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NCT02659059: CheckMate 568

Nivolumab in Combination With Ipilimumab (Part 1); Nivolumab Plus Ipilimumab in Combination With Chemotherapy (Part 2) as First Line Therapy in Stage IV Non-Small Cell Lung Cancer

Completed Phase 2 Results posted Last updated 5 April 2023
What this trial tests

Phase 2 trial testing Nivolumab in Non-Small-Cell Lung Cancer in 324 participants. Completed in 7 March 2022.

Timeline
15 February 2016
Primary endpoint
22 June 2018
7 March 2022

Quick facts

Lead sponsorBristol-Myers Squibb
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment324
Start date15 February 2016
Primary completion22 June 2018
Estimated completion7 March 2022
Sites32 locations across Canada, United States

Drugs / interventions tested

Conditions studied

Sponsor

Bristol-Myers Squibb — full company profile →

Who can join

18 and older, any sex, with Non-Small-Cell Lung 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.

Objective Response Rate (ORR) by PD-L1 Positive and Negative Levels - Part 1 Primary · From first dose to database lock (Up to 18 months)

Objective response rate (ORR) in PD-L1 positive (PD-L1 ≥1%) and PD-L1 negative (PD-L1 \<1%) participants was defined as the percentage of treated participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 based on Blinded Independent Central Review (BICR) assessment.

PD-L1 ≥1%
GroupValue95% CI
Nivolumab+Ipilimumab41.333.0 – 50.0
PD-L1 <1%
GroupValue95% CI
Nivolumab+Ipilimumab14.98.9 – 22.8
Number of Participants With Dose Limiting Toxicities (DLTs) - Part 2 Primary · 9 weeks after first dose

Dose limiting toxicities (DLTs) were defined as any of the items listed below. 1. Any Grade 2 drug-related uveitis or eye pain that does not respond to topical therapy and does not improve to Grade 1 severity within the re-treatment period OR requires systemic treatment. 2. Any Grade 2 drug-related pneumonitis or interstitial lung disease that does not resolve to dose delay and systemic steroids in 14 days. 3. Any Grade 3 non-skin drug-related adverse event with the exception of laboratory abnormalities that cannot be alleviated or controlled by appropriate care within 14 days. 4. Any Grade 4

GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy1
Number of Participants With Adverse Events (AEs) - Part 2 Primary · Deaths are from first dose to database lock (Up to 24 months). AEs and SAEs are from first dose to 30 days post last dose

Number of participants with adverse events (AEs) including serious adverse events (SAEs) and deaths graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine the safety and tolerability of Nivolumab and Ipilimumab combined with chemotherapy.

Adverse Events (AEs)
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy36
Serious Adverse Events (SAEs)
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy26
Deaths due to Disease progression
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy9
Deaths due to Study drug toxicity
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy0
Deaths due to unknown causes
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy1
Deaths due to other causes
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy6
Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 Primary · From first dose to 30 days post last dose

Number of participant with specific liver laboratory abnormalities graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine the safety and tolerability of Nivolumab and Ipilimumab combined with chemotherapy.

ALT OR AST >3XULN
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy2
ALT OR AST >5XULN
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy2
ALT OR AST >10XULN
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy1
ALT OR AST >20XULN
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy1
TOTAL BILIRUBIN >2XULN
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy0
Concurrent ALT OR AST >3XULN & BILIRUBIN >2XULN within 1 day
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy0
Concurrent ALT OR AST >3XULN & BILIRUBIN >2XULN within 30 days
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy0
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 Primary · From first dose to 30 days post last dose

Number of participants with specific thyroid laboratory abnormalities graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine the safety and tolerability of Nivolumab and Ipilimumab combined with chemotherapy.

TSH > ULN
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy10
TSH > ULN with TSH <= ULN at baseline
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy7
TSH > ULN with at least one FT3/FT4 test value < LLN
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy8
TSH > ULN with all other FT3/FT4 test values ≥ LLN
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy1
TSH > ULN with FT3/FT4 test missing
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy1
TSH < LLN
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy13
TSH < LLN with TSH >= LLN at baseline
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy12
TSH < LLN with at least one FT3/FT4 test value > ULN
GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy7
Overall Survival (OS) - Part 1 Secondary · From the date of first treatment to the date of death due to any cause (Up to approximately 72 months)

Overall survival (OS) was defined as the time from date of first treatment to the date of death due to any cause. A participant who has not died will be censored at the last known date alive.

