margins. The extent of the surgical margins is determined by three factors: (1) Wide margins result in a reduced risk of local recurrence. (2) There is no benefit to excising margins beyond 1 cm in thin melanoma. (3) There is no demonstrated benefit to excising margins beyond 2 cm in any thickness melanoma. The guidelines suggest a margin between 1 cm and 2 cm for primary cutaneous melanoma. Furthermore, the guidelines state that an excision should be performed to the level of muscle fascia or depending on tumour location at least to the level of the deep adipose tissue. However, in the case of stage 0 melanoma, an excision margin between 0.5 and 1.0 cm margin is acceptable. In the case of stage 0 lentigo maligna, margins may need to be extended to >0.5 cm, due to characteristically widespread subclinical extension. Permanent section total peripheral margin control and Moh's micrographic surgery have been used to achieve histological control of the margins. However, there is a paucity of evidence to support their use [4].

There are several trials performed to determine the optimal extent of the margins when excising melanoma. In thin melanomas, an international, randomised prospective study examined 1 cm margins in the context of primary cutaneous melanomas less than 2 mm depth. A total of 612 patients were included in the trial, with 305 randomised to 1 cm margins and 307 randomised to wide margins less than 3 cm. The disease-free and overall survival was similar in the two groups [5]. In the case of intermediate-thickness tumours (1 to 4 mm depth), a large, multicentre randomised trial demonstrated that margins of 2 cm were acceptable with respect to 5-year survival. Reducing the margins from 4 to 2 cm led to a significant reduction in skin grafting and total length of hospital stay [6]. In another multicentre trial, they investigated the optimal excision margins in high-risk melanoma. High-risk melanoma was defined as localised melanoma 2 mm or greater in thickness on the trunk or limbs. Elective lymph-node dissection, sentinel biopsy and adjuvant therapies were not permitted. Patients were either randomised to 1 cm or 3 cm margins. The trial demonstrated that a 1 cm margin in high-risk melanoma is associated with a significant increase in regional recurrence vs. a 3 cm margin, but both patient populations had a similar overall survival rate [3]. A Cochrane review examined the different excision margins in melanoma. A narrow margin was defined as 1–2 cm, and a wide margin was defined as 3–5 cm. The systematic review included data from randomised trials for 1633 participants in the narrow excision margin group and 1664 in the wide excision margin group. There was no statistically significant difference in terms of overall survival and recurrence free survival between wide and narrow margins. However, there was a trend toward improved overall survival and recurrence free survival. The review concluded that there was inadequate evidence to determine the optimal excision margins for primary cutaneous melanoma [7].

Sentinel lymph node biopsy should be considered in patients with a primary cutaneous melanoma of 1 mm or greater depth. Sentinel lymph node biopsy is generally not advised in patients with stage 0 or stage 1a melanoma. The use of sentinel lymph node biopsy is only recommended in stage 1B in the presence of adverse prognostic indictors [4]. The likelihood of a positive sentinel lymph node biopsy increases with the Breslow's depth, with 2% in 1 mm, 7% in 1–1.99 mm, 13% in 1–1.99 mm, and 31% in 3 mm. In 710 cases of sentinel lymph node biopsy, 638 (88.5%) were alive without evidence of disease [8].

**2.2. Stage 3**

motherapy or intralesional therapy [2].

vs. 54.4% in the placebo arm [12].

arm [13].

melanoma [14].

The ESMO guidelines suggest surgical excision and removal of the surrounding lymph nodes. They note that it is not sufficient to merely remove the disease-containing nodes. These guidelines define high-risk situations as the presence of multiple bulky lymph node metastases. The surgical management of stage III melanoma follows the same principles as above. The guidelines suggest the consideration of localised radiation therapy to the surrounding area in the case of high-risk disease. In the presence of inoperable, regionally advanced disease, the guidelines suggest therapies such as isolated limb perfusion, radiation therapy, electroche-

The Modern Approach to Targeting Melanoma http://dx.doi.org/10.5772/intechopen.73489 91

In the presence of high-risk disease, systemic therapy should be considered. A recent phase 3 trial investigated the role of adjuvant immunotherapy in high risk regionally advanced to prevent recurrence. The trial entitled EORTC 18071 enrolled participants who underwent a surgical excision of cutaneous melanoma with clear margins. A total of 951 patients were randomly assigned to the treatment with either placebo or ipilimumab. The median recurrence survival was significantly improved in the ipilimumab treatment arm (26.1 months vs. 17.1 months). There were a large number of patients who discontinued ipilimumab due to adverse events (245/471). These adverse events were most commonly GI (75/472), hepatic (50/472), and endocrine (40/471). There were five treatment-related deaths in the ipilimumab treatment arm (three due to colitis, one due to myocarditis and one due to Guillain-Barré syndrome) [11]. The overall 5-year survival in the ipilimumab treatment arm at 5 years was 65.4%

