NCT03068455: CheckMate 915

An Investigational Immuno-therapy Study of Nivolumab Combined With Ipilimumab Compared to Nivolumab by Itself After Complete Surgical Removal of Stage IIIb/c/d or Stage IV Melanoma

Completed Phase 3 Results posted Last updated 20 September 2021

What this trial tests

Phase 3 trial testing nivolumab in Melanoma in 1,844 participants. Completed in 2 February 2021.

Timeline

11 April 2017

Primary endpoint
12 June 2020

2 February 2021

Quick facts

Lead sponsor	Bristol-Myers Squibb
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	1,844
Start date	11 April 2017
Primary completion	12 June 2020
Estimated completion	2 February 2021
Sites	124 locations across Italy, Poland, New Zealand, Russia, Belgium, United States, France, Greece

Drugs / interventions tested

• nivolumab (nivolumab) — full drug profile →
• ipilimumab — full drug profile →

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) - All Randomized Participants Primary · From randomization to Primary Completion Date (up to approximately 3 years)

RFS was 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 (from any cause), whichever occurred first. Median values based on Kaplan-Meier Estimates.

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	NA – NA
Arm B: Nivo	NA	NA – NA

Recurrence-free Survival (RFS) - All Randomized Participants With PD-L1 Expression Level < 1% Primary · From randomization to Primary Completion Date (up to approximately 3 years)

RFS was 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 (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates.

Group	Value	95% CI
Arm A: Nivo + Ipi	33.15	22.21 – NA
Arm B: Nivo	27.63	19.81 – NA

Overall Survival (OS) - All Randomized Participants Secondary · From randomization to date of death (up to approximately 45 months)

OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates.

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	NA – NA
Arm B: Nivo	NA	NA – NA

Overall Survival (OS) - All Randomized Participants With PD-L1 Expression Level < 1% Secondary · From randomization to date of death (up to approximately 45 months)

OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates.

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	41.72 – NA
Arm B: Nivo	NA	NA – NA

Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression Secondary · From randomization to Study Completion Date (up to approximately 45 months)

RFS was 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 (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates.

< 1% Tumor PD-L1 Expression

Group	Value	95% CI
Arm A: Nivo + Ipi	33.18	22.21 – NA
Arm B: Nivo	25.33	19.81 – NA

≥ 1% Tumor PD-L1 Expression

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	NA – NA
Arm B: Nivo	NA	NA – NA

≥ 5% Tumor PD-L1 Expression

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	NA – NA
Arm B: Nivo	NA	NA – NA

< 5% Tumor PD-L1 Expression

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	31.18 – NA
Arm B: Nivo	NA	27.63 – NA

Non-quantifiable Tumor PD-L1 Expression

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	22.41 – NA
Arm B: Nivo	NA	10.87 – NA

Time to Next-Line Therapies - All Randomized Participants Secondary · From randomization to start of next therapy or second next therapy (up to approximately 45 months)

Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date.

Time to next therapy

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	NA – NA
Arm B: Nivo	NA	NA – NA

Time to second next therapy

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	NA – NA
Arm B: Nivo	NA	NA – NA

Time to Next-Line Therapies - All Randomized Participants With PD-L1 Expression Level < 1% Secondary · From randomization to start of next therapy or second next therapy (up to approximately 45 months)

Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date

Time to next therapy

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	NA – NA
Arm B: Nivo	NA	NA – NA

Time to second next therapy

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	NA – NA
Arm B: Nivo	NA	NA – NA

Time From Next Therapy to Second Next Therapy - All Randomized Participants Secondary · From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months)

Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment.

Group	Value	95% CI
Arm A: Nivo + Ipi	4.60	0.8 – 23.7
Arm B: Nivo	4.80	0.0 – 27.7

Time From Next Therapy to Second Next Therapy - All Randomized Participants With PD-L1 Expression Level < 1% Secondary · From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months)

Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment.

Group	Value	95% CI
Arm A: Nivo + Ipi	4.44	0.8 – 23.7
Arm B: Nivo	5.04	0.9 – 27.7

Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants Secondary · From randomization to progression event (up to approximately 45 months)

PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death.

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	NA – NA
Arm B: Nivo	NA	NA – NA

Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants With PD-L1 Expression Level < 1% Secondary · From randomization to progression event (up to approximately 45 months)

PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death.

