Combination Therapies of Metastatic Melanoma and Melanoma

Brain Metastases

Jiarui Jiang

Department of Biology, University of Washington, Seattle, Washington, U.S.A.

Keywords: Immune Checkpoint Inhibitors, Combination Therapies, Metastatic Melanoma, Melanoma Brain

Metastases.

Abstract: Melanoma is a fatal cancer that develops in melanocytes and has the highest mortality rates in all types of

skin cancers. It generally starts as a primary tumor, spreads to adjacent lymph nodes, migrates to distant

sites of body through bloodstream, and becomes metastatic in this case. Melanoma brain metastases occur

when melanoma cancer cells disperse to the brain. However, compared to the survival rate of melanoma that

is localized (stage I, II) or regional (stage III), the survival rate in metastatic melanoma (stage IV) decreases

a lot, and it is imperative to find an effective treatment to prolong the survival. As immunotherapy has been

developed, one of the methods, checkpoint inhibitors provide higher overall survival and more enduring

objective response, which can be both used as monotherapies and combination therapies. In this review, we

will focus on the combination of checkpoint inhibitors as an impressive therapy for metastatic melanoma

and melanoma brain metastases and summarize its effect on the overall survival and response rate in

different clinical trials. The combination of radiotherapy and checkpoint inhibitors for treating melanoma

brain metastases is also explored. These combination therapies serve as potent treatments of metastatic

melanoma and its brain metastases.

1 INTRODUCTION

Ultraviolet rays (UV) from the sunlight are the

major cause of melanoma. Excessive sunlight

exposure leads to mutations in DNA in the skin

cells, and the mutation in the BRAF oncogene is the

most common one that found in almost half of the

melanomas. NRAS, CDKN2A, and NF1 are the

other genes affected by UVs. When mutations occur,

they keep turning on the oncogenes and make

melanocytes grow and divide abnormally, which

stimulates them to become cancerous (What Causes

Melanoma?, n.d.).

Melanoma develops from a primary tumor and

then propagate to distant sites of the body, such as

lymph nodes, the skin, brain, lungs, bones, and liver,

and such condition is called metastatic melanoma.

Symptoms are shown when there are metastases in

distant sites of the body. Melanoma is lethal, and

metastatic melanoma is the one that has extremely

poor survival rate in contrast to the melanoma that is

localized. Conventionally, surgery was utilized when

https://orcid.org/0000-0002-9651-0843

the tumor is dispersed to only one or several sites of

the body, and they were resectable. However, for

metastatic melanoma, surgery is impotent, and the

treatments of chemotherapy, radiotherapy, and

immunotherapy have become more appropriate.

Chemo drugs are applied in chemotherapy for

slowing the growth of cancer cells, such as

dacarbazine (DTIC) and temozolomide (Temodar).

Radiotherapy is given when the tumors are in the

location that can’t be moved easily, such as brain, or

in many sites of the body, and it is able to shrink

tumors. As the field of immunotherapy advances, it

has become the preferred treatment for metastatic

melanoma. Immune checkpoint inhibitors (ICI),

ipilimumab and nivolumab, are one of them that are

helpful and provide improved survival and

prolonged responses. Nivolumab and

pembrolizumab are anti-PD-1 checkpoint inhibitors,

which both can be employed as monotherapies or in

combination with ipilimumab. Ipilimumab is an anti-

CTLA-4 immune checkpoint inhibitor that triggers

the immune system to attack melanoma cells, but it

is less efficient than nivolumab and pembrolizumab

when it is using alone. Many studies have stated the

686

Jiang, J.

Combination Therapies of Metastatic Melanoma and Melanoma Brain Metastases.

DOI: 10.5220/0011255600003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 686-693

ISBN: 978-989-758-595-1

beneficial effects of using ipilimumab or nivolumab

monotherapy as treatments for metastatic cancers.

However, these monotherapies are not effective for

all patients with metastatic melanoma and melanoma

brain metastases. Therefore, in this review, we will

not only discuss the combination of nivolumab and

ipilimumab for treating metastatic uveal melanoma

and mucosal melanoma and its effect on patients in

clinical trials, but also explore the effect of

radiotherapy plus anti-PD-1 inhibitors or anti-

CTLA-4 inhibitors for treating melanoma brain

metastases.

2 MELANOMA

Melanoma is the deadliest form of skin cancer, and

it is brought about by the malignant tumor derive

from melanocytes which is a type of cell derived

from neural crest stem cells (NCSCs) that produces

and contains a UV absorbing pigment called

melanin. There are two forms of melanin generated

by melanocytes. One is, a black or brown pigment,

eumelanin. Since this pigment is dark, it serves as a

great shield for UV radiation, and that is why people

with darker skin have lower risk of skin cancer.

Indeed, the risk of getting skin cancer is related to

the color of skin, hair, and eyes. People who have

light skin, blond or red hair, and light eyes has

higher risk of gaining skin cancer than those with

darker ones. The other pigment is called

pheomelanin, which is red or yellow. Compared to

eumelanin, it offers less protection against UV

radiation, and the yielding of pheomelanin

stimulates the advent of cancer. This is due to

pheomelanin give more ultraviolet-A-induced

reactive oxidative species (ROS) which results in

more DNA damage reacting to UV radiation (Davis

et al., 2019).

2.1 Mortality Rates, Pathology, and

Clinical Manifestations of

Melanoma

Skin cancer is one of the most common cancers.

Although melanoma only occupies 1% of the skin

cancer, more than 75% mortalities was induced by it

among all types of skin cancers. According to

National Cancer Institute and SEER Database, there

are approximately 106,110 new cases of melanoma

in 2021, and 7,180 people will die due to this disease

(Melanoma of the Skin - Cancer Stat Facts, n.d.).

Melanoma is caused by the mutations in DNA which

are induced by excessive sun exposure. It can be

metastatic when melanocytes become malignant and

start to disperse to distant body parts, including soft

tissues (skin, muscle, and lymph nodes) and major

organs (liver, lung, and brain) (DiCaprio et al., 2020;

Rebecca et al., 2020). The first step of metastases is

to disseminate from the primary tumor to nearby

lymph nodes, and then the cancer cells enter the

bloodstream and travel to other body parts to form

new tumors (Melanoma Cells That Pass through

Lymph More Likely to Spread - National Cancer

Institute, 2020). Symptoms of melanoma that has

spread to other sites of body, for example, are

hardened lumps under skin, swollen or painful

lymph nodes, trouble breathing, bone pain, and

swelling of liver (Peri, n.d.). The survival rate of

metastatic melanoma is much lower than that of

melanoma that doesn’t spread based on statistics

from Cancer.Net, which drops from 80% to 27% in

metastatic melanoma (Melanoma - Statistics, 2012).

2.2 Conventional Treatments of

Melanoma

Conventional melanoma treatments include surgery,

chemotherapy, and radiation therapy. However,

surgery is not robust enough to treat metastatic

melanoma due to too many sites of tumors

throughout the body. Chemotherapy and

radiotherapy are more useful as the treatments for

metastatic melanoma. As Table 1 showed, there are

six chemotherapeutic drugs that are primarily used.

Dacarbazine (DTIC) was granted by Food and Drug

Administration (FDA) in 1975. However, when it

works as a single agent, it has poor efficacy on

treating metastatic melanoma, thus it doesn’t have

much effect on increasing the OS of patients. The

other chemotherapeutic drug temozolomide is a

substitute of DTIC and can be taken orally. There is

no significant difference on the effect of utilizing

DTIC and temozolomide. The major problem that

induces such low effectiveness is that melanoma

cells are intrinsically resistant to chemotherapy

(Mishra et al., 2018). Radiotherapy is mainly

utilized when melanoma spreads to the brain, which

is effective in shrinking the tumors. For melanoma

brain metastases, one of the radiotherapies called

stereotactic radiation therapy applies to only parts of

the brain that have tumor while preventing it from

damaging the surrounding normal brain cells

(Patient Education: Melanoma Treatment;

Advanced or Metastatic Melanoma (Beyond the

Basics) - UpToDate, n.d.). As the field of

immunology gets developed, the better

understanding of immune systems leads to a novel

Combination Therapies of Metastatic Melanoma and Melanoma Brain Metastases

687

method of treating metastatic cancers, which is

employing immune cells against cancers.

Table 1: The Chemo Drugs that Used to Treat Metastatic

Melanoma. (Commissioner, 2021).

Drug Name (Brand

Name

)

Years Approved by FDA

Dacarbazine (DTIC) May 1975 and January

1998

Temozolomide

(Temodar)

August 11th, 1999

Nab-paclitaxel

(

Abraxane

)

January 2005

Paclitaxel (Abraxane) January 25th, 2002

Cisplatin (Platinol) December 19th, 1978

Carbo

latin

(

Para

latin

)

Jul

14th, 2003

3 MONOTHERAPIES OF

MELANOMA

3.1 Nivolumab

Nivolumab is a fully human immunoglobulin (Ig)

G4 monoclonal antibody that binds to programmed

cell death protein 1(PD-1), a T-cell surface receptor,

and prevents it from being activated by the

programmed cell death ligand 1 (PD-L1) and

programmed cell death ligand 2 (PD-L2). Activated

PD-1 down regulates T-cell activation, helps tumors

evade from the immune attack, and promotes its

growth. By exploiting nivolumab, PD-1 remains

inactivated which enables T cell activation against

the tumors. Nivolumab is commonly used as a

remedy for melanoma, especially for the situation

when the tumor is unresectable or has metastasized.

(National Cancer Institute).

As a monotherapy, nivolumab improves the

objective response rate (ORR), progression free

survival (PFS), and overall survival (OS) compared

to chemotherapy. As Figure 1 showed, Larkin et al.

compared the overall survival in patients with

advanced melanoma using nivolumab versus

chemotherapy as a treatment in a phase III trial

(CheckMate 037). There were 272 patients treated

with nivolumab, and 133 patients were involved in

chemotherapy. The median OS was 16 months for

nivolumab and 14 months for chemotherapy. The

median PFS was 3.1 months in patients with

nivolumab and 3.7 months with chemotherapy.

Besides, the ORR was higher in nivolumab than in

chemotherapy (27% vs. 10%) (Larkin et al., 2018).

Another phase III trial, CheckMate 066, also

justified the increment in survival. There were 418

patients with metastatic melanoma, the ORR was

40% in those who had nivolumab and 13.9% for

patients with dacarbazine, a chemotherapy drug. The

median PFS was 5.1 months in nivolumab and 2.2

months in people with chemotherapy (O’Reilly &

Larkin, 2017). Figure 2 demonstrated that the overall

response rate was higher in melanoma patients

treated with nivolumab than those of treated with

chemotherapy in both phase III trials. Due to the

nivolumab’s durable response, this indication has

been approved by authorities, such as Food and

Drug Administration (FDA) and European Union

(EU). On December 20, 2017, nivolumab was

approved by FDA as a treatment for melanoma.

(Food and Drug Administration). Nivolumab was

also granted for treating advanced melanoma in

adults in EU. (European Medicines Agency).

Figure 1: The Overall Survival of Advanced Melanoma

Patients Using Nivolumab vs. Chemotherapy in

CheckMate 037.

Figure 2: The Overall Response Rate (ORR) of Melanoma

Patients Treating with Nivolumab or Chemotherapy in

CheckMate 037 vs. CheckMate 066.

3.2 Ipilimumab

Ipilimumab is a recombinant human

immunoglobulin (Ig) G1 monoclonal antibody that

targets cytotoxic T-lymphocyte-associated antigen 4

(CTLA-4), a surface receptor on T-cell. Since

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

688

CTLA-4 down regulates the immune system,

ipilimumab binds to and inhibits it in order to

activate the immune responses. Ipilimumab also

shuts down the inhibitory mechanisms on cytotoxic

T lymphocytes (CTLs), which kill cancer cells, thus

immune responses against cancer are boosted up.

Ipilimumab can be favorable for patients who have

had surgery for removing melanoma, in which it can

work as an adjuvant therapy. Similar to nivolumab,

it can also be effective for adults who have

metastatic melanoma. (National Cancer Institute).

In contrast to nivolumab monotherapy,

ipilimumab monotherapy has shorter PFS and

ORRs. In a phase III trial, CheckMate 238, there

were 906 patients who were undergone IV

melanoma. At 18 months follow-up, the 12 months

recurrence-free survival was 70.5% in patients with

nivolumab and 60.8% in ipilimumab (Weber et al.,

2017). As Figure 3 displayed, a phase III trial

(CheckMate 067) conducted by Hodi et al. also

proved that nivolumab had greater overall survival

than ipilimumab. There were 945 patients involved

in the study. Three hundred and sixteen patients

were assigned with nivolumab, 315 patients were

given ipilimumab, and other patients gained

nivolumab plus ipilimumab. The median OS was

36.9 months in the nivolumab group and 19.9

months in the ipilimumab group. The median PFS

was 6.9 months in nivolumab while the ipilimumab

group was much lower (2.9 months) (Hodi et al.,

2018). Ipilimumab was approved by FDA as a

therapy for melanoma prior to nivolumab. (Food and

Drug Administration). Many recent studies

illustrated that nivolumab plus ipilimumab as first-

line therapy can achieve a more durable and

continuous survival benefit in patients with

advanced melanoma.

Figure 3: The Overall Survival of Advanced Melanoma

Patients Treated with Nivolumab vs. Ipilimumab in

CheckMate 067.

4 COMBINATION OF

ANTI-CTLA-4 ANTIBODY AND

ANTI-PD-1 ANTIBODY

To minimize adverse events and increase the

response rate using immunotherapies, it is vital to

discover decent checkpoints to adjust the immune

response and monoclonal antibodies that target the

checkpoints. CTLA-4 and PD-1 are the two potent

checkpoints, and there are drugs that are developed

modulate the effect of CTLA-4 and PD-1 for

treating metastatic melanoma, including CTLA-4

blockers ipilimumab, PD-1 blockers nivolumab, and

PD-1 blockers pembrolizumab (Rotte, 2019). The

two antibodies ipilimumab and nivolumab are

approved on December 22, 2014, by Food and Drug

Administration (FDA) for treating metastatic

melanoma (Hazarika et al., 2017). Anti-CTLA-4 and

anti-PD-1 antibodies can generate durable response

and their adverse events are manageable. However,

these advantages can’t be demonstrated when

utilizing either CTLA-4 blockers or PD-1 blockers

as monotherapies. Patients with metastatic

melanoma are rarely respond to monotherapy (Rotte,

2019). In this case, combination therapies become

significance because they activate anti-tumor

response, increase response rates, and provide rapid

and considerable tumor regression. There are many

clinical studies focused on combination therapies for

treating melanoma. For instance, when phase I

studies received the combination of nivolumab and

ipilimumab, they displayed that tumor regression

appeared in approximately 50% patients with

metastatic melanoma, and 85% of them still survive

after 1-year treatment (Koppolu, n.d.).

4.1 CTLA-4 Inhibitor Plus PD-1

Inhibitor for Metastatic Uveal

Melanoma and Mucosal Melanoma

The addition of CTLA-4 inhibitor and PD-1

inhibitor can also be useful in treating subtypes of

melanoma. For example, it can be impressive for

metastatic uveal melanoma. Uveal melanoma arises

from melanocytes in the iris. It is very rare, and only

five of one million people getting this type of

melanoma each year (Afzal et al., 2018).

