Trial Outcomes & Findings for An Exploratory Study of the Effects of Nivolumab Combined With Ipilimumab in Patients With Treatment-Naive Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) (NCT NCT03001882)

Last Updated: 2024-05-20

Results Overview

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to \<10 mm. Blood tumor mutational burden (bTMB) is the total number of nonsynonymous somatic mutations produced by a tumor that are detected in serum. CR+PR, confidence interval based on the Clopper and Pearson method.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

230 participants

Primary outcome timeframe

From first dose up to the date of objectively documented progression, or the date of initiation of palliative local therapy or the date of initiation of subsequent anticancer therapy (up to approximately 58 months)

Results posted on

2024-05-20

Participant Flow

In Part 1, upon determination of PD-L1 status (cut-off of 1%), 2 cohorts were defined: PD-L1 positive and negative. In Part 2, a separate group of participants were treated regardless of their PD-L1 status.

Participant milestones

Participant milestones
Measure	PART 1: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1 Status Independent Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Overall Study STARTED	31	28	1	170
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	31	28	1	170

Reasons for withdrawal

Reasons for withdrawal
Measure	PART 1: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1 Status Independent Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Overall Study Death	1	0	0	3
Overall Study Participant withdrew consent	0	1	0	5
Overall Study Other reasons	1	2	0	5
Overall Study Administrative reason by sponsor	0	0	0	1
Overall Study Participant requested to discontinue study treatment	0	0	0	2
Overall Study Not reported	0	0	0	6
Overall Study Maximum clinical benefit	2	3	0	10
Overall Study AE unrelated to study drug	3	3	0	11
Overall Study Study Drug Toxicity	8	5	0	37
Overall Study Disease progression	16	14	1	90

Baseline Characteristics

An Exploratory Study of the Effects of Nivolumab Combined With Ipilimumab in Patients With Treatment-Naive Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PART 1: PD-L1+ Status n=31 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status n=28 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status n=1 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1 Status Independent n=170 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	Total n=230 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	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	10 Participants n=5 Participants	15 Participants n=7 Participants	0 Participants n=5 Participants	76 Participants n=4 Participants	101 Participants n=21 Participants
Age, Categorical >=65 years	21 Participants n=5 Participants	13 Participants n=7 Participants	1 Participants n=5 Participants	94 Participants n=4 Participants	129 Participants n=21 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	11 Participants n=7 Participants	0 Participants n=5 Participants	54 Participants n=4 Participants	80 Participants n=21 Participants
Sex: Female, Male Male	16 Participants n=5 Participants	17 Participants n=7 Participants	1 Participants n=5 Participants	116 Participants n=4 Participants	150 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	4 Participants n=4 Participants	6 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	24 Participants n=5 Participants	25 Participants n=7 Participants	1 Participants n=5 Participants	98 Participants n=4 Participants	148 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	6 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	68 Participants n=4 Participants	76 Participants n=21 Participants
Race/Ethnicity, Customized White	27 Participants n=5 Participants	25 Participants n=7 Participants	1 Participants n=5 Participants	164 Participants n=4 Participants	217 Participants n=21 Participants
Race/Ethnicity, Customized Black or African American	3 Participants n=5 Participants	3 Participants n=7 Participants	0 Participants n=5 Participants	5 Participants n=4 Participants	11 Participants n=21 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants

PRIMARY outcome

Timeframe: From first dose up to the date of objectively documented progression, or the date of initiation of palliative local therapy or the date of initiation of subsequent anticancer therapy (up to approximately 58 months)

Population: All treated PD-L1 and bTMB evaluable Part 1 and 2 participants (Blood TMB Cut-point = 16 mutations/MB). Non-evaluable PD-L1 status means that PD-L1 status could not be determined, thus the Arm population did not meet this criteria. Participants in Part 2: PD-L1(+/-) Status groups were stratified from the PART 2: PD-L1 Status Independent Arm. Not all participants were bTMB evaluable. To be analyzed participants had to be both PD-L1 evaluable and bTMB evaluable.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=19 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status n=16 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status n=39 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status n=62 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Objective Response Rate (ORR) Per Investigator by Blood TMB (bTMB) Within PD-L1 Subgroup (TMB Cut-point = 16 Mutations/MB) bTMB High (Cut-point = 16-mutations)	30 Percent of Participants Interval 6.7 to 65.2	50 Percent of Participants Interval 18.7 to 81.3	—	58.8 Percent of Participants Interval 32.9 to 81.6	30.3 Percent of Participants Interval 15.6 to 48.7
Objective Response Rate (ORR) Per Investigator by Blood TMB (bTMB) Within PD-L1 Subgroup (TMB Cut-point = 16 Mutations/MB) bTMB Low (Cut-point = 16-mutations)	33.3 Percent of Participants Interval 7.5 to 70.1	33.3 Percent of Participants Interval 4.3 to 77.7	—	31.8 Percent of Participants Interval 13.9 to 54.9	24.1 Percent of Participants Interval 10.3 to 43.5