GroupValue95% CI
Nivolumab+Ipilimumab20.8314.46 – 25.20
Overall Survival (OS) - Part 2 Secondary · From the date of first treatment to the date of death due to any cause (Up to approximately 59 months)

Overall survival (OS) was defined as the time from date of first treatment to the date of death due to any cause. A participant who has not died will be censored at the last known date alive.

GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy19.356.54 – 35.42
Progression Free Survival (PFS) - Part 1 Secondary · From first dose to the first date of documented progression, or death due to any cause, whichever occurred first (Up to approximately 72 months)

Progression Free Survival (PFS) was defined as the time between the date of first dose and the first date of documented progression, as determined by blinded independent central review (BICR), or death due to any cause, whichever occurred first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

GroupValue95% CI
Nivolumab+Ipilimumab5.193.06 – 5.82
Progression Free Survival (PFS) - Part 2 Secondary · From first dose to the first date of documented progression, or death due to any cause, whichever occurred first (Up to approximately 59 months)

Progression Free Survival (PFS) was defined as the time between the date of first dose and the first date of documented progression, as determined by investigator (per RECIST 1.1), or death due to any cause, whichever occurred first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy10.815.26 – 16.13
Objective Response Rate (ORR) - Part 1 Secondary · From first dose up to approximately 72 months

Objective response rate (ORR) was defined as the percentage of treated participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 based on Blinded Independent Central Review (BICR) assessment. CR = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

GroupValue95% CI
Nivolumab+Ipilimumab32.326.9 – 38.0
Objective Response Rate (ORR) - Part 2 Secondary · From first dose up to approximately 59 months

Objective response rate (ORR) was defined as the percentage of treated participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 based on investigator assessment. CR = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

GroupValue95% CI
Nivolumab+Ipilimumab+Chemotherapy47.230.4 – 64.5
Overall Survival (OS) by PD-L1 Expression Levels - Part 1 Secondary · From the date of first treatment to the date of death due to any cause (Up to approximately 72 months)

Overall survival (OS) by PD-L1 expression levels was defined as the time from date of first treatment to the date of death due to any cause. A participant who has not died will be censored at the last known date alive. PD-L1 ≥1% = PD-L1 positive (membranous staining in ≥ 1% tumor cells) PD-L1 \<1% = PD-L1 negative (membranous staining in \<1% tumor cells)

PD-L1 ≥1%
GroupValue95% CI
Nivolumab+Ipilimumab26.5117.12 – 43.17
PD-L1 <1%
GroupValue95% CI
Nivolumab+Ipilimumab13.7010.71 – 21.91

Adverse events — posted to ClinicalTrials.gov

Time frame: Part 1: SAEs and AEs are assessed from first dose to 30 days post last dose (Up to approximately 25 months). Participants were assessed for all-cause mortality from their first dose to study completion (Up to approximately 72 months). Part 2: SAEs and AEs are assessed from first dose to 30 days post last dose (Up to approximately 25 months). Participants were assessed for all-cause mortality from their first dose to study completion (Up to approximately 59 months).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Nivolumab+Ipilimumab
Serious: 171/288 (59%)
Deaths: 209/288
Nivolumab+Ipilimumab+Chemotherapy
Serious: 26/36 (72%)
Deaths: 28/36

Serious adverse events (162 terms)

ReactionSystemNivolumab+IpilimumabNivolumab+Ipilimumab+Chemo…
PneumoniaInfections and infestations
Malignant neoplasm progressionNeoplasms benign, malignant and unspecified (incl cysts and polyps)
DyspnoeaRespiratory, thoracic and mediastinal disorders
PneumonitisRespiratory, thoracic and mediastinal disorders
DiarrhoeaGastrointestinal disorders
Pulmonary embolismRespiratory, thoracic and mediastinal disorders
ColitisGastrointestinal disorders
SepsisInfections and infestations
PyrexiaGeneral disorders
DehydrationMetabolism and nutrition disorders
Pleural effusionRespiratory, thoracic and mediastinal disorders
NauseaGastrointestinal disorders
Respiratory failureRespiratory, thoracic and mediastinal disorders
ConstipationGastrointestinal disorders
VomitingGastrointestinal disorders
Muscular weaknessMusculoskeletal and connective tissue disorders
Acute kidney injuryRenal and urinary disorders
Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders
AnaemiaBlood and lymphatic system disorders
Pericardial effusionCardiac disorders
HypophysitisEndocrine disorders
InfluenzaInfections and infestations
Cerebrovascular accidentNervous system disorders
HaemoptysisRespiratory, thoracic and mediastinal disorders
EmbolismVascular disorders
Other adverse events (97 terms — click to expand)