Group	Value	95% CI
Arm A: Nivo + Ipi	NA	NA – NA
Arm B: Nivo	NA	35.94 – NA

Adverse events — posted to ClinicalTrials.gov

Time frame: All-cause mortality was assessed from first dose to study completion date (up to approximately 45 months). Serious Adverse Events and Non Serious Adverse Events above 5% were assessed from first dose to 100 days post last dose (up to approximately 15 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Arm A: Nivo + Ipi

Serious: 374/916 (41%)

Deaths: 122/916

Arm B: Nivo

Serious: 242/917 (26%)

Deaths: 121/917

Serious adverse events (339 terms)

Reaction	System	Arm A: Nivo + Ipi	Arm B: Nivo
Colitis	Gastrointestinal disorders	—	—
Hypophysitis	Endocrine disorders	—	—
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Immune-mediated enterocolitis	Gastrointestinal disorders	—	—
Malignant neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Autoimmune hepatitis	Hepatobiliary disorders	—	—
Pyrexia	General disorders	—	—
Squamous cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Pneumonia	Infections and infestations	—	—
Adrenal insufficiency	Endocrine disorders	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—
Autoimmune colitis	Gastrointestinal disorders	—	—
Sarcoidosis	Immune system disorders	—	—
Malignant melanoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Fatigue	General disorders	—	—
Hepatitis	Hepatobiliary disorders	—	—
Immune-mediated hepatitis	Hepatobiliary disorders	—	—
Melanoma recurrent	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Hyperthyroidism	Endocrine disorders	—	—
Cellulitis	Infections and infestations	—	—
Erysipelas	Infections and infestations	—	—
Atrial fibrillation	Cardiac disorders	—	—
Gastritis	Gastrointestinal disorders	—	—
Pancreatitis	Gastrointestinal disorders	—	—

Other adverse events (40 terms — click to expand)

Reaction	System	Arm A: Nivo + Ipi	Arm B: Nivo
Fatigue	General disorders	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Headache	Nervous system disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Hypothyroidism	Endocrine disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Hyperthyroidism	Endocrine disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Asthenia	General disorders	—	—
Alanine aminotransferase increased	Investigations	—	—
Lipase increased	Investigations	—	—
Pyrexia	General disorders	—	—
Aspartate aminotransferase increased	Investigations	—	—
Nasopharyngitis	Infections and infestations	—	—
Constipation	Gastrointestinal disorders	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Dry mouth	Gastrointestinal disorders	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Hypophysitis	Endocrine disorders	—	—
Insomnia	Psychiatric disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Amylase increased	Investigations	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Dizziness	Nervous system disorders	—	—
Influenza like illness	General disorders	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—
Adrenal insufficiency	Endocrine disorders	—	—
Infusion related reaction	Injury, poisoning and procedural complications	—	—
Blood creatine phosphokinase increased	Investigations	—	—
Vitiligo	Skin and subcutaneous tissue disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—
Anxiety	Psychiatric disorders	—	—
Hypertension	Vascular disorders	—	—

Most-reported serious reactions: Colitis, Hypophysitis, Basal cell carcinoma, Diarrhoea, Immune-mediated enterocolitis, Malignant neoplasm progression, Autoimmune hepatitis, Pyrexia.

Data from ClinicalTrials.gov NCT03068455 adverse events section.

Sponsor's own description

The purpose of this study is to determine whether an investigational immunotherapy Nivolumab, when combined with Ipilimumab, is more effective than Nivolumab by itself, in delaying the return of cancer in patients who have had a complete surgical removal of stage IIIb/c/d or stage IV Melanoma

Publications & conference data

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

1. Immune checkpoint inhibitors: recent progress and potential biomarkers.
   Darvin P, Toor SM, Sasidharan Nair V, Elkord E. · · 2018 · cited 1495× · PMID 30546008 · DOI 10.1038/s12276-018-0191-1
2. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.
   Amaria RN, Reddy SM, Tawbi HA, Davies MA, et al · · 2018 · cited 637× · PMID 30297909 · DOI 10.1038/s41591-018-0197-1
3. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends.
   Sun Q, Hong Z, Zhang C, Wang L, et al · · 2023 · cited 387× · PMID 37635168 · DOI 10.1038/s41392-023-01522-4
4. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation.
   Wu M, Huang Q, Xie Y, Wu X, et al · · 2022 · cited 336× · PMID 35279217 · DOI 10.1186/s13045-022-01242-2
5. Immunotherapy of Melanoma: Facts and Hopes.
   Weiss SA, Wolchok JD, Sznol M. · · 2019 · cited 232× · PMID 30923036 · DOI 10.1158/1078-0432.ccr-18-1550
6. Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations.
   Zerdes I, Matikas A, Bergh J, Rassidakis GZ, et al · · 2018 · cited 223× · PMID 29765155 · DOI 10.1038/s41388-018-0303-3
7. Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma.
   Khair DO, Bax HJ, Mele S, Crescioli S, et al · · 2019 · cited 181× · PMID 30941125 · DOI 10.3389/fimmu.2019.00453
8. Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915).
   Weber JS, Schadendorf D, Del Vecchio M, Larkin J, et al · · 2023 · cited 123× · PMID 36162037 · DOI 10.1200/jco.22.00533