NCT04099251: CheckMate76K

Effectiveness Study of Nivolumab Compared to Placebo in Prevention of Recurrent Melanoma After Complete Resection of Stage IIB/C Melanoma

Active, enrolled Phase 3 Results posted Last updated 9 April 2026

What this trial tests

Phase 3 trial testing Nivolumab in Melanoma in 790 participants. Participants enrolled and being followed up; not accepting new ones.

Timeline

28 October 2019

Primary endpoint
28 June 2022

29 June 2027

Quick facts

Lead sponsor	Bristol-Myers Squibb
Phase	Phase 3
Status	Active, enrolled
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	treatment
Enrollment	790
Start date	28 October 2019
Primary completion	28 June 2022
Estimated completion	29 June 2027
Sites	130 locations across Italy, Finland, Poland, Denmark, Netherlands, Belgium, Sweden, United States

Drugs / interventions tested

• Nivolumab (nivolumab) — full drug profile →
• Placebo

Conditions studied

• Melanoma — all drugs for Melanoma →

Sponsor

Bristol-Myers Squibb — full company profile →

Who can join

12 and older, any sex, with Melanoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Recurrence Free Survival (RFS) Primary · From randomization up to the date of first recurrence, new primary melanoma, or death (whatever the cause), whichever occurs first (up to 32 months)

Recurrence Free Survival (RFS) is defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (whatever the cause), whichever occurs first. For participants who remain alive and whose disease has not recurred or did not die, RFS will be censored on the date of last evaluable disease assessment. For those participants who remained alive and had no recorded post-randomization tumor assessment, RFS will be censored on the day of randomization.

Group	Value	95% CI
Nivolumab	NA	28.52 – NA
Placebo	NA	21.62 – NA

Distant Metastasis-Free Survival (DMFS) Secondary · From randomization up to the date of first distant metastasis or date of death (whatever the cause), whichever occurs first (up to approximately 32 months)

Investigator-assessed distant metastasis-free survival (DMFS) is defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. Participants with no baseline disease assessment, no on-study disease assessments and no death, and no distant metastasis and no death will be censored. Participants with no baseline disease assessment and no on-study disease assessments and death are censored on the date of randomization. Participants with no recurrence and no death will be censored on the date of their las

Group	Value	95% CI
Nivolumab	NA	28.52 – NA
Placebo	NA	NA – NA

Duration of Treatment on Next Line Therapy Per Investigator Assessment Secondary · From first dose date of next-line therapy to last dose date of next-line therapy (up to approximately 32 months)

Duration of treatment is an investigator-assessed outcome of next-line therapy (NLT) defined as the time from first dose date of NLT to last dose date of NLT. Participants who did not stop the NLT were censored.

Group	Value	95% CI
Nivolumab	4.17	2.69 – 8.38
Placebo	11.14	5.85 – NA

Progression-Free Survival Through Next-Line Therapy Secondary · From randomization to recurrence/objective disease progression after the start of the next-line therapy, or to the start of a second next-line systemic therapy, or to death from any cause, whichever occurs first (up to approximately 32 months)

Progression-free survival through next-line therapy (PFS2) is defined as the time from randomization to recurrence/objective disease progression after the start of the next-line of systemic anti-cancer therapy, or to the start of a second next-line systemic therapy, or to death from any cause, whichever occurs first. Participants who did not receive subsequent systemic anti-cancer therapy who died will be considered as having the event on the date of death. Participants who received subsequent systemic anti-cancer therapy who had a disease progression after the start of therapy will be conside

Group	Value	95% CI
Nivolumab	NA	NA – NA
Placebo	NA	NA – NA

Number of Participants Experiencing Adverse Events (AEs) Secondary · From first dose up to 30 days post last dose of the blinded phase (up to 13 months)

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events a

Any Grade

Group	Value	95% CI
Nivolumab	502
Placebo	229

Grade 3-4

Group	Value	95% CI
Nivolumab	115
Placebo	32

Number of Participants Experiencing Adverse Events Leading to Discontinuation Secondary · From first dose up to 30 days post last dose of the blinded phase (up to 13 months)

An Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.

