NCT03143153: CheckMate 648

A Study to Evaluate Efficacy in Subjects With Esophageal Cancer Treated With Nivolumab and Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin

Completed Phase 3 Results posted Last updated 17 February 2026

What this trial tests

Phase 3 trial testing Nivolumab in Various Advanced Cancer in 970 participants. Completed in 13 January 2025.

Timeline

29 June 2017

Primary endpoint
18 January 2021

13 January 2025

Quick facts

Lead sponsor	Bristol-Myers Squibb
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	970
Start date	29 June 2017
Primary completion	18 January 2021
Estimated completion	13 January 2025
Sites	190 locations across Hong Kong, Colombia, Italy, Japan, Taiwan, Poland, South Korea, Denmark

Drugs / interventions tested

• Nivolumab (nivolumab) — full drug profile →
• Ipilimumab — full drug profile →
• Cisplatin (cisplatin) — full drug profile →
• Fluorouracil — full drug profile →

Conditions studied

• Various Advanced Cancer — all drugs for Various Advanced Cancer →

Sponsor

Bristol-Myers Squibb — full company profile →

Who can join

18 and older, any sex, with Various Advanced Cancer. 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.

Overall Survival (OS) in Participants With Tumor Cell PD-L1 Primary · From the date of randomization to up to the date of death (up to approximately 20 months)

Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	13.70	11.24 – 17.02
Arm B: Nivolumab + Chemotherapy	15.44	11.93 – 19.52
Arm C: Chemotherapy	9.07	7.69 – 9.95

Progression-free Survival (PFS) as Assessed by BICR in Participants With Tumor Cell PD-L1 Primary · From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 9 months)

Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	4.04	2.40 – 4.93
Arm B: Nivolumab + Chemotherapy	6.93	5.68 – 8.34
Arm C: Chemotherapy	4.44	2.89 – 5.82

Overall Survival (OS) in All Randomized Participants Secondary · From the date of randomization to up to the date of death (up to approximately 88 months)

Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	12.747	11.269 – 15.474
Arm B: Nivolumab + Chemotherapy	13.207	11.105 – 15.671
Arm C: Chemotherapy	10.710	9.396 – 12.090

Progression-free Survival (PFS) in All Randomized Participants as Assessed by BICR Secondary · From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 88 months)

Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	2.891	2.661 – 4.172
Arm B: Nivolumab + Chemotherapy	5.782	5.520 – 6.998
Arm C: Chemotherapy	5.618	4.304 – 5.914

Objective Response Rate (ORR) as Assessed by BICR Secondary · From the date of randomization to up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to 88 months)

Objective response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation as determined by BICR, recorded between the date of randomization and the date of objectively documented progression (per RECIST 1.1) or the date of subsequent anti-cancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesio

Participants with baseline PD-L1 status < 1%

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	20.1	14.3 – 27.1
Arm B: Nivolumab + Chemotherapy	41.7	34.1 – 49.7
Arm C: Chemotherapy	33.7	26.6 – 41.5

Participants with baseline PD-L1 status >= 1%

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	35.4	28.0 – 43.4
Arm B: Nivolumab + Chemotherapy	53.2	45.1 – 61.1
Arm C: Chemotherapy	19.9	13.9 – 27.0

Participants with baseline PD-L1 status < 5%

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	22.3	16.7 – 28.6
Arm B: Nivolumab + Chemotherapy	44.8	37.8 – 51.9
Arm C: Chemotherapy	30.9	24.7 – 37.7

Participants with baseline PD-L1 status >= 5%

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	36.7	28.1 – 45.9
Arm B: Nivolumab + Chemotherapy	51.7	42.4 – 60.9
Arm C: Chemotherapy	20.0	13.1 – 28.5

Participants with baseline PD-L1 status < 10%

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	23.3	17.9 – 29.5
Arm B: Nivolumab + Chemotherapy	46.1	39.4 – 53.0
Arm C: Chemotherapy	29.3	23.5 – 35.8

Participants with baseline PD-L1 status >= 10%

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	36.9	27.6 – 47.0
Arm B: Nivolumab + Chemotherapy	50.0	39.9 – 60.1
Arm C: Chemotherapy	21.6	13.9 – 31.2

Participants with baseline PD-L1 status indeterminate, not evaluable, or missing

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	33.3	0.8 – 90.6
Arm C: Chemotherapy	0.0	0.0 – 84.2

All randomized participants

Group	Value	95% CI
Arm A: Nivolumab + Ipilimumab	27.4	22.6 – 32.6
Arm B: Nivolumab + Chemotherapy	47.4	41.8 – 53.0
Arm C: Chemotherapy	26.9	22.1 – 32.0

