Trial Outcomes & Findings for 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 (NCT NCT02659059)

Last Updated: 2023-04-05

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

324 participants

Primary outcome timeframe

From first dose to database lock (Up to 18 months)

Results posted on

2023-04-05

Participant Flow

324 participants treated

Participant milestones

Participant milestones
Measure	Nivolumab+Ipilimumab Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W	Nivolumab+Ipilimumab+Chemotherapy Part 2 Nivolumab IV 360mg Q3W + Ipilimumab IV 1 mg/kg Q6W + 2 cycles Platinum Doublet Chemotherapy
Overall Study STARTED	288	36
Overall Study COMPLETED	37	4
Overall Study NOT COMPLETED	251	32

Reasons for withdrawal

Reasons for withdrawal
Measure	Nivolumab+Ipilimumab Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W	Nivolumab+Ipilimumab+Chemotherapy Part 2 Nivolumab IV 360mg Q3W + Ipilimumab IV 1 mg/kg Q6W + 2 cycles Platinum Doublet Chemotherapy
Overall Study Other reasons	6	1
Overall Study Disease Progression	143	16
Overall Study Study Drug toxicity	56	9
Overall Study Death	3	1
Overall Study Adverse Event unrelated to Study drug	32	4
Overall Study Participant request to discontinue study treatment	5	0
Overall Study Participant withdrew consent	6	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Nivolumab+Ipilimumab n=288 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W	Nivolumab+Ipilimumab+Chemotherapy n=36 Participants Part 2 Nivolumab IV 360mg Q3W + Ipilimumab IV 1 mg/kg Q6W + 2 cycles Platinum Doublet Chemotherapy	Total n=324 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	135 Participants n=5 Participants	13 Participants n=7 Participants	148 Participants n=5 Participants
Age, Categorical >=65 years	153 Participants n=5 Participants	23 Participants n=7 Participants	176 Participants n=5 Participants
Sex: Female, Male Female	146 Participants n=5 Participants	13 Participants n=7 Participants	159 Participants n=5 Participants
Sex: Female, Male Male	142 Participants n=5 Participants	23 Participants n=7 Participants	165 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	12 Participants n=5 Participants	0 Participants n=7 Participants	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	258 Participants n=5 Participants	36 Participants n=7 Participants	294 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	18 Participants n=5 Participants	0 Participants n=7 Participants	18 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	19 Participants n=5 Participants	4 Participants n=7 Participants	23 Participants n=5 Participants
Race (NIH/OMB) White	259 Participants n=5 Participants	32 Participants n=7 Participants	291 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	7 Participants n=5 Participants	0 Participants n=7 Participants	7 Participants n=5 Participants

PRIMARY outcome

Timeframe: From first dose to database lock (Up to 18 months)

Population: All PD-L1 evaluable participants -Part 1

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=252 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Objective Response Rate (ORR) by PD-L1 Positive and Negative Levels - Part 1 PD-L1 ≥1%	41.3 Percentage of participants Interval 33.0 to 50.0
Objective Response Rate (ORR) by PD-L1 Positive and Negative Levels - Part 1 PD-L1 <1%	14.9 Percentage of participants Interval 8.9 to 22.8

PRIMARY outcome

Timeframe: 9 weeks after first dose

Population: All treated participants -Part 2

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.

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=36 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Number of Participants With Dose Limiting Toxicities (DLTs) - Part 2	1 Participants

PRIMARY outcome

Timeframe: 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

Population: All treated participants -Part 2

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.

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=36 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Number of Participants With Adverse Events (AEs) - Part 2 Adverse Events (AEs)	36 Participants
Number of Participants With Adverse Events (AEs) - Part 2 Serious Adverse Events (SAEs)	26 Participants
Number of Participants With Adverse Events (AEs) - Part 2 Deaths due to Disease progression	9 Participants
Number of Participants With Adverse Events (AEs) - Part 2 Deaths due to Study drug toxicity	0 Participants
Number of Participants With Adverse Events (AEs) - Part 2 Deaths due to unknown causes	1 Participants
Number of Participants With Adverse Events (AEs) - Part 2 Deaths due to other causes	6 Participants

PRIMARY outcome

Timeframe: From first dose to 30 days post last dose

Population: All treated participants with at least one on-treatment measurement of the corresponding laboratory parameter -Part 2

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.