ReactionSystemNivolumab+IpilimumabNivolumab+Ipilimumab+Chemo…
FatigueGeneral disorders
DiarrhoeaGastrointestinal disorders
NauseaGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
CoughRespiratory, thoracic and mediastinal disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
PruritusSkin and subcutaneous tissue disorders
ArthralgiaMusculoskeletal and connective tissue disorders
ConstipationGastrointestinal disorders
AnaemiaBlood and lymphatic system disorders
Weight decreasedInvestigations
HyponatraemiaMetabolism and nutrition disorders
VomitingGastrointestinal disorders
Back painMusculoskeletal and connective tissue disorders
HeadacheNervous system disorders
HypoalbuminaemiaMetabolism and nutrition disorders
Lipase increasedInvestigations
Oedema peripheralGeneral disorders
PyrexiaGeneral disorders
RashSkin and subcutaneous tissue disorders
Rash maculo-papularSkin and subcutaneous tissue disorders
InsomniaPsychiatric disorders
HypokalaemiaMetabolism and nutrition disorders
Dry skinSkin and subcutaneous tissue disorders
Aspartate aminotransferase increasedInvestigations
DizzinessNervous system disorders
HypomagnesaemiaMetabolism and nutrition disorders
HypertensionVascular disorders
ChillsGeneral disorders
Upper respiratory tract infectionInfections and infestations
Nasal congestionRespiratory, thoracic and mediastinal disorders
Abdominal painGastrointestinal disorders
PneumoniaInfections and infestations
Amylase increasedInvestigations
HypothyroidismEndocrine disorders
Dry mouthGastrointestinal disorders
AnxietyPsychiatric disorders
Alanine aminotransferase increasedInvestigations
Blood alkaline phosphatase increasedInvestigations
HyperglycaemiaMetabolism and nutrition disorders

Most-reported serious reactions: Pneumonia, Malignant neoplasm progression, Dyspnoea, Pneumonitis, Diarrhoea, Pulmonary embolism, Colitis, Sepsis.

Data from ClinicalTrials.gov NCT02659059 adverse events section.

Sponsor's own description

The purpose of part 1 of this study is to determine the objective response rate (ORR) in stage IV NSCLC subjects treated with nivolumab in combination with ipilimumab as first line therapy. The purpose of part 2 of this study is to determine the safety and tolerability of nivolumab and ipilimumab combined with a short course of chemotherapy in first line stage IV NSCLC.

Publications & conference data

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

  1. The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker.
    Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. · · 2021 · cited 935× · PMID 33125859 · DOI 10.1016/j.ccell.2020.10.001
  2. Combination of CTLA-4 and PD-1 blockers for treatment of cancer.
    Rotte A. · · 2019 · cited 708× · PMID 31196207 · DOI 10.1186/s13046-019-1259-z
  3. First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers.
    Ready N, Hellmann MD, Awad MM, Otterson GA, et al · · 2019 · cited 453× · PMID 30785829 · DOI 10.1200/jco.18.01042
  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. Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC).
    Chae YK, Arya A, Iams W, Cruz MR, et al · · 2018 · cited 336× · PMID 29769148 · DOI 10.1186/s40425-018-0349-3
  6. Tumor mutational burden quantification from targeted gene panels: major advancements and challenges.
    Fancello L, Gandini S, Pelicci PG, Mazzarella L. · · 2019 · cited 245× · PMID 31307554 · DOI 10.1186/s40425-019-0647-4
  7. Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions.
    Stenzinger A, Allen JD, Maas J, Stewart MD, et al · · 2019 · cited 184× · PMID 30664300 · DOI 10.1002/gcc.22733
  8. Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies.
    Shi ZD, Pang K, Wu ZX, Dong Y, et al · · 2023 · cited 168× · PMID 36906600 · DOI 10.1038/s41392-023-01383-x

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Trials by the same sponsor.

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Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT02659059.

Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing