A Study to Compare the Administration of Pembrolizumab After Surgery Versus Administration Both Before and After Surgery for High-Risk Melanoma

• ClinicalTrials.gov Identifier: NCT03698019
• Recruitment Status: Active, not recruiting
• First Posted: October 5, 2018
• Results First Posted: November 21, 2023
• Last Update Posted: February 15, 2024
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Acral Lentiginous Melanoma; Clinical Stage III Cutaneous Melanoma AJCC v8; Clinical Stage IV Cutaneous Melanoma AJCC v8; Mucosal Melanoma
• Interventions: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Biological: Pembrolizumab; Procedure: Therapeutic Conventional Surgery
• Enrollment: 313

Participant Flow

Recruitment Details
Pre-assignment Details	Three hundred forty-five participants were assessed for eligibility. Thirty-two participants were deemed ineligible for either not having measurable disease, per RECIST criteria (27 participants), or having an ineligible disease stage (5). The remaining 313 eligible participants were randomized.

Arm/Group Title	Arm I (Adjuvant Pembrolizumab)	Arm II (Adjuvant and Neoadjuvant Pembrolizumab)
Arm/Group Description	Within 17 days (preferably within 14 days) days after IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery	Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3 cycles, then undergo surgery within 3 weeks. Within 84 days, patients receive pembrolizumab IV over 30 minutes every 3 weeks for 15 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery
Period Title: Step 1: Registration
Started	159	154
Completed	151	127
Not Completed	8	27
Reason Not Completed
Still receiving protocol therapy	0	10
Withdrawal by Subject	7	2
Toxicity	0	1
Disease Progression	0	12
Co-morbidities	0	1
Scheduling Issues	1	0
Participant Refusal	0	1
Period Title: Step 2: Surgery
Started	151	127
Completed	130	109
Not Completed	21	18
Reason Not Completed
Participant Refusal	2	1
Neoadjuvant Toxicity	0	3
Metastatic Disease	16	9
Residual Disease	2	1
Trial Closed due to Covid-19	0	1
Concerns about Exposure to Covid-19	0	1
Disease other than melanoma identified at surgery	0	2
Radiotherapy-related Delays	1	0
Period Title: Step 3: Adjuvant Pembrolizumab
Started	130	109
Completed	38	50
Not Completed	92	59
Reason Not Completed
Still receiving protocol therapy	41	33
Disease Progression	41	9
Death	4	1
Other, unspecified reasons	6	16