However, the role of ipilimumab as the optimal adjuvant therapy has recently been challenged with the publication of a phase 3 trial, comparing adjuvant nivolumab vs. ipilimumab in resected stage 3 or 4 melanoma. A total of 906 patients were randomly assigned to either receive treatment with ipilimumab or nivolumab. The patients were followed up for at least 18 months. When the 12-month recurrence-free survival was compared in both groups, it was significantly higher in the nivolumab group (70.5% vs. 60.8% respectively). Nivolumab appeared to have a better overall side-effect profile, with 14.4% reporting grade 3 or 4 adverse treatment effects vs. 45.9% in the ipilimumab-treatment arm. Furthermore, while there were two deaths reported in the ipilimumab arm, there were no deaths recorded in the nivolumab

A recent phase 3 trial published in 2017 suggests that the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib prove the optimal treatment option in stage III melanoma patients with the BRAF V600 mutations. A more detailed discussion regarding the mechanism of these drugs will be discussed in the stage IV section. They randomised patients with either a BRAF V600E or V600 K mutation to receive either a combination of dabrafenib and trametinib or placebo. They recruited 870 patients with adequately resected stage 3 melanoma. The overall 3-year survival was improved in the treatment arm vs. placebo (86% vs. 77%). The 3-year relapse free survival was 58% vs. 39% in the treatment vs. placebo arm, respectively. This trial suggests a role for combination BRAF/MEK therapy in stage 3

Lymph node dissection plays an important role in the surgical management of melanoma. The MSLT-1 was a multicentre phase 3 trial, which randomised two groups of patients with localised melanoma more than 1 mm deep to receive either wide excision with lymphatic mapping and sentinel lymph node biopsy with immediate complete lymphadenectomy for sentinel node metastases or wide excision plus postoperative observation with a deferral of the complete lymphadenectomy until clinically evident disease became apparent. The trial comprised of 1270 patients with intermediate-thickness melanoma, 290 with thick melanoma, and 232 with thin melanoma. There was no difference between the immediate and delayed complete lymphadenectomy group in the absence of nodal disease in either the intermediate or thick melanomas group with respect to 10-year melanoma-specific survival rates. The survival rate was much improved in the presence of nodal disease in the biopsy vs. observation group in the intermediate thickness group. However, a similar benefit was not observed in the thick melanoma group. The patients with a positive sentinel lymph node biopsy had a worse prognosis vs. the patients with negative sentinel lymph node biopsy. Thus, there is a clear benefit to immediately complete lymphadenectomy following the identification of clinically occult disease in intermediate-thickness melanoma with respect to nodal recurrence, distant metastases and melanoma-specific survival. The timing of the complete lymphadenectomy does not appear to play an important role in thick melanomas. There is no benefit to immediate complete lymphadenectomy in the absence of clinically occult disease. Finally, the trial demonstrates that sentinel lymph node biopsy serves as an important prognostic tool [9].

Another important trial which assessed the role of complete lymph node dissection was the phase 3, multicentre, DeCOG-SLT trial. They examined whether complete lymph node dissection results in a better overall survival vs. conservative management in patients with positive sentinel lymph node biopsies. The patients had cutaneous melanoma of at least 1 mm depth and positive sentinel lymph node biopsies. The trial randomised 483 patients to either complete lymph node dissection or observation. There was no significant difference in terms of distant-metastasis free survival in the treatment or observation arm (74.9% vs. 77.0%). Furthermore, there was no significant difference in terms of 3 year overall survival between the treatment and observation arm (81.2% vs. 81.7%). There was only a small improvement in disease control in the treatment vs. the observation group 8% vs. 15%). It is important to note that the majority of patients in that study had a low tumour burden [10].

#### *2.1.2. Non-surgical*

Surgical management is the treatment of choice for primary cutaneous melanoma. Hence, the non-surgical options should only be advised in specific cases, where surgery is not possible. The options include topical imiquimod, radiation therapy, cryosurgery and observation [4].

#### **2.2. Stage 3**

patients with stage 0 or stage 1a melanoma. The use of sentinel lymph node biopsy is only recommended in stage 1B in the presence of adverse prognostic indictors [4]. The likelihood of a positive sentinel lymph node biopsy increases with the Breslow's depth, with 2% in 1 mm, 7% in 1–1.99 mm, 13% in 1–1.99 mm, and 31% in 3 mm. In 710 cases of sentinel lymph node

Lymph node dissection plays an important role in the surgical management of melanoma. The MSLT-1 was a multicentre phase 3 trial, which randomised two groups of patients with localised melanoma more than 1 mm deep to receive either wide excision with lymphatic mapping and sentinel lymph node biopsy with immediate complete lymphadenectomy for sentinel node metastases or wide excision plus postoperative observation with a deferral of the complete lymphadenectomy until clinically evident disease became apparent. The trial comprised of 1270 patients with intermediate-thickness melanoma, 290 with thick melanoma, and 232 with thin melanoma. There was no difference between the immediate and delayed complete lymphadenectomy group in the absence of nodal disease in either the intermediate or thick melanomas group with respect to 10-year melanoma-specific survival rates. The survival rate was much improved in the presence of nodal disease in the biopsy vs. observation group in the intermediate thickness group. However, a similar benefit was not observed in the thick melanoma group. The patients with a positive sentinel lymph node biopsy had a worse prognosis vs. the patients with negative sentinel lymph node biopsy. Thus, there is a clear benefit to immediately complete lymphadenectomy following the identification of clinically occult disease in intermediate-thickness melanoma with respect to nodal recurrence, distant metastases and melanoma-specific survival. The timing of the complete lymphadenectomy does not appear to play an important role in thick melanomas. There is no benefit to immediate complete lymphadenectomy in the absence of clinically occult disease. Finally, the trial demonstrates that sentinel lymph node biopsy serves as an important prognostic tool [9].

Another important trial which assessed the role of complete lymph node dissection was the phase 3, multicentre, DeCOG-SLT trial. They examined whether complete lymph node dissection results in a better overall survival vs. conservative management in patients with positive sentinel lymph node biopsies. The patients had cutaneous melanoma of at least 1 mm depth and positive sentinel lymph node biopsies. The trial randomised 483 patients to either complete lymph node dissection or observation. There was no significant difference in terms of distant-metastasis free survival in the treatment or observation arm (74.9% vs. 77.0%). Furthermore, there was no significant difference in terms of 3 year overall survival between the treatment and observation arm (81.2% vs. 81.7%). There was only a small improvement in disease control in the treatment vs. the observation group 8% vs. 15%). It is important to note

Surgical management is the treatment of choice for primary cutaneous melanoma. Hence, the non-surgical options should only be advised in specific cases, where surgery is not possible. The options include topical imiquimod, radiation therapy, cryosurgery and observation [4].

that the majority of patients in that study had a low tumour burden [10].

*2.1.2. Non-surgical*

biopsy, 638 (88.5%) were alive without evidence of disease [8].

90 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

The ESMO guidelines suggest surgical excision and removal of the surrounding lymph nodes. They note that it is not sufficient to merely remove the disease-containing nodes. These guidelines define high-risk situations as the presence of multiple bulky lymph node metastases. The surgical management of stage III melanoma follows the same principles as above. The guidelines suggest the consideration of localised radiation therapy to the surrounding area in the case of high-risk disease. In the presence of inoperable, regionally advanced disease, the guidelines suggest therapies such as isolated limb perfusion, radiation therapy, electrochemotherapy or intralesional therapy [2].

In the presence of high-risk disease, systemic therapy should be considered. A recent phase 3 trial investigated the role of adjuvant immunotherapy in high risk regionally advanced to prevent recurrence. The trial entitled EORTC 18071 enrolled participants who underwent a surgical excision of cutaneous melanoma with clear margins. A total of 951 patients were randomly assigned to the treatment with either placebo or ipilimumab. The median recurrence survival was significantly improved in the ipilimumab treatment arm (26.1 months vs. 17.1 months). There were a large number of patients who discontinued ipilimumab due to adverse events (245/471). These adverse events were most commonly GI (75/472), hepatic (50/472), and endocrine (40/471). There were five treatment-related deaths in the ipilimumab treatment arm (three due to colitis, one due to myocarditis and one due to Guillain-Barré syndrome) [11]. The overall 5-year survival in the ipilimumab treatment arm at 5 years was 65.4% vs. 54.4% in the placebo arm [12].

