Malignant melanoma is a type of skin cancer that results from malignant changes of cells that produce melanin. Usually, it manifests in the skin but may also present in eyes, ears, stomach, lips and mucosa of reproductive organs. Statistical reports show that the incidence of malignant melanoma is rising. In South Korea, malignant melanoma accounts for 211 cases (16%) of total of 1,322 cases in skin cancers. 
Curative resection may be possible in early diagnosis in melanoma. However, patients with lymph node and distant metastasis cannot be surgically treated. Instead, they receive systemic chemotherapy. In the past, IFN-alpha was the standard of treatment with a median overall survival of 6-9 months. However, immune checkpoint inhibitors such as PD-1 inhibitors (nivolumab, pembrolizumab) have shown superior efficacy and are now standard treatment options.
There are different types of malignant melanoma. In South Korea, the most common type is acral-lentigious which accounts for 60% of all melanoma. Usually it involves the hands, feet and mucosa. This subtype is not related with UV (ultraviolet) ray and have lower response to PD-1 inhibitors. 
Thus, the purpose of our phase 2 study is to maximize the efficacy of PD-1 inhibitors by adding radiotherapy to the current standard of treatment. Recently, pre-clinical data shows that radiotherapy increases PD-1 expressions, thereby increasing the efficacy PD-1 inhibitors. There were also reports that even lesions not treated with radiotherapy benefitted from radiotherapy. This phenomenon, known as abscopal effect, was also evident in malignant melanoma. Our study aims to evaluate the objective response rate (ORR) of the combination of PD-1 inhibitors such as nivolumab and pembrolizumab with radiotherapy. 
This clinical trial will be conducted in Yonsei Cancer Center with a total enrollment of 52 patients. We expect our study duration to be 3 years. Patients will either receive nivolumab every two weeks or pembrolizumab intravenously every three weeks. Patients are to get regular physical examinations, laboratory test and check-ups to evaluate adverse events. Treatment schedules and doses may change depending on the patient’s condition or laboratory and imaging results. Response evaluation will be conducted every two months. Treatments will be discontinued if the patient’s disease progress, experiences adverse events from treatment or wishes to withhold from the clinical trial. Patients will be followed regularly every three months to follow up on disease status, treatment history and survival.

Treatment

Patients diagnosed with stage IIIB-IVM1c malignant melanoma will be enrolled in the clinical trial. They will be treated with anti-PD-1 agents such as nivolumab or pembrolizumab. Nivolumab will be administered 3mg/kg every two weeks and pembrolizumab 200mg as fixed dose every three weeks. We plan to start radiotherapy on the day PD-1 inhibitor is given, but will allow window period of 2 weeks once the PD-1 inhibitor is administered. Radiation dose and schedule may vary depending on the location of radiation field. After the radiotherapy is completed, patients will continue receiving PD-1 inhibitor until disease progression or adverse events.

Arm Label

Target Number of Participant

Arm Type

Arm Description

They will be treated with anti-PD-1 agents such as nivolumab or pembrolizumab. Nivolumab will be administered 3mg/kg every two weeks and pembrolizumab 200mg as fixed dose every three weeks. We plan to start radiotherapy on the day PD-1 inhibitor is given, but will allow window period of 2 weeks once the PD-1 inhibitor is administered.

Gender

Age

Description

1. Subject has provided informed consent prior to initiation of any study-specific activities/procedures
2. Male or female age ≥ 20 years at the time of informed consent 
3. Histologically confirmed diagnosis of malignant melanoma
4. unresectable stage IIIB, IIIC, IVM1a, IVM1b or IVM1c melanoma 
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
6. Screening labs performed within 14 days of randomization demonstrating adequate hematologic, coagulation, liver, and kidney functions
7. Indications for radiotherapy
8. BRAF status must be checked, but patient is eligible regardless of BRAF mutations (BRAF V600 mutation positive patients are eligible)

1. Ocular melanoma
2. Active, uncontrolled brain metastasis (requires 1 month of washout period radiation therapy, surgery or gamma-knife surgery)
3. Previous treatment with chemotherapy, a CTLA-4 or PD-1/PD-L1 antagonist agent, including treatment in adjuvant setting for immunotherapy 
4. Concurrent medical disease which would significantly limit full compliance with the study such as, but not limited to the following: heart failure (III, IV as per NYHA classification), renal insufficiency, active infection (requires negative gest for clinically suspected HIV, hepatitis B virus, hepatitis C virus).
If positive results are not indicative of true active or chronic infection, the subject may enter the study after discussion and agreement between the investigator and medical director. 
5. Has known malignancy diagnosed within three years that is progressing and requires active treatment are excluded.
6. Autoimmune disease requiring chronic treatment with systemic corticosteroids or any other immunosuppressive agents 7 days prior to inclusion
-Exception: intranasal glucocorticoid and intra-articular steroid injections
-Exception: administration of prednisolone 10mg/day or equivalent as physiologic dose for adrenal insufficiency
-Exception: steroid as pre-medication to prevent anaphylactic shock (contrast with CT, other systemic treatment)
8. Has known psychiatric or substance abuse disorders that would interfere with cooperation requirements of the trial 
9. Lack of availability for clinical follow-up assessments

objective response rate, ORR

adverse event

1 year PFS (%))

overall survival, OS