Group	Value	95% CI
Nivolumab	91
Placebo	9

Number of Participants Experiencing Select Adverse Events Secondary · From first dose up to 30 days post last dose of the blinded phase (up to 13 months)

The number of participants experiencing all-cause select adverse events (AEs). An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.

Endocrine

Group	Value	95% CI
Nivolumab	116
Placebo	14

Gastrointestinal

Group	Value	95% CI
Nivolumab	122
Placebo	41

Hepatic

Group	Value	95% CI
Nivolumab	86
Placebo	35

Pulmonary

Group	Value	95% CI
Nivolumab	10
Placebo	1

Renal

Group	Value	95% CI
Nivolumab	30
Placebo	10

Skin

Group	Value	95% CI
Nivolumab	217
Placebo	64

Hypersensitivity/Infusion Reactions

Group	Value	95% CI
Nivolumab	33
Placebo	2

Number of Participants Experiencing Serious Adverse Events (SAEs) Secondary · From first dose up to 30 days post last dose of the blinded phase (up to 13 months)

A Serious Adverse Events (SAE) is defined as any untoward or unfavorable medical occurrence in a participants that results in death, is life threatening, or places the participant at immediate risk of death from the event as it occurred, requires or prolongs hospitalization, causes persistent or significant disability or incapacity, results in congenital anomalies or birth defects, and is another condition which investigators judge to represent significant hazards.

Group	Value	95% CI
Nivolumab	74
Placebo	29

Number of Participants Experiencing Death Secondary · From first dose up to 30 days post last dose of the blinded phase (up to 13 months)

All study participants who died during the blinded phase of the study following treatment.

Group	Value	95% CI
Nivolumab	14
Placebo	8

Number of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities in Selected Hematology Parameters Secondary · From first dose up to 30 days post last dose of the blinded phase (up to 13 months)

The number of participants experiencing Grade 3 or 4 laboratory abnormalities in the specific pre-determined hematology tests.

PLATELET COUNT

Group	Value	95% CI
Nivolumab	1
Placebo	0

LYMPHOCYTES (ABSOLUTE), LOCAL LAB

Group	Value	95% CI
Nivolumab	5
Placebo	4

ABSOLUTE NEUTROPHIL COUNT

Group	Value	95% CI
Nivolumab	0
Placebo	1

Number of Participants Experiencing Laboratory Abnormalities in Selected Liver Parameters Secondary · From first dose up to 30 days post last dose of the blinded phase (up to 13 months)

The number of participants experiencing laboratory abnormalities in the specific pre-determined liver tests.

ALT OR AST > 3XULN

Group	Value	95% CI
Nivolumab	29
Placebo	5

ALT OR AST > 5XULN

Group	Value	95% CI
Nivolumab	16
Placebo	2

ALT OR AST > 10XULN

Group	Value	95% CI
Nivolumab	6
Placebo	0

ALT OR AST > 20XULN

Group	Value	95% CI
Nivolumab	2
Placebo	0

TOTAL BILIRUBIN > 2XULN

Group	Value	95% CI
Nivolumab	3
Placebo	5

ALP > 1.5XULN

Group	Value	95% CI
Nivolumab	20
Placebo	1

Adverse events — posted to ClinicalTrials.gov

Time frame: Participants were assessed for all-cause mortality from their randomization to primary completion, (up to approximately 32 months). SAEs and Other AEs were assessed from first dose to 100 days following last dose (up to approximately 32 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Nivolumab

Serious: 95/524 (18%)

Deaths: 14/526

Placebo

Serious: 37/264 (14%)

Deaths: 8/264

Open-Label Nivolumab

Serious: 5/30 (17%)

Deaths: 2/32

Serious adverse events (134 terms)

