**7.4 Targeted therapies**

Immune checkpoint inhibitors have become the standard of care in the treatment of metastatic CM. However, their role in MM is still under investigation. Cytotoxic T-lymphocyte-associated antigen (CTLA-4) and programmed-death (PD1) protein are the most common immune checkpoint targets expressed on activated T-cells with immunosuppressive effects. Ipilimumab is a fully human monoclonal that blocks the binding of CTLA4 with CD80 and CD86 ligands. It was the first agent approved for the treatment of advanced melanoma. It has an indirect effect on the T-cell mediated antitumor immune response. It prolongs survival in about 20% patients [58].

The ligands of PD1, PDL1 (B7H8) and PDL2 (B7DC) are expressed on tumor cells and other cell types. The immunosuppression of PD1 receptor is due to the interaction between T lymphocytes and tumor cells. PD1 blockage seems to be more effective toward t-cell activation than CTLA-4 inhibition. Nivolumab and pembrolizumab are humanized monoclonal antibodies against PD1. In a study of 44 MM patients having metastasis including 14 patients with AM, pembrolizumab was found to be more effective than ipilimumab in prolonging the PFS [59]. Another study reported the objective response rate of 23% and 37% in MM patients receiving nivolumab alone and in combination with ipilimumab respectively [60]. A study of eight patients treated by immunotherapy, one patient on PD-1 based combination therapy had stable disease and one patient with PD-1 monotherapy had complete response while rest of the six patients had progressive disease [35].

Mitogen-activated protein kinase (MAPK) pathway plays an important role in the cell survival, multiplication and differentiation. Overactivation of this pathway has been detected in various human cancers. Through this pathway many enzymatic kinases are expressed that are part of phosphorylation cascade including RAS, RAK, MEK and ERK kinases [61]. Overactivation of BRAF is one of the most common cause of abnormal MAPK signaling seen in cancers [62]. The MAPK pathway is activated in 40–50% cases of metastatic melanomas [63]. Hence, various BRAF and MEK inhibitors have been used for the treatment of metastatic melanoma.

Dabrafenib is a competitive reversible ATP inhibitor with selective BRAF inhibition. It has been found to be effective in 50–70% cases of melanomas with BRAF V600E or V600K mutations [64, 65]. Additionally, use of MEK inhibitors in combination with BRAF inhibitors such as vemurafenib plus cobimetinib or dabrafenib plus trametinib have prolonged PFS and OS of melanoma patients.

KIT kinase inhibitors such as sorafenib, imatinib, dasatinib, have been found to be very useful in the treatment of gastrointestinal stromal tumors. But they have not been very successful in the treatment of melanomas. However, some studies on KIT-mutated metastatic MM have shown good response to these KIT kinase inhibitors [66–69].

NRAS mutations are present in 15–20% cases of melanoma [70]. Tumors with NRAS mutations have aggressive tumor biology and show poor response to immune check point inhibitors [70]. MEK inhibitors especially binimetinib has shown promising results in phase II/III studies [71]. Several phase I/II trials testing the role of MEK inhibitors in combination with PI3K/AKT inhibitors are underway mainly including metastatic CM patients [70].

In summary, patients with AM, unlike CM, have poor response to targeted therapies. Also, the type of targeted therapy to be used depends upon the mutation analysis of the tumor as highlighted in **Figure 8**. However, the response rates with targeted therapies are better than conventional chemotherapy and are being increasingly used in clinical trials and oncology practice. Some immune checkpoints inhibitors and BRAF inhibitors are being used as adjuvant therapies in the ongoing clinical trials to reduce the recurrence rate after complete surgical excision.

## **7.5 Other therapies such as immune mediators such as interferon-a, interleukin-2**

Studies have found alfa-interferon to improve relapse-free survival and overall survival in patients with CM. In CM, particularly in patients with positive nodal involvement, α-interferon at the dose of 20 MU/m2/day intravenously 5 day weekly

**59**

*Anorectal Melanoma*

*DOI: http://dx.doi.org/10.5772/intechopen.93759*

However, their role in AM is not clear.

the resection margins were tumor-free [74].

**8. Prognostic factors**

**Figure 8.**

for 4 weeks, followed by 10 MU/m2/day subcutaneously three times weekly for 4–8 weeks had demonstrated a significant prolongation of DFS and OS [72].

*A flow chart outlining the use of various targeted therapies for the patients with anorectal melanoma (molecular testing—Mutation testing can be done by immunohistochemistry or next-generation or high-throughput sequencing (NSG); BRAF inhibitors—Dabrafenib, vemurafenib, encorafenib; MEK inhibitors—Trametinib, cobimetinib, binimetinib (MEK162); KIT inhibitors—Imatinib, sunitinib, nilotinib;* 

*immune checkpoint inhibitors—Ipilimumab, nivolumab, pembrolizumab).*

The 5-year survival rate of colorectal melanoma ranges from 4.3% to 17.4% [73]. The median survival of AM has been reported as 21 months [95% CI: 11–30] [15]. The

5-year OS rates of Stage I, II and III are 26.7%, 9.8% and 0% respectively [35]. A recent study by Menon et al. of 209 nonmetastatic AM patients found no significant difference in the median overall survival with chemotherapy (1.41 vs., 2.24 years, p = 0.16), radiotherapy (2.55 vs. 1.96 years, p = 0.31) and targeted therapy (2.07 vs. 1.96 years, p = 0.95) [52]. This study also found no benefit of adjuvant therapy in nonmetastatic AM cases after surgery. On the other hand, in 116 patients with metastatic disease, targeted therapy showed a trend toward higher survival (1.33 vs. 0.55 years, p = 0.06). On multivariate analysis, younger age, urban location of the patients and surgery were associated with better OS [52]. Other studies have found that age, tumor thickness, presence of ulceration, lymphovascular invasion, perineural invasion and tumor AJCC stage are the main predictors of survival [15, 39, 40]. The reported 1-,2-,3-,4-OS rates have been 67,40,40 and 32% in APR group and 100,100,67, and 67% in WLE group [39]. The median survival in WLE and APR groups were 36 and 13 months respectively [3]. In another study by Bello et al., no significant difference was found between WLE (n = 81) and APR (n = 14) provided

The site of origin of melanoma affects the prognosis as seen in cutaneous and mucosal melanoma. Whether the location of the tumor such as anal, rectal or anorectal affects the prognosis is not clear. In a study of 120 AM patients by Bello et al., the authors divided the patients in to three groups: anal (tumor below dentate line), anorectal (tumor at or traversing dentate line) and rectal (tumor above the dentate line). They found no significant difference in the DFS (23 vs. 28 vs. 27 months, p = 0.887) and

#### **Figure 8.**

*Melanoma*

disease [35].

inhibitors [66–69].

**interleukin-2**

including metastatic CM patients [70].

about 20% patients [58].

effect on the T-cell mediated antitumor immune response. It prolongs survival in

The ligands of PD1, PDL1 (B7H8) and PDL2 (B7DC) are expressed on tumor cells and other cell types. The immunosuppression of PD1 receptor is due to the interaction between T lymphocytes and tumor cells. PD1 blockage seems to be more effective toward t-cell activation than CTLA-4 inhibition. Nivolumab and pembrolizumab are humanized monoclonal antibodies against PD1. In a study of 44 MM patients having metastasis including 14 patients with AM, pembrolizumab was found to be more effective than ipilimumab in prolonging the PFS [59]. Another study reported the objective response rate of 23% and 37% in MM patients receiving nivolumab alone and in combination with ipilimumab respectively [60]. A study of eight patients treated by immunotherapy, one patient on PD-1 based combination therapy had stable disease and one patient with PD-1 monotherapy had complete response while rest of the six patients had progressive

Mitogen-activated protein kinase (MAPK) pathway plays an important role in the cell survival, multiplication and differentiation. Overactivation of this pathway has been detected in various human cancers. Through this pathway many enzymatic kinases are expressed that are part of phosphorylation cascade including RAS, RAK, MEK and ERK kinases [61]. Overactivation of BRAF is one of the most common cause of abnormal MAPK signaling seen in cancers [62]. The MAPK pathway is activated in 40–50% cases of metastatic melanomas [63]. Hence, various BRAF and

Dabrafenib is a competitive reversible ATP inhibitor with selective BRAF inhibition. It has been found to be effective in 50–70% cases of melanomas with BRAF V600E or V600K mutations [64, 65]. Additionally, use of MEK inhibitors in combination with BRAF inhibitors such as vemurafenib plus cobimetinib or dabrafenib

KIT kinase inhibitors such as sorafenib, imatinib, dasatinib, have been found to be very useful in the treatment of gastrointestinal stromal tumors. But they have not been very successful in the treatment of melanomas. However, some studies on KIT-mutated metastatic MM have shown good response to these KIT kinase

NRAS mutations are present in 15–20% cases of melanoma [70]. Tumors with NRAS mutations have aggressive tumor biology and show poor response to immune check point inhibitors [70]. MEK inhibitors especially binimetinib has shown promising results in phase II/III studies [71]. Several phase I/II trials testing the role of MEK inhibitors in combination with PI3K/AKT inhibitors are underway mainly

In summary, patients with AM, unlike CM, have poor response to targeted therapies. Also, the type of targeted therapy to be used depends upon the mutation analysis of the tumor as highlighted in **Figure 8**. However, the response rates with targeted therapies are better than conventional chemotherapy and are being increasingly used in clinical trials and oncology practice. Some immune checkpoints inhibitors and BRAF inhibitors are being used as adjuvant therapies in the ongoing

clinical trials to reduce the recurrence rate after complete surgical excision.

Studies have found alfa-interferon to improve relapse-free survival and overall survival in patients with CM. In CM, particularly in patients with positive nodal involvement, α-interferon at the dose of 20 MU/m2/day intravenously 5 day weekly

**7.5 Other therapies such as immune mediators such as interferon-a,** 

MEK inhibitors have been used for the treatment of metastatic melanoma.

plus trametinib have prolonged PFS and OS of melanoma patients.

**58**

*A flow chart outlining the use of various targeted therapies for the patients with anorectal melanoma (molecular testing—Mutation testing can be done by immunohistochemistry or next-generation or high-throughput sequencing (NSG); BRAF inhibitors—Dabrafenib, vemurafenib, encorafenib; MEK inhibitors—Trametinib, cobimetinib, binimetinib (MEK162); KIT inhibitors—Imatinib, sunitinib, nilotinib; immune checkpoint inhibitors—Ipilimumab, nivolumab, pembrolizumab).*

for 4 weeks, followed by 10 MU/m2/day subcutaneously three times weekly for 4–8 weeks had demonstrated a significant prolongation of DFS and OS [72]. However, their role in AM is not clear.

### **8. Prognostic factors**

The 5-year survival rate of colorectal melanoma ranges from 4.3% to 17.4% [73]. The median survival of AM has been reported as 21 months [95% CI: 11–30] [15]. The 5-year OS rates of Stage I, II and III are 26.7%, 9.8% and 0% respectively [35].

A recent study by Menon et al. of 209 nonmetastatic AM patients found no significant difference in the median overall survival with chemotherapy (1.41 vs., 2.24 years, p = 0.16), radiotherapy (2.55 vs. 1.96 years, p = 0.31) and targeted therapy (2.07 vs. 1.96 years, p = 0.95) [52]. This study also found no benefit of adjuvant therapy in nonmetastatic AM cases after surgery. On the other hand, in 116 patients with metastatic disease, targeted therapy showed a trend toward higher survival (1.33 vs. 0.55 years, p = 0.06). On multivariate analysis, younger age, urban location of the patients and surgery were associated with better OS [52]. Other studies have found that age, tumor thickness, presence of ulceration, lymphovascular invasion, perineural invasion and tumor AJCC stage are the main predictors of survival [15, 39, 40].

The reported 1-,2-,3-,4-OS rates have been 67,40,40 and 32% in APR group and 100,100,67, and 67% in WLE group [39]. The median survival in WLE and APR groups were 36 and 13 months respectively [3]. In another study by Bello et al., no significant difference was found between WLE (n = 81) and APR (n = 14) provided the resection margins were tumor-free [74].

The site of origin of melanoma affects the prognosis as seen in cutaneous and mucosal melanoma. Whether the location of the tumor such as anal, rectal or anorectal affects the prognosis is not clear. In a study of 120 AM patients by Bello et al., the authors divided the patients in to three groups: anal (tumor below dentate line), anorectal (tumor at or traversing dentate line) and rectal (tumor above the dentate line). They found no significant difference in the DFS (23 vs. 28 vs. 27 months, p = 0.887) and

#### *Melanoma*

OS (22 vs. 28 vs. 27 months, p = 0.696) between the three groups [74]. Additionally, they found no survival benefit with adjuvant radiation or systemic therapy.

In the largest study of 60 Asian patients with AM, the authors found age > 70 years, tumor size more than 5 cm, tumor thickness more than 10.5 mm, lymph nodal metastasis, tumor invasion beyond deep muscular layer to be associated with poor disease-specific survival on univariate analysis. Among these parameters, only age > 70 years and depth of tumor invasion were independent predictors of low disease-specific survival [75].