However, the role of ipilimumab as the optimal adjuvant therapy has recently been challenged with the publication of a phase 3 trial, comparing adjuvant nivolumab vs. ipilimumab in resected stage 3 or 4 melanoma. A total of 906 patients were randomly assigned to either receive treatment with ipilimumab or nivolumab. The patients were followed up for at least 18 months. When the 12-month recurrence-free survival was compared in both groups, it was significantly higher in the nivolumab group (70.5% vs. 60.8% respectively). Nivolumab appeared to have a better overall side-effect profile, with 14.4% reporting grade 3 or 4 adverse treatment effects vs. 45.9% in the ipilimumab-treatment arm. Furthermore, while there were two deaths reported in the ipilimumab arm, there were no deaths recorded in the nivolumab arm [13].

A recent phase 3 trial published in 2017 suggests that the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib prove the optimal treatment option in stage III melanoma patients with the BRAF V600 mutations. A more detailed discussion regarding the mechanism of these drugs will be discussed in the stage IV section. They randomised patients with either a BRAF V600E or V600 K mutation to receive either a combination of dabrafenib and trametinib or placebo. They recruited 870 patients with adequately resected stage 3 melanoma. The overall 3-year survival was improved in the treatment arm vs. placebo (86% vs. 77%). The 3-year relapse free survival was 58% vs. 39% in the treatment vs. placebo arm, respectively. This trial suggests a role for combination BRAF/MEK therapy in stage 3 melanoma [14].

In conclusion, surgery with removal of surrounding lymph nodes remains the mainstay therapy for stage III disease. Several recent publications suggest a benefit to systemic therapy with checkpoint inhibitors or BRAF inhibitors if applicable in high-risk disease. Future guidelines will likely incorporate this recent research into their treatment strategies for regionally advanced disease.

80 years old harbouring the mutation. Furthermore, older patients are less likely to have the V600E mutation. Finally, patients with the mutant BRAF had historically worse outcomes

The Modern Approach to Targeting Melanoma http://dx.doi.org/10.5772/intechopen.73489 93

As a result of this new understanding of the underpinning genetic events that give rise to MM, there have been several drugs developed known as targeted therapy of the MAPK pathway. Initially, the broad spectrum tyrosine kinase, sorafenib, was trialled in melanoma patients [17]. The clinical trial results proved disappointing. There are two targeted therapies subsequently developed and currently licenced, which inhibit mutated BRAF: vemurafenib (formerly known as PLX4032) and dabrafenib. Vemurafenib was the first selective tyrosine kinase inhibitor licenced by the FDA in 2011. Dabrafenib is a potent and selective inhibitor of BRAF V600E kinase. Inhibition of the pathway may also be achieved by MEK inhibitors. Trametinib is a potent and selective inhibitor of MEK 1 and 2. These three MAPK targeted therapies are licenced by the US Food and Drink Authority for single-agent therapy against non-resectable or metastatic cutaneous MM. Combining MAPK pathway inhibitors is an important therapeutic strategy to minimise the development of drug resistance. There is an additional MEK inhibitor, known as cobimetinib licenced for combination therapy with vemurafenib. Similarly, dabrafenib and trametinib are licenced for combination therapy [18, 19]. BVD-523 (ulixertinib), an ERK1/2 inhibitor with high potency and selectivity, is currently under investigation. Preclinical investigations in vivo and in vitro appear promising, and clinical trials are underway. This may prove an important combination therapy or refractory

An important therapeutic limitation is the development of resistance to the MAPK pathway inhibitors. The current literature suggests that progression-free survival for patients receiving BRAF/MEK inhibitor combinations ranges from 9 to 11 months [21–23]. The exact mechanism of resistance has not been fully elucidated, and there is ongoing research into the development of resistance. Several different mechanisms of resistance have been posed in the literature.

As seen in the previous section, melanoma is a highly mutated cancer. Similarly, it is extremely an immunogenic cancer. Attenuating the immune system has proved an important therapeutic strategy. Immunotherapy targets 4 broad areas: (1) Checkpoint inhibitors. These agents negatively regulate inhibitors of pre-existing anti-tumour immune response (effectively augmenting the response of the immune system to the tumour cells, e.g., Anti-CTLA-4 inhibitors (ipilimumab), anti-PD-1/PD-L1 antibodies (nivolumab/pembrolizumab/atezolizumab) and IDO1 Inhibitors (Epacadostat); (2) Increasing the anti-tumour T cell response by administration of autologous ex-vivo augmented tumour infiltrating lymphocytes; (3) Administering oncolytic viruses into the metastatic cells to break-up the cells and increase the immune response and (4) Targeting dendritic cells to start and/or increase tumour antigen-specific

than the wild-type BRAF [16].

in future clinical practice [20].

**3. Immunotherapy**

immune responses [24].

#### **2.3. Stage 4**

The most significant breakthrough in melanoma in recent years has included the therapies designed for metastatic malignant melanoma. The main determinant of treatment strategy is the presence of resectable or unresectable disease. In the presence of resectable disease, the disease may be managed as the above. In the case of unresectable disease, the ESMO guidelines note that the optimal 1st-line therapy in melanoma remains under considerable debate. They suggest either anti-PD1 therapies or BRAFi/MEKi for BRAF-mutated melanomas. Chemotherapy has been relegated to 2nd-line therapy in the guidelines. However, in the case of aggressive metastatic disease, the guidelines note some benefit to polypharmacy, containing paclitaxel and carboplatin/cisplatin, vindesine, and dacarbazine [2]. Furthermore, radiation therapy is recommended in the presence of symptomatic brain metastases or painful bony metastases. However, the guidelines will likely evolve dramatically following the development of further therapeutic strategies.

#### *2.3.1. MAPK pathway inhibitors*

Dysregulation of the RAS/RAF/MEK/ERK MAPK pathway plays a pivotal role in the development of MM. In healthy cells, this pathway regulates several physiological cellular processes. The MAPK pathway is activated by growth factors which bind to the extracellular kinase receptor. This receptor-ligand complex leads to autophosphorylation of intracellular domains, which in turn results in phosphorylation and activation of the membrane-bound guanosine triphosphatase RAS. There is dimerisation of the serine/threonine kinases RAF. RAF is encoded by three different isoforms: ARAF, BRAF, and CRAF. The BRAF isoform encodes for the most powerful activator of the MAPK pathway. Activation of RAF causes a phosphorylation cascade, with the eventual activation of ERK. ERK is then free to translocate to the nucleus, where it activates several transcription factors that induce the expression of genes implicated in normal cell turnover and survival [15, 16].

In 2002, there was an exciting discovery that activating mutations in MAPK pathways play an essential role in most MM. A dysregulated MAPK pathway is present in ~40–50% of MM cases. The most common mutation resulting in dysregulation of the MAPK pathway is present on exon 15 and results in the switching of glutamate for valine at codon 600 (V600E). This mutation is located within the activating segment of the kinase domain. The mutant form of BRAF is more potent than the wild type variant. The mutant form results in constitutive activation of the MAPK pathway and increased ERK. The cellular endpoint is increased turnover and survival. The presence of BRAF mutations seems to be dictated by age; with 80% of patients less than 30 years old harbouring a mutation, while only 20% of patients over 80 years old harbouring the mutation. Furthermore, older patients are less likely to have the V600E mutation. Finally, patients with the mutant BRAF had historically worse outcomes than the wild-type BRAF [16].

As a result of this new understanding of the underpinning genetic events that give rise to MM, there have been several drugs developed known as targeted therapy of the MAPK pathway. Initially, the broad spectrum tyrosine kinase, sorafenib, was trialled in melanoma patients [17]. The clinical trial results proved disappointing. There are two targeted therapies subsequently developed and currently licenced, which inhibit mutated BRAF: vemurafenib (formerly known as PLX4032) and dabrafenib. Vemurafenib was the first selective tyrosine kinase inhibitor licenced by the FDA in 2011. Dabrafenib is a potent and selective inhibitor of BRAF V600E kinase. Inhibition of the pathway may also be achieved by MEK inhibitors. Trametinib is a potent and selective inhibitor of MEK 1 and 2. These three MAPK targeted therapies are licenced by the US Food and Drink Authority for single-agent therapy against non-resectable or metastatic cutaneous MM. Combining MAPK pathway inhibitors is an important therapeutic strategy to minimise the development of drug resistance. There is an additional MEK inhibitor, known as cobimetinib licenced for combination therapy with vemurafenib. Similarly, dabrafenib and trametinib are licenced for combination therapy [18, 19]. BVD-523 (ulixertinib), an ERK1/2 inhibitor with high potency and selectivity, is currently under investigation. Preclinical investigations in vivo and in vitro appear promising, and clinical trials are underway. This may prove an important combination therapy or refractory in future clinical practice [20].

An important therapeutic limitation is the development of resistance to the MAPK pathway inhibitors. The current literature suggests that progression-free survival for patients receiving BRAF/MEK inhibitor combinations ranges from 9 to 11 months [21–23]. The exact mechanism of resistance has not been fully elucidated, and there is ongoing research into the development of resistance. Several different mechanisms of resistance have been posed in the literature.