Reaction	System	Nivolumab	Placebo	Open-Label Nivolumab
Colitis	Gastrointestinal disorders	—	—	—
COVID-19	Infections and infestations	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—	—
Adrenal insufficiency	Endocrine disorders	—	—	—
Diverticulitis	Infections and infestations	—	—	—
Metastatic malignant melanoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—
Acute myocardial infarction	Cardiac disorders	—	—	—
Cardiac failure	Cardiac disorders	—	—	—
Myocarditis	Cardiac disorders	—	—	—
Hypopituitarism	Endocrine disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Pancreatitis	Gastrointestinal disorders	—	—	—
Generalised oedema	General disorders	—	—	—
Autoimmune hepatitis	Hepatobiliary disorders	—	—	—
Infected seroma	Infections and infestations	—	—	—
Pneumonia	Infections and infestations	—	—	—
Sepsis	Infections and infestations	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—
Myositis	Musculoskeletal and connective tissue disorders	—	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—	—
Invasive breast carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Melanoma recurrent	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—

Other adverse events (37 terms — click to expand)

Reaction	System	Nivolumab	Placebo	Open-Label Nivolumab
Fatigue	General disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Hypothyroidism	Endocrine disorders	—	—	—
Asthenia	General disorders	—	—	—
Blood creatine phosphokinase increased	Investigations	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
COVID-19	Infections and infestations	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Hyperthyroidism	Endocrine disorders	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Pyrexia	General disorders	—	—	—
Hypertension	Vascular disorders	—	—	—
Infusion related reaction	Injury, poisoning and procedural complications	—	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—	—
Lipase increased	Investigations	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Blood bilirubin increased	Investigations	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—
Pain	General disorders	—	—	—
Haematuria	Renal and urinary disorders	—	—	—
Eructation	Gastrointestinal disorders	—	—	—
Confusional state	Psychiatric disorders	—	—	—
Embolism	Vascular disorders	—	—	—

Most-reported serious reactions: Colitis, COVID-19, Alanine aminotransferase increased, Aspartate aminotransferase increased, Pulmonary embolism, Adrenal insufficiency, Diverticulitis, Metastatic malignant melanoma.

Data from ClinicalTrials.gov NCT04099251 adverse events section.

Sponsor's own description

The purpose of this study is to determine the effectiveness of nivolumab adjuvant immunotherapy compared to placebo in adults and pediatric participants after complete resection of Stage IIB/C melanoma with no evidence of disease (NED) who are at high risk for recurrence.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets.
   Zhang S, Xiao X, Yi Y, Wang X, et al · · 2024 · cited 192× · PMID 38890350 · DOI 10.1038/s41392-024-01848-7
2. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial.
   Kirkwood JM, Del Vecchio M, Weber J, Hoeller C, et al · · 2023 · cited 133× · PMID 37845511 · DOI 10.1038/s41591-023-02583-2
3. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results from CheckMate 238.
   Larkin J, Del Vecchio M, Mandalá M, Gogas H, et al · · 2023 · cited 108× · PMID 37058595 · DOI 10.1158/1078-0432.ccr-22-3145
4. Prognostic Gene Expression Profiling in Cutaneous Melanoma: Identifying the Knowledge Gaps and Assessing the Clinical Benefit.
   Grossman D, Okwundu N, Bartlett EK, Marchetti MA, et al · · 2020 · cited 75× · PMID 32725204 · DOI 10.1001/jamadermatol.2020.1729
5. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0.
   Pavlick AC, Ariyan CE, Buchbinder EI, Davar D, et al · · 2023 · cited 38× · PMID 37852736 · DOI 10.1136/jitc-2023-006947
6. Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy.
   Trojaniello C, Luke JJ, Ascierto PA. · · 2021 · cited 32× · PMID 34178657 · DOI 10.3389/fonc.2021.670726
7. Adjuvant Therapy for Melanoma: Past, Current, and Future Developments.
   Testori AAE, Chiellino S, van Akkooi ACJ. · · 2020 · cited 30× · PMID 32708268 · DOI 10.3390/cancers12071994
8. Circulating Tumour DNA in Melanoma-Clinic Ready?
   Tivey A, Britton F, Scott JA, Rothwell D, et al · · 2022 · cited 29× · PMID 35133615 · DOI 10.1007/s11912-021-01151-6