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

• Nivolumab (Biological), also known as BMS-936558, Opdivo: Specified Dose on Specified Days
• Ipilimumab (Biological), also known as BMS-734016, Yervoy: Specified Dose on Specified Days
• Platinum Doublet Chemotherapy (Drug), also known as Carboplatin + Paclitaxel, Cisplatin + pemetrexed

Primary outcomes

• Objective Response Rate (ORR) by PD-L1 Positive and Negative Levels - Part 1 [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.
• Number of Participants With Dose Limiting Toxicities (DLTs) - Part 2 [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 drug-related adverse event including laboratory abnormalities except Grade 4 leukopenia or neutropenia lasting < 14 days and asymptomatic amylase/lipase elevation. 5. Drug-related hepatic function laboratory abnormalities.
• Number of Participants With Adverse Events (AEs) - Part 2 [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.
• Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 [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.
• Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 [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.

Secondary outcomes

• Overall Survival (OS) - Part 1 [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.
• Overall Survival (OS) - Part 2 [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.
• Progression Free Survival (PFS) - Part 1 [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.
• Progression Free Survival (PFS) - Part 2 [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.
• Objective Response Rate (ORR) - Part 1 [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.
• Objective Response Rate (ORR) - Part 2 [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.
• Overall Survival (OS) by PD-L1 Expression Levels - Part 1 [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)
• Progression Free Survival (PFS) by PD-L1 Expression Levels - Part 1 [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) by PD-L1 expression levels 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. PD-L1 ≥1% = PD-L1 positive (membranous staining in ≥ 1% tumor cells) PD-L1 <1% = PD-L1 negative (membranous staining in <1% tumor cells)
• Objective Response Rate (ORR) by PD-L1 Expression Levels-Part 1 [From first dose up to approximately 72 months]: Objective response rate (ORR) by PD-L1 expression levels 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. PD-L1 ≥1% = PD-L1 positive (membranous staining in ≥ 1% tumor cells) PD-L1 <1% = PD-L1 negative (membranous staining in <1% tumor cells)
• Overall Survival (OS) by Tumor Mutation Burden (TMB) Levels - Part 1 [From the date of first treatment to the date of death due to any cause (Up to approximately 72 months)]: Overall survival (OS) by tumor mutational burden (TMB) using DNA derived from tumor specimens 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. High TMB = ≥ 10 mutations per megabase Low TMB = < 10 mutations per megabase
• Progression Free Survival (PFS) by Tumor Mutation Burden (TMB) Levels - Part 1 [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) by tumor mutational burden (TMB) using DNA derived from tumor specimens 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. High TMB = ≥ 10 mutations per megabase Low TMB = < 10 mutations per megabase
• Objective Response Rate (ORR) by Tumor Mutation Burden (TMB) Levels - Part 1 [From first dose up to approximately 72 months]: Objective response rate (ORR) by tumor mutational burden (TMB) using DNA derived from tumor specimens 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. High TMB = ≥ 10 mutations per megabase Low TMB = < 10 mutations per megabase

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Men and Women ≥ 18 years of age
* Diagnosed with stage IV Non-Small Cell Lung Cancer
* Diagnosed with recurrent stage IIIB non-small cell lung cancer and failed previous concurrent chemoradiation with no further curative options.

Exclusion Criteria:

* Subjects with untreated CNS metastases are excluded.
* Subjects with carcinomatous meningitis
* Subjects with an active, known or suspected autoimmune disease.
* Subjects with a condition requiring systemic treatment with either corticosteroids ( > 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first treatment.
* Women who are pregnant, plan to become pregnant, and/or breastfeed during the study.

Other protocol defined inclusion/exclusion criteria apply

Participant flow

Outcome results

• Objective Response Rate (ORR) by PD-L1 Positive and Negative Levels - Part 1 (Primary), Number, Percentage of participants: Nivolumab+Ipilimumab 41.3 (33.0 to 50.0)
• Number of Participants With Dose Limiting Toxicities (DLTs) - Part 2 (Primary), Count of participants, Participants: Nivolumab+Ipilimumab+Chemotherapy 1
• Number of Participants With Adverse Events (AEs) - Part 2 (Primary), Count of participants, Participants: Nivolumab+Ipilimumab+Chemotherapy 36
• Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 (Primary), Count of participants, Participants: Nivolumab+Ipilimumab+Chemotherapy 2
• Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 (Primary), Count of participants, Participants: Nivolumab+Ipilimumab+Chemotherapy 10
• Overall Survival (OS) - Part 1 (Secondary), Median, Months: Nivolumab+Ipilimumab 20.83 (14.46 to 25.20)
• Overall Survival (OS) - Part 2 (Secondary), Median, Months: Nivolumab+Ipilimumab+Chemotherapy 19.35 (6.54 to 35.42)
• Progression Free Survival (PFS) - Part 1 (Secondary), Median, Months: Nivolumab+Ipilimumab 5.19 (3.06 to 5.82)
• Progression Free Survival (PFS) - Part 2 (Secondary), Median, Months: Nivolumab+Ipilimumab+Chemotherapy 10.81 (5.26 to 16.13)
• Objective Response Rate (ORR) - Part 1 (Secondary), Number, Percentage of participants: Nivolumab+Ipilimumab 32.3 (26.9 to 38.0)
• Objective Response Rate (ORR) - Part 2 (Secondary), Number, Percentage of participants: Nivolumab+Ipilimumab+Chemotherapy 47.2 (30.4 to 64.5)
• Overall Survival (OS) by PD-L1 Expression Levels - Part 1 (Secondary), Median, Months: Nivolumab+Ipilimumab 26.51 (17.12 to 43.17)
• Progression Free Survival (PFS) by PD-L1 Expression Levels - Part 1 (Secondary), Median, Months: Nivolumab+Ipilimumab 6.80 (4.17 to 10.97)
• Objective Response Rate (ORR) by PD-L1 Expression Levels-Part 1 (Secondary), Number, Percentage of participants: Nivolumab+Ipilimumab 44.2 (35.8 to 52.9)
• Overall Survival (OS) by Tumor Mutation Burden (TMB) Levels - Part 1 (Secondary), Median, Months: Nivolumab+Ipilimumab 47.31 (14.46 to NA)
• Progression Free Survival (PFS) by Tumor Mutation Burden (TMB) Levels - Part 1 (Secondary), Median, Months: Nivolumab+Ipilimumab 10.84 (3.61 to 22.21)
• Objective Response Rate (ORR) by Tumor Mutation Burden (TMB) Levels - Part 1 (Secondary), Number, Percentage of participants: Nivolumab+Ipilimumab 52.1 (37.2 to 66.7)

Adverse events

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).

Serious adverse events by term

102 more terms not shown.

Other adverse events by term

37 more terms not shown.

• Results publication: Ready N, Hellmann MD, Awad MM, Otterson GA, Gutierrez M, Gainor JF, Borghaei H, Jolivet J, Horn L, Mates M, Brahmer J, Rabinowitz I, Reddy PS, Chesney J, Orcutt J, Spigel DR, Reck M, O'Byrne KJ, Paz-Ares L, Hu W, Zerba K, Li X, Lestini B, Geese WJ, Szustakowski JD, Green G, Chang H, Ramalingam SS. 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. J Clin Oncol. 2019 Apr 20;37(12):992-1000. doi: 10.1200/JCO.18.01042. Epub 2019 Feb 20. PMID 30785829

• Study Protocol (PDF, 2018-01-11)
• Statistical Analysis Plan (PDF, 2019-04-25)

• Bristol-Myers Squibb, Study director, Bristol-Myers Squibb