Traditionally, metastatic uveal melanoma (MUM)

was treated with chemotherapy alone, but most

patients had poor response or no response to it. In a

systematic review, 841 patients from 40 different

reports were investigated. The overall response rate

(ORR) is only 4.6%, and there were 22 studies that

demonstrated no response to chemotherapy (Buder

The median OS The median PFS

Months

Nivolumab (N = 316) Ipilimumab (N = 315)

Combination Therapies of Metastatic Melanoma and Melanoma Brain Metastases

689

et al., 2013). Compared to employing chemotherapy

alone, the efficacy of combining nivolumab and

ipilimumab on treating MUM is greater based on the

data listed in the prospective phase II GEM1402 trial

(NCT02626962). The ORR was 12%, the median

progression free survival (PFS) was 3.3 months, and

the median OS was 12.7 months (Piulats Rodriguez

et al., 2018). Heppt et al. also analyzed the effect of

utilizing both PD-1 inhibitors only and the

combination of ipilimumab and PD-1 inhibitors in a

clinical trial with 96 MUM patients. For PD-1

inhibitor monotherapy, pembrolizumab was given in

54 patients (25 females and 29 males), and

nivolumab was in 32 patients (13 females and 19

males). The ORR was 4.7% with four patients

demonstrated a PR, and there was no complete

response observed. The median PFS was 3.1 months

in patients with pembrolizumab and 2.8 months with

nivolumab. The median OS was 14.0 months for

pembrolizumab and 10.0 months for nivolumab.

Combining ipilimumab and PD-1 inhibitors leads to

higher ORR compared to monotherapy. Fifteen

patients were investigated, and twelve patients

developed response. There was still no complete

response and only two PRs. The ORR was 16.7%,

which is much larger than the 4.7% ORR in

monotherapy (Heppt et al., 2017).

The potency of the combination of ipilimumab

and nivolumab is also compelling in treating patients

with mucosal melanoma (MM). It is a rare and

aggressive disease with insufficient prognosis. Only

1.5 per million people every year are diagnosed with

MM. The common sites for MM are head and neck

(41%). The cutting of surgery is the primary method

for head and neck MMs, and radiotherapy is always

applied for local control after the surgery (Ascierto

et al., 2017). Even though immune checkpoint

inhibitors have become a promising option for MMs,

the clinical use for it still remains inadequate (Li et

al., 2020). In a pooled analysis, Sandra et al.

reported the competence of nivolumab alone and the

mix with ipilimumab. In clinical studies, 889

patients were received only nivolumab. Among

them, 86 (10%) were mucosal melanoma patients

and 665 (75%) had cutaneous melanoma. For the

addition of nivolumab and ipilimumab, there were

35 mucosal melanoma patients and 326 patients with

cutaneous melanoma. The outcome illustrated that

the median PFS was 3.0 months, and Figure 4

showed that the ORR was 23.3% for MM patients

who accepted nivolumab monotherapy. Combining

nivolumab and ipilimumab manifested a higher

median PFS in patients that was 5.9 months. As

Figure 4 displayed, the ORR was also boosted to

37.1% (D’Angelo et al., 2017). The performance of

the combo seems to be more superior than that of the

agent using alone. Another case report by Fujimura

et al. confirmed the efficiency of this combination

method again. The patient was an 81-year-old

Japanese woman who had anti-PD-1 Ab-resistant

recurrent malignant melanoma of nasal cavity. They

found out that denosumab could enhance the anti-

tumor effects of incorporating nivolumab and

ipilimumab and successfully resolve the advanced

anti-PD-1 Ab-resistant mucosal melanoma by

blending denosumab, nivolumab, and ipilimumab as

a second-line therapy (Fujimura et al., 2020).

Figure 4: The Overall Response Rate in Mucosal

Melanoma Patients Treated with Nivolumab Monotherapy

vs. Nivolumab and Ipilimumab Combination Therapy.

5 COMBINED TREATMENTS

FOR MELANOMA BRAIN

METASTASES

Approximately 20% patients with cancer will

develop brain metastases. Melanoma brain

metastases (MBM) is one of the major ones (7% -

16%) (Berghoff et al., 2016). Brain metastases occur

when tumor cells disperse from a primary tumor

through the blood to the brain microvasculature. The

microenvironment of the brain microvasculature

bolsters the growth of tumors. Among different

ethnic groups, African Americans who are 50 to 59-

year-old with melanoma tended to have larger

probability getting brain metastases. For various

subsets of brain metastases, people with melanoma

have the highest likelihood of obtaining

leptomeningeal metastases, the one in the lining of

brain or spine (Achrol et al., 2019).