Baseline Characteristics

Arm/Group Title		Arm I (Adjuvant Pembrolizumab)	Arm II (Adjuvant and Neoadjuvant Pembrolizumab)	Total
Arm/Group Description		Within 17 days (preferably within 14 days) days after IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery	Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3 cycles, then undergo surgery within 3 weeks. Within 84 days, patients receive pembrolizumab IV over 30 minutes every 3 weeks for 15 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery	Total of all reporting groups
Overall Number of Baseline Participants		159	154	313
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	159 participants	154 participants	313 participants
		62; (22 to 88)	64; (19 to 90)	64; (19 to 90)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	159 participants	154 participants	313 participants
	Female	48 30.2%	62 40.3%	110 35.1%
	Male	111 69.8%	92 59.7%	203 64.9%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	159 participants	154 participants	313 participants
	Hispanic or Latino	4 2.5%	9 5.8%	13 4.2%
	Not Hispanic or Latino	151 95.0%	136 88.3%	287 91.7%
	Unknown or Not Reported	4 2.5%	9 5.8%	13 4.2%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	159 participants	154 participants	313 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	2 1.3%	2 1.3%	4 1.3%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	2 1.3%	1 0.6%	3 1.0%
	White	150 94.3%	141 91.6%	291 93.0%
	More than one race	1 0.6%	0 0.0%	1 0.3%
	Unknown or Not Reported	4 2.5%	10 6.5%	14 4.5%
Zubrod Performance Status Score [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	159 participants	154 participants	313 participants
0		125 78.6%	113 73.4%	238 76.0%
1		33 20.8%	39 25.3%	72 23.0%
2		0 0.0%	1 0.6%	1 0.3%
Missing/Not Reported		1 0.6%	1 0.6%	2 0.6%
		[1] Measure Description: Zubrod's performance-status scores range from 0 to 5, with higher scores indicating greater disability; a score of 0 indicates that the participant is fully active, 1 that the patient is restricted in strenuous activity but is ambulatory, and 2 that the participant is unable to work but is ambulatory and capable of self-care and up and about more than 50% of waking hours.
LDH Level [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	159 participants	154 participants	313 participants
Low or Normal		138 86.8%	132 85.7%	270 86.3%
High		21 13.2%	22 14.3%	43 13.7%
		[1] Measure Description: LDH denotes lactate dehydrogenase.
Disease Stage [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	159 participants	154 participants	313 participants
IIIB		64 40.3%	62 40.3%	126 40.3%
IIIC		74 46.5%	69 44.8%	143 45.7%
IIID		10 6.3%	9 5.8%	19 6.1%
IV		11 6.9%	14 9.1%	25 8.0%
		[1] Measure Description: Stages are defined according to the American Joint Committee on Cancer 'Cancer Staging Manual', 8th edition.
Primary Melanoma Subtype; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	159 participants	154 participants	313 participants
Cutaneous or Unknown		153 96.2%	143 92.9%	296 94.6%
Acral		5 3.1%	4 2.6%	9 2.9%
Mucosal		0 0.0%	4 2.6%	4 1.3%
Missing/Not Reported		1 0.6%	3 1.9%	4 1.3%
Ulceration; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	159 participants	154 participants	313 participants
Yes		46 28.9%	56 36.4%	102 32.6%
No		58 36.5%	50 32.5%	108 34.5%
Unknown		55 34.6%	46 29.9%	101 32.3%
Missing/Not Reported		0 0.0%	2 1.3%	2 0.6%
BRAF Mutation Status; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	159 participants	154 participants	313 participants
Mutated		38 23.9%	41 26.6%	79 25.2%
Wild-type		64 40.3%	62 40.3%	126 40.3%
Unknown		57 35.8%	51 33.1%	108 34.5%
Previous BRAF and MEK Adjuvant Therapy; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	159 participants	154 participants	313 participants
Yes		1 0.6%	3 1.9%	4 1.3%
No		158 99.4%	151 98.1%	309 98.7%
Previous Radiotherapy; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	159 participants	154 participants	313 participants
Yes		1 0.6%	2 1.3%	3 1.0%
No		158 99.4%	152 98.7%	310 99.0%

Outcome Measures

1. Primary Outcome

Title	Two-Year Event-Free Survival Rate
Description	Event-free survival (EFS) is measured from date of randomization to date of first: documentation of progression that render participant unable to receive planned protocol surgery, off protocol therapy for any reason without subsequent protocol surgery, failure to begin adjuvant therapy within 84 days after surgery, relapse after surgery or death due to any cause. Participants last known to be alive and event-free are censored at date of last contact. All events that occurred before the start of adjuvant therapy were assigned an event date of 84 days.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Adjuvant Pembrolizumab)	Arm II (Adjuvant and Neoadjuvant Pembrolizumab)
Arm/Group Description:	Within 17 days (preferably within 14 days) days after IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery	Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3 cycles, then undergo surgery within 3 weeks. Within 84 days, patients receive pembrolizumab IV over 30 minutes every 3 weeks for 15 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery
Overall Number of Participants Analyzed	159	154
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	49; (41 to 59)	72; (64 to 80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Adjuvant Pembrolizumab), Arm II (Adjuvant and Neoadjuvant Pembrolizumab)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.004
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Number of Participants With Grade 3 Through 5 Adverse Events That Are Related to Study Drug
Description	Only adverse events that are possibly, probably or definitely related to study drug are reported.
Time Frame	Duration of treatment and follow-up until relapse, death, or 3.5 years post randomization.

Outcome Measure Data

Analysis Population Description

Eligible participants that received protocol treatment

Arm/Group Title	Arm I (Adjuvant Pembrolizumab)	Arm II (Adjuvant and Neoadjuvant Pembrolizumab)
Arm/Group Description:	Within 17 days (preferably within 14 days) days after IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery	Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3 cycles, then undergo surgery within 3 weeks. Within 84 days, patients receive pembrolizumab IV over 30 minutes every 3 weeks for 15 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery
Overall Number of Participants Analyzed	141	152
Measure Type: Number; Unit of Measure: Participants
Adrenal insufficiency	0	1
Alanine aminotransferase increased	3	5
Alkaline phosphatase increased	0	1
Anemia	0	1
Arthralgia	1	0
Arthritis	1	0
Aspartate aminotransferase increased	2	4
Blood and lymphatic system disorders - Other, spec	1	0
Cardiac disorders - Other, specify	1	0
Cardiac troponin I increased	0	1
Chest wall pain	1	0
Cognitive disturbance	1	0
Colitis	0	1
Dehydration	0	1
Diarrhea	1	2
Electrocardiogram QT corrected interval prolonged	0	1
Fall	0	1
Fatigue	2	0
Febrile neutropenia	1	0
Fever	0	2
Gallbladder infection	1	0
Headache	0	1
Hematoma	1	0
Hepatobiliary disorders - Other, specify	1	0
Hyperglycemia	3	2
Hypertension	2	3
Hypokalemia	0	2
Hyponatremia	0	1
Hypothyroidism	1	0
Infections and infestations - Other, specify	1	0
Lung infection	0	2
Lymphocyte count decreased	3	0
Metabolism and nutrition disorders - Other, specif	1	0
Myalgia	1	0
Myocarditis	1	2
Myositis	1	0
Nausea	0	2
Neutrophil count decreased	0	1
Platelet count decreased	1	0
Pneumonitis	0	2
Pruritus	2	1
Rash maculo-papular	4	2
Respiratory failure	1	0
Sepsis	0	1
Seroma	1	1
Skin and subcutaneous tissue disorders - Other, sp	0	1
Skin infection	1	1
Small intestinal obstruction	1	0
Soft tissue infection	0	1
Stroke	0	1
Surgical and medical procedures - Other, specify	0	1
Syncope	1	2
Thromboembolic event	1	1
Urinary tract infection	1	1
Vomiting	0	1
White blood cell decreased	0	1
Wound dehiscence	0	1
Wound infection	0	2

3. Secondary Outcome

Title	Two-Year Overall Survival Rate
Description	Overall survival (OS) is measured from date of randomization to date of death due to any cause. Participants known to be alive are censored at date of last contact.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Adjuvant Pembrolizumab)	Arm II (Adjuvant and Neoadjuvant Pembrolizumab)
Arm/Group Description:	Within 17 days (preferably within 14 days) days after IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery	Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3 cycles, then undergo surgery within 3 weeks. Within 84 days, patients receive pembrolizumab IV over 30 minutes every 3 weeks for 15 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery
Overall Number of Participants Analyzed	159	154
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	79; (71 to 89)	87; (80 to 95)

4. Secondary Outcome

Title	Response Rate
Description	On the neoadjuvant arm, the response rate was assessed after neoadjuvant therapy and before surgical resection. The response rate includes both complete response (CR) and partial response (PR). CR is defined as complete disappearance of all target and non-target lesions, no new lesions, and no disease related symptoms. PR is defined as greater than or equal to 30% decrease under baseline of the sum of all appropriate diameters of all target measurable lesions, no unequivocal progression or non-measurable disease, and no new lesions. The best response rate is calculated from the sequence of objective statuses. CR is defined as two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. PR is defined as two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration, but not qualifying as CR.
Time Frame	2 years