Adverse events — posted to ClinicalTrials.gov

Time frame: All cause mortality was collected till 88 months and Serious and Non-Serious AEs from first dose (Day 1) to 100 days post last dose (up to 43 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Arm A: Nivolumab + Ipilimumab

Serious: 243/322 (75%)

Deaths: 270/325

Arm B: Nivolumab + Chemotherapy

Serious: 226/310 (73%)

Deaths: 273/321

Arm C: Chemotherapy

Serious: 174/304 (57%)

Deaths: 286/324

Serious adverse events (342 terms)

Reaction	System	Arm A: Nivolumab + Ipilimu…	Arm B: Nivolumab + Chemoth…	Arm C: Chemotherapy
Malignant neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Pneumonia	Infections and infestations	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—
Pyrexia	General disorders and administration site conditions	—	—	—
Oesophageal stenosis	Gastrointestinal disorders	—	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Pneumonia aspiration	Infections and infestations	—	—	—
Hepatic function abnormal	Hepatobiliary disorders	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—
Adrenal insufficiency	Endocrine disorders	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—
Hypopituitarism	Endocrine disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Hypophysitis	Endocrine disorders	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—
Colitis	Gastrointestinal disorders	—	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Oesophageal obstruction	Gastrointestinal disorders	—	—	—
Asthenia	General disorders and administration site conditions	—	—	—

Other adverse events (62 terms — click to expand)

Reaction	System	Arm A: Nivolumab + Ipilimu…	Arm B: Nivolumab + Chemoth…	Arm C: Chemotherapy
Nausea	Gastrointestinal disorders	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Fatigue	General disorders and administration site conditions	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Pyrexia	General disorders and administration site conditions	—	—	—
Neutrophil count decreased	Investigations	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—
Hiccups	Respiratory, thoracic and mediastinal disorders	—	—	—
Malaise	General disorders and administration site conditions	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—
White blood cell count decreased	Investigations	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Platelet count decreased	Investigations	—	—	—
Oedema peripheral	General disorders and administration site conditions	—	—	—
Hypothyroidism	Endocrine disorders	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Weight decreased	Investigations	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—
Blood creatinine increased	Investigations	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—
Mucosal inflammation	General disorders and administration site conditions	—	—	—
Pneumonia	Infections and infestations	—	—	—
Hypoalbuminaemia	Metabolism and nutrition disorders	—	—	—
Peripheral sensory neuropathy	Nervous system disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Asthenia	General disorders and administration site conditions	—	—	—
Weight increased	Investigations	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Hypertension	Vascular disorders	—	—	—

Most-reported serious reactions: Malignant neoplasm progression, Pneumonia, Dysphagia, Pyrexia, Oesophageal stenosis, Pneumonitis, Vomiting, Pneumonia aspiration.

Data from ClinicalTrials.gov NCT03143153 adverse events section.

Sponsor's own description

The main purpose of this study is to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin

Publications & conference data

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

1. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.
   Doki Y, Ajani JA, Kato K, Xu J, et al · · 2022 · cited 879× · PMID 35108470 · DOI 10.1056/nejmoa2111380
2. Cold and hot tumors: from molecular mechanisms to targeted therapy.
   Wu B, Zhang B, Li B, Wu H, et al · · 2024 · cited 280× · PMID 39420203 · DOI 10.1038/s41392-024-01979-x
3. 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
4. The immune landscape of esophageal cancer.
   Huang TX, Fu L. · · 2019 · cited 189× · PMID 31771653 · DOI 10.1186/s40880-019-0427-z
5. Understanding and targeting resistance mechanisms in cancer.
   Lei ZN, Tian Q, Teng QX, Wurpel JND, et al · · 2023 · cited 174× · PMID 37229486 · DOI 10.1002/mco2.265
6. Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials.
   Kooshkaki O, Derakhshani A, Hosseinkhani N, Torabi M, et al · · 2020 · cited 95× · PMID 32580338 · DOI 10.3390/ijms21124427
7. Combination regimens with PD-1/PD-L1 immune checkpoint inhibitors for gastrointestinal malignancies.
   Wang D, Lin J, Yang X, Long J, et al · · 2019 · cited 68× · PMID 31014381 · DOI 10.1186/s13045-019-0730-9
8. Blockade of novel immune checkpoints and new therapeutic combinations to boost antitumor immunity.
   Archilla-Ortega A, Domuro C, Martin-Liberal J, Muñoz P. · · 2022 · cited 61× · PMID 35164813 · DOI 10.1186/s13046-022-02264-x