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=35 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 Concurrent ALT OR AST >3XULN & BILIRUBIN >2XULN within 30 days	0 Participants
Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 ALT OR AST >3XULN	2 Participants
Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 ALT OR AST >5XULN	2 Participants
Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 ALT OR AST >10XULN	1 Participants
Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 ALT OR AST >20XULN	1 Participants
Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 TOTAL BILIRUBIN >2XULN	0 Participants
Number of Participants With Laboratory Abnormalities in Hepatic Tests - Part 2 Concurrent ALT OR AST >3XULN & BILIRUBIN >2XULN within 1 day	0 Participants

PRIMARY outcome

Timeframe: From first dose to 30 days post last dose

Population: All treated participants with at least one on-treatment TSH measurement -Part 2

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.

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=34 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 TSH > ULN	10 Participants
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 TSH > ULN with TSH <= ULN at baseline	7 Participants
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 TSH > ULN with at least one FT3/FT4 test value < LLN	8 Participants
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 TSH > ULN with all other FT3/FT4 test values ≥ LLN	1 Participants
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 TSH > ULN with FT3/FT4 test missing	1 Participants
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 TSH < LLN	13 Participants
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 TSH < LLN with TSH >= LLN at baseline	12 Participants
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 TSH < LLN with at least one FT3/FT4 test value > ULN	7 Participants
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 TSH < LLN with all other FT3/FT4 test values <= ULN	6 Participants
Number of Participants With Laboratory Abnormalities in Thyroid Tests - Part 2 TSH < LLN with FT3/Ft4 test missing	0 Participants

SECONDARY outcome

Timeframe: From the date of first treatment to the date of death due to any cause (Up to approximately 72 months)

Population: All treated participants in Part 1

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.

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=288 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Overall Survival (OS) - Part 1	20.83 Months Interval 14.46 to 25.2

SECONDARY outcome

Timeframe: From the date of first treatment to the date of death due to any cause (Up to approximately 59 months)

Population: All treated participants in Part 2

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.

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=36 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Overall Survival (OS) - Part 2	19.35 Months Interval 6.54 to 35.42

SECONDARY outcome

Timeframe: From first dose to the first date of documented progression, or death due to any cause, whichever occurred first (Up to approximately 72 months)

Population: All treated participants in Part 1

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.

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=288 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Progression Free Survival (PFS) - Part 1	5.19 Months Interval 3.06 to 5.82

SECONDARY outcome

Timeframe: From first dose to the first date of documented progression, or death due to any cause, whichever occurred first (Up to approximately 59 months)

Population: All treated participants in Part 2

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.

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=36 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Progression Free Survival (PFS) - Part 2	10.81 Months Interval 5.26 to 16.13

SECONDARY outcome

Timeframe: From first dose up to approximately 72 months

Population: All treated participants in Part 1

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.

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=288 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Objective Response Rate (ORR) - Part 1	32.3 Percentage of participants Interval 26.9 to 38.0

SECONDARY outcome

Timeframe: From first dose up to approximately 59 months

Population: All treated participants in Part 2

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.

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=36 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Objective Response Rate (ORR) - Part 2	47.2 Percentage of participants Interval 30.4 to 64.5

SECONDARY outcome

Timeframe: From the date of first treatment to the date of death due to any cause (Up to approximately 72 months)

Population: All PD-L1 evaluable participants in Part 1. Data was pre-specified to be collected only in Part 1 arm

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)

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=255 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Overall Survival (OS) by PD-L1 Expression Levels - Part 1 PD-L1 ≥1%	26.51 Months Interval 17.12 to 43.17
Overall Survival (OS) by PD-L1 Expression Levels - Part 1 PD-L1 <1%	13.70 Months Interval 10.71 to 21.91

SECONDARY outcome

Timeframe: From first dose to the first date of documented progression, or death due to any cause, whichever occurred first (Up to approximately 72 months)

Population: All PD-L1 evaluable participants in Part 1. Data was pre-specified to be collected only in Part 1 arm

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)

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=255 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Progression Free Survival (PFS) by PD-L1 Expression Levels - Part 1 PD-L1 ≥1%	6.80 Months Interval 4.17 to 10.97
Progression Free Survival (PFS) by PD-L1 Expression Levels - Part 1 PD-L1 <1%	2.92 Months Interval 2.17 to 4.11

SECONDARY outcome

Timeframe: From first dose up to approximately 72 months

Population: All PD-L1 evaluable participants in Part 1. Data was pre-specified to be collected only in Part 1 arm

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)

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=255 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Objective Response Rate (ORR) by PD-L1 Expression Levels-Part 1 PD-L1 ≥1%	44.2 Percentage of participants Interval 35.8 to 52.9
Objective Response Rate (ORR) by PD-L1 Expression Levels-Part 1 PD-L1 <1%	17.1 Percentage of participants Interval 10.8 to 25.2

SECONDARY outcome

Timeframe: From the date of first treatment to the date of death due to any cause (Up to approximately 72 months)

Population: All TMB evaluable participants in Part 1. Data was pre-specified to be collected only in Part 1 arm

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

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=98 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Overall Survival (OS) by Tumor Mutation Burden (TMB) Levels - Part 1 High TMB (>=10 Mutations/MB)	47.31 Months Interval 14.46 to The 95% upper limit was not reached per the Kaplan-Meier method, as the probability of survival was still above 50%
Overall Survival (OS) by Tumor Mutation Burden (TMB) Levels - Part 1 Low TMB (<10 Mutations/MB)	11.33 Months Interval 6.6 to 13.7

SECONDARY outcome

Timeframe: From first dose to the first date of documented progression, or death due to any cause, whichever occurred first (Up to approximately 72 months)

Population: All TMB evaluable participants in Part 1. Data was pre-specified to be collected only in Part 1 arm

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

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=98 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Progression Free Survival (PFS) by Tumor Mutation Burden (TMB) Levels - Part 1 High TMB (>=10 Mutations/MB)	10.84 Months Interval 3.61 to 22.21
Progression Free Survival (PFS) by Tumor Mutation Burden (TMB) Levels - Part 1 Low TMB (<10 Mutations/MB)	2.79 Months Interval 1.38 to 5.39

SECONDARY outcome

Timeframe: From first dose up to approximately 72 months

Population: All TMB evaluable participants in Part 1. Data was pre-specified to be collected only in Part 1 arm

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

Outcome measures

Outcome measures
Measure	Nivolumab+Ipilimumab n=98 Participants Part 1 Nivolumab IV 3 mg/kg Q2W + Ipilimumab IV 1 mg/kg Q6W
Objective Response Rate (ORR) by Tumor Mutation Burden (TMB) Levels - Part 1 High TMB (>=10 Mutations/MB)	52.1 Percentage of participants Interval 37.2 to 66.7
Objective Response Rate (ORR) by Tumor Mutation Burden (TMB) Levels - Part 1 Low TMB (<10 Mutations/MB)	16.0 Percentage of participants Interval 12.1 to 34.2

Adverse Events

Nivolumab+Ipilimumab

Serious events: 171 serious events

Other events: 282 other events

Deaths: 209 deaths

Nivolumab+Ipilimumab+Chemotherapy

Serious events: 26 serious events

Other events: 35 other events

Deaths: 28 deaths

Serious adverse events

Other adverse events

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Phone: Please Email

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Publication restrictions are in place

Restriction type: OTHER