Outcome Measure Data Not Reported

5. Secondary Outcome

Title	Number of Participants Receiving Surgery
Description	To determine the number of participants on each arm who received the surgery planned at randomization.
Time Frame	2.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Adjuvant Pembrolizumab)	Arm II (Adjuvant and Neoadjuvant Pembrolizumab)
Arm/Group Description:	Within 17 days (preferably within 14 days) days after IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery	Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3 cycles, then undergo surgery within 3 weeks. Within 84 days, patients receive pembrolizumab IV over 30 minutes every 3 weeks for 15 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery
Overall Number of Participants Analyzed	159	154
Measure Type: Count of Participants; Unit of Measure: Participants
	151 95.0%	127 82.5%

Adverse Events

Time Frame	Duration of treatment and follow-up until relapse, death, or 3.5 years post randomization
Adverse Event Reporting Description	AEs and SAEs are reported by CTCAE v5.0. 152 participants on the neoadjuvant arm and 141 participants on the adjuvant arm that were eligible and received some protocol treatment were evaluable for AEs. 154 eligible participants on the neoadjuvant arm and 159 eligible participants on the adjuvant arm were analyzed for all-cause mortality.
Arm/Group Title	Arm I (Adjuvant Pembrolizumab)	Arm II (Adjuvant and Neoadjuvant Pembrolizumab)
Arm/Group Description	Within 17 days (preferably within 14 days) days after IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery	Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3 cycles, then undergo surgery within 3 weeks. Within 84 days, patients receive pembrolizumab IV over 30 minutes every 3 weeks for 15 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. Biospecimen Collection: Undergo collection of blood Computed Tomography: Undergo CT Magnetic Resonance Imaging: Undergo MRI Pembrolizumab: Given IV Therapeutic Conventional Surgery: Undergo surgery
All-Cause Mortality
	Arm I (Adjuvant Pembrolizumab)	Arm II (Adjuvant and Neoadjuvant Pembrolizumab)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	22/159 (13.84%)	14/154 (9.09%)
Serious Adverse Events
	Arm I (Adjuvant Pembrolizumab)	Arm II (Adjuvant and Neoadjuvant Pembrolizumab)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	33/141 (23.40%)	34/152 (22.37%)
Blood and lymphatic system disorders
Anemia †	0/141 (0.00%)	1/152 (0.66%)
Cardiac disorders
Cardiac disorders-Other †	1/141 (0.71%)	0/152 (0.00%)
Chest pain - cardiac †	1/141 (0.71%)	0/152 (0.00%)
Myocarditis †	1/141 (0.71%)	2/152 (1.32%)
Endocrine disorders
Adrenal insufficiency †	0/141 (0.00%)	1/152 (0.66%)
Endocrine disorders-Other †	1/141 (0.71%)	0/152 (0.00%)
Hypothyroidism †	2/141 (1.42%)	0/152 (0.00%)
Gastrointestinal disorders
Abdominal pain †	2/141 (1.42%)	0/152 (0.00%)
Colitis †	0/141 (0.00%)	2/152 (1.32%)
Diarrhea †	1/141 (0.71%)	3/152 (1.97%)
Nausea †	0/141 (0.00%)	3/152 (1.97%)
Pancreatitis †	1/141 (0.71%)	0/152 (0.00%)
Upper gastrointestinal hemorrhage †	1/141 (0.71%)	0/152 (0.00%)
Vomiting †	0/141 (0.00%)	3/152 (1.97%)
General disorders
Edema limbs †	0/141 (0.00%)	1/152 (0.66%)
Fatigue †	3/141 (2.13%)	0/152 (0.00%)
Fever †	1/141 (0.71%)	8/152 (5.26%)
Flu like symptoms †	1/141 (0.71%)	0/152 (0.00%)
General disorders and administration site conditio †	0/141 (0.00%)	1/152 (0.66%)
Hypothermia †	1/141 (0.71%)	0/152 (0.00%)
Hepatobiliary disorders
Cholecystitis †	0/141 (0.00%)	1/152 (0.66%)
Hepatobiliary disorders-Other †	1/141 (0.71%)	0/152 (0.00%)
Infections and infestations
Gallbladder infection †	1/141 (0.71%)	0/152 (0.00%)
Lung infection †	1/141 (0.71%)	3/152 (1.97%)
Sepsis †	1/141 (0.71%)	1/152 (0.66%)
Skin infection †	3/141 (2.13%)	2/152 (1.32%)
Soft tissue infection †	0/141 (0.00%)	1/152 (0.66%)
Urinary tract infection †	1/141 (0.71%)	1/152 (0.66%)
Wound infection †	1/141 (0.71%)	1/152 (0.66%)
Injury, poisoning and procedural complications
Fall †	1/141 (0.71%)	2/152 (1.32%)
Fracture †	0/141 (0.00%)	1/152 (0.66%)
Injury, poisoning and procedural complications-Oth †	0/141 (0.00%)	2/152 (1.32%)
Seroma †	0/141 (0.00%)	1/152 (0.66%)
Wound dehiscence †	0/141 (0.00%)	1/152 (0.66%)
Investigations
Alanine aminotransferase increased †	3/141 (2.13%)	4/152 (2.63%)
Alkaline phosphatase increased †	0/141 (0.00%)	2/152 (1.32%)
Aspartate aminotransferase increased †	2/141 (1.42%)	5/152 (3.29%)
Creatinine increased †	0/141 (0.00%)	1/152 (0.66%)
Neutrophil count decreased †	0/141 (0.00%)	1/152 (0.66%)
Platelet count decreased †	1/141 (0.71%)	0/152 (0.00%)
Weight loss †	0/141 (0.00%)	1/152 (0.66%)
White blood cell decreased †	0/141 (0.00%)	1/152 (0.66%)
Metabolism and nutrition disorders
Dehydration †	0/141 (0.00%)	1/152 (0.66%)
Hyperglycemia †	1/141 (0.71%)	1/152 (0.66%)
Hypoglycemia †	1/141 (0.71%)	0/152 (0.00%)
Hypokalemia †	0/141 (0.00%)	1/152 (0.66%)
Hyponatremia †	0/141 (0.00%)	1/152 (0.66%)
Metabolism and nutrition disorders-Other †	1/141 (0.71%)	0/152 (0.00%)
Musculoskeletal and connective tissue disorders
Arthritis †	1/141 (0.71%)	0/152 (0.00%)
Flank pain †	1/141 (0.71%)	0/152 (0.00%)
Muscle weakness upper limb †	1/141 (0.71%)	0/152 (0.00%)
Myositis †	1/141 (0.71%)	0/152 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl †	1/141 (0.71%)	0/152 (0.00%)
Nervous system disorders
Cognitive disturbance †	1/141 (0.71%)	0/152 (0.00%)
Facial muscle weakness †	1/141 (0.71%)	0/152 (0.00%)
Headache †	0/141 (0.00%)	1/152 (0.66%)
Intracranial hemorrhage †	0/141 (0.00%)	2/152 (1.32%)
Stroke †	0/141 (0.00%)	1/152 (0.66%)
Syncope †	1/141 (0.71%)	0/152 (0.00%)
Transient ischemic attacks †	1/141 (0.71%)	0/152 (0.00%)
Vasovagal reaction †	1/141 (0.71%)	1/152 (0.66%)
Pregnancy, puerperium and perinatal conditions
Pregnancy, puerperium and perinatal conditions-Oth †	0/141 (0.00%)	1/152 (0.66%)
Psychiatric disorders
Personality change †	0/141 (0.00%)	1/152 (0.66%)
Respiratory, thoracic and mediastinal disorders
Cough †	0/141 (0.00%)	1/152 (0.66%)
Pneumonitis †	0/141 (0.00%)	2/152 (1.32%)
Pneumothorax †	2/141 (1.42%)	0/152 (0.00%)
Skin and subcutaneous tissue disorders
Pruritus †	2/141 (1.42%)	1/152 (0.66%)
Rash maculo-papular †	2/141 (1.42%)	2/152 (1.32%)
Skin ulceration †	0/141 (0.00%)	1/152 (0.66%)
Vascular disorders
Hematoma †	0/141 (0.00%)	2/152 (1.32%)
Hypertension †	1/141 (0.71%)	1/152 (0.66%)
Lymph leakage †	0/141 (0.00%)	1/152 (0.66%)
Thromboembolic event †	1/141 (0.71%)	0/152 (0.00%)
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Arm I (Adjuvant Pembrolizumab)	Arm II (Adjuvant and Neoadjuvant Pembrolizumab)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	132/141 (93.62%)	148/152 (97.37%)
Blood and lymphatic system disorders
Anemia †	37/141 (26.24%)	54/152 (35.53%)
Blood and lymphatic system disorders-Other †	8/141 (5.67%)	10/152 (6.58%)
Eosinophilia †	10/141 (7.09%)	6/152 (3.95%)
Endocrine disorders
Hyperthyroidism †	11/141 (7.80%)	6/152 (3.95%)
Hypothyroidism †	26/141 (18.44%)	26/152 (17.11%)
Eye disorders
Blurred vision †	6/141 (4.26%)	10/152 (6.58%)
Eye disorders-Other †	7/141 (4.96%)	10/152 (6.58%)
Gastrointestinal disorders
Abdominal pain †	9/141 (6.38%)	14/152 (9.21%)
Constipation †	19/141 (13.48%)	22/152 (14.47%)
Diarrhea †	34/141 (24.11%)	39/152 (25.66%)
Dry mouth †	15/141 (10.64%)	7/152 (4.61%)
Gastrointestinal disorders-Other †	6/141 (4.26%)	11/152 (7.24%)
Nausea †	33/141 (23.40%)	40/152 (26.32%)
Vomiting †	13/141 (9.22%)	18/152 (11.84%)
General disorders
Chills †	13/141 (9.22%)	11/152 (7.24%)
Edema limbs †	33/141 (23.40%)	39/152 (25.66%)
Fatigue †	90/141 (63.83%)	90/152 (59.21%)
Fever †	10/141 (7.09%)	10/152 (6.58%)
Pain †	33/141 (23.40%)	33/152 (21.71%)
Infections and infestations
Infections and infestations-Other †	17/141 (12.06%)	13/152 (8.55%)
Skin infection †	15/141 (10.64%)	15/152 (9.87%)
Upper respiratory infection †	3/141 (2.13%)	8/152 (5.26%)
Urinary tract infection †	8/141 (5.67%)	5/152 (3.29%)
Injury, poisoning and procedural complications
Seroma †	11/141 (7.80%)	7/152 (4.61%)
Investigations
Alanine aminotransferase increased †	17/141 (12.06%)	27/152 (17.76%)
Alkaline phosphatase increased †	13/141 (9.22%)	21/152 (13.82%)
Aspartate aminotransferase increased †	17/141 (12.06%)	29/152 (19.08%)
Blood bilirubin increased †	8/141 (5.67%)	13/152 (8.55%)
Creatinine increased †	17/141 (12.06%)	28/152 (18.42%)
Investigations-Other †	8/141 (5.67%)	5/152 (3.29%)
Lymphocyte count decreased †	19/141 (13.48%)	30/152 (19.74%)
Platelet count decreased †	9/141 (6.38%)	13/152 (8.55%)