Treatments for brain metastases include surgery

if it is in a surgically accessible region, whole brain

radiotherapy (WBRT) for multiple symptomatic

brain metastases, stereotactic radiosurgery (SRS)

treating metastatic lesions without damaging the

surrounding brain tissues, systemic therapy that

conjugates with local therapy and provides greater

intracranial control, cytotoxic therapy, targeted

therapy, and immunotherapy (Rishi & Yu, 2020).

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

690

5.1 Nivolumab Plus Ipilimumab

Treatment

Within immunotherapy, the combination of

nivolumab and ipilimumab presented an essential

efficaciousness in patients who had melanoma brain

metastases. According to a phase II study

(NCT02320058) with 94 melanoma patients who

had at least one brain metastasis (tumor diameter 0.5

to 3 cm). The trial indicated that the intracranial

clinical benefit rate (CBR) was 57%, the complete

response was 26%, and partial response was 30%.

This study affirmed that adding nivolumab and

ipilimumab was impressive for melanoma patients

who had untreated brain metastases (Combined

Nivolumab and Ipilimumab in Melanoma Metastatic

to the Brain | NEJM, n.d.). Recently, this phase II

study (NCT02320058) updated their data for

asymptomatic patients. The intracranial CBR was

58.4% for 101 asymptomatic patients, and the PFS

and OS were still investigating. Due to the reliable

clinical benefits in asymptomatic MBM patients,

nivolumab plus ipilimumab was considered as the

first-line therapy (Tawbi et al., 2021).

5.2 Radiotherapy Plus PD-1 or

CTLA-4 Blockers

Moreover, except for conjoining the immune

checkpoint inhibitors, stereotactic radiosurgery

(SRS) along with nivolumab or ipilimumab can also

serve as a way for patients with MBM. Giuseppe et

al. examined the adequacy of concurrent SRS plus

nivolumab or ipilimumab for patients with untreated

MBM. Eighty patients with 326 MBM were engaged

in the study. There were 45 patients gained the SRS

and ipilimumab, and 35 patients got SRS and

nivolumab. The median follow-up was 15 months.

Among the 45 patients with SRS and ipilimumab, 32

of them (71%) obtained an intracranial progression

event while 20 patients (57%) in the SRS and

nivolumab group got such advancement. The median

OS was 22.0 months for the SRS and nivolumab

group and 14.7 months in patients with SRS and

ipilimumab. Besides, the 12-month and 24-month

survival probabilities were 78% and 42% for the

SRS and nivolumab patients. Compared to that, the

SRS and ipilimumab group had lower rate, which

were 68% and 20% individually. Both groups

exhibited valid intracranial activities, and the combo

of SRS and nivolumab had more excellent

intracranial control (Minniti et al., 2019).

6 CONCLUSIONS

Combination therapies of immune checkpoint

inhibitors have the bright future for treating

metastatic melanoma and melanoma brain

metastases. As I mentioned before, immune

checkpoint inhibitors, anti-PD-1 and anti-CTLA-4

inhibitors target the checkpoint proteins and turn on

the immune response against the melanoma cells.

However, no matter checkpoint inhibitors are used

as individual therapy or combing with one another,

all of them can generate immune-related adverse

events (irAEs), which can be life-threatening. For

ICIs that combines with another existing therapy,

this may cause severe immune related adverse

events happen more frequently. For instance,

therapies that involve anti-CTLA-4 inhibitors have

higher incidence of irAEs occurring in the

gastrointestinal tract, renal system, and endocrine

system. Most irAEs of anti-PD-1 therapies appear at

endocrine system, gastrointestinal tract,

musculoskeletal system, and hepatobiliary system.

Thus, it is necessary for future research to identify

predictive biomarkers for irAEs which can not only

help patients with metastatic melanoma and select

the therapy that has optimal benefits, but also avoid

the toxicities. There’s also a need for next generation

research to investigate and evaluate the drugs that

can improve the response to ICIs, such as microbiota

modifiers, drugs targeting co-inhibitory receptors,

and oncolytic viruses.

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