Thyroid stimulating hormone increased †	10/141 (7.09%)	16/152 (10.53%)
Weight loss †	18/141 (12.77%)	13/152 (8.55%)
White blood cell decreased †	8/141 (5.67%)	11/152 (7.24%)
Metabolism and nutrition disorders
Anorexia †	15/141 (10.64%)	27/152 (17.76%)
Hypercalcemia †	8/141 (5.67%)	9/152 (5.92%)
Hyperglycemia †	46/141 (32.62%)	48/152 (31.58%)
Hyperkalemia †	6/141 (4.26%)	13/152 (8.55%)
Hypoalbuminemia †	12/141 (8.51%)	19/152 (12.50%)
Hypocalcemia †	18/141 (12.77%)	9/152 (5.92%)
Hypoglycemia †	6/141 (4.26%)	8/152 (5.26%)
Hypokalemia †	9/141 (6.38%)	18/152 (11.84%)
Hyponatremia †	23/141 (16.31%)	22/152 (14.47%)
Musculoskeletal and connective tissue disorders
Arthralgia †	26/141 (18.44%)	29/152 (19.08%)
Arthritis †	6/141 (4.26%)	8/152 (5.26%)
Back pain †	17/141 (12.06%)	13/152 (8.55%)
Myalgia †	19/141 (13.48%)	17/152 (11.18%)
Neck pain †	10/141 (7.09%)	9/152 (5.92%)
Pain in extremity †	26/141 (18.44%)	29/152 (19.08%)
Nervous system disorders
Dizziness †	13/141 (9.22%)	14/152 (9.21%)
Dysgeusia †	8/141 (5.67%)	6/152 (3.95%)
Headache †	23/141 (16.31%)	29/152 (19.08%)
Paresthesia †	20/141 (14.18%)	18/152 (11.84%)
Peripheral sensory neuropathy †	9/141 (6.38%)	9/152 (5.92%)
Psychiatric disorders
Anxiety †	8/141 (5.67%)	16/152 (10.53%)
Insomnia †	13/141 (9.22%)	13/152 (8.55%)
Renal and urinary disorders
Urinary frequency †	8/141 (5.67%)	7/152 (4.61%)
Respiratory, thoracic and mediastinal disorders
Cough †	34/141 (24.11%)	30/152 (19.74%)
Dyspnea †	23/141 (16.31%)	20/152 (13.16%)
Nasal congestion †	10/141 (7.09%)	7/152 (4.61%)
Postnasal drip †	5/141 (3.55%)	8/152 (5.26%)
Skin and subcutaneous tissue disorders
Dry skin †	14/141 (9.93%)	12/152 (7.89%)
Pruritus †	36/141 (25.53%)	43/152 (28.29%)
Rash acneiform †	9/141 (6.38%)	10/152 (6.58%)
Rash maculo-papular †	42/141 (29.79%)	44/152 (28.95%)
Skin and subcutaneous tissue disorders-Other †	26/141 (18.44%)	25/152 (16.45%)
Skin hypopigmentation †	8/141 (5.67%)	12/152 (7.89%)
Surgical and medical procedures
Surgical and medical procedures-Other †	2/141 (1.42%)	8/152 (5.26%)
Vascular disorders
Hypertension †	40/141 (28.37%)	44/152 (28.95%)
Lymphedema †	15/141 (10.64%)	22/152 (14.47%)
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Melanoma Committee Statistician
• Organization: SWOG Statistics and Data Management Center
• Phone: 2066674623
• EMail: jmoon@fredhutch.org

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03698019
• Other Study ID Numbers: NCI-2018-02107; NCI-2018-02107 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); S1801 ( Other Identifier: SWOG ); S1801 ( Other Identifier: CTEP ); U10CA180888 ( U.S. NIH Grant/Contract )
• First Submitted: October 4, 2018
• First Posted: October 5, 2018
• Results First Submitted: August 28, 2023
• Results First Posted: November 21, 2023
• Last Update Posted: February 15, 2024