PRIMARY outcome

Population: All treated PD-L1 and bTMB evaluable Part 1 and Part 2 participants (Blood TMB Cut-point = 21-mutations/MB). Non-evaluable PD-L1 status means that PD-L1 status could not be determined, thus the Arm population did not meet this criteria. Participants in Part 2: PD-L1(+/-) Status groups were stratified from the PART 2: PD-L1 Status Independent Arm. Not all participants were bTMB evaluable. To be analyzed participants had to be both PD-L1 evaluable and bTMB evaluable.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=19 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status n=16 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status n=39 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status n=62 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Objective Response Rate (ORR) Per Investigator by Blood TMB (bTMB) Within PD-L1 Subgroup (Blood TMB Cut-point = 21-mutations/MB) bTMB High (Cut-point = 21-mutations)	33.3 Percent of Participants Interval 4.3 to 77.7	66.7 Percent of Participants Interval 22.3 to 95.7	—	64.3 Percent of Participants Interval 35.1 to 87.2	40.9 Percent of Participants Interval 20.7 to 63.6
Objective Response Rate (ORR) Per Investigator by Blood TMB (bTMB) Within PD-L1 Subgroup (Blood TMB Cut-point = 21-mutations/MB) bTMB Low (Cut-point = 21-mutations)	30.8 Percent of Participants Interval 9.1 to 61.4	30.0 Percent of Participants Interval 6.7 to 65.2	—	32.0 Percent of Participants Interval 14.9 to 53.5	20.0 Percent of Participants Interval 9.1 to 35.6

PRIMARY outcome

Population: All treated PD-L1 and bTMB evaluable Part 1 and Part 2 participants (Blood TMB Cut-point = 10-mutations/MB). Non-evaluable PD-L1 status means that PD-L1 status could not be determined, thus the Arm population did not meet this criteria. Participants in Part 2: PD-L1(+/-) Status groups were stratified from the PART 2: PD-L1 Status Independent Arm. Not all participants were bTMB evaluable. To be analyzed participants had to be both PD-L1 evaluable and bTMB evaluable.

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to \<10 mm. Tissue tumor mutational burden (tTMB) is the total number of nonsynonymous somatic mutations produced by a tumor that are detected in tumor tissue samples. CR+PR, confidence interval based on the Clopper and Pearson method.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=19 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status n=16 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status n=31 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status n=57 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Objective Response Rate (ORR) Per Investigator by Tissue TMB Within PD-L1 Subgroup (Tissue TMB Cut-point = 10-mutations/MB) tTMB High (Cut-point = 10-mutations)	25.0 Percent of Participants Interval 3.2 to 65.1	71.4 Percent of Participants Interval 29.0 to 96.3	—	60.0 Percent of Participants Interval 32.3 to 83.7	46.7 Percent of Participants Interval 21.3 to 73.4
Objective Response Rate (ORR) Per Investigator by Tissue TMB Within PD-L1 Subgroup (Tissue TMB Cut-point = 10-mutations/MB) tTMB Low (Cut-point = 10-mutations	27.3 Percent of Participants Interval 6.0 to 61.0	22.2 Percent of Participants Interval 2.8 to 60.0	—	25.0 Percent of Participants Interval 7.3 to 52.4	21.4 Percent of Participants Interval 10.3 to 36.8

SECONDARY outcome

Timeframe: From first dose until the date of objectively documented progression, or the date of initiation of palliative local therapy or the date of initiation of subsequent anticancer therapy, whichever occurs first (Up to approximately 67 months)

Population: All treated Part 1 and Part 2 participants

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete Response (CR) is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to \<10 mm. CR+PR, confidence interval based on the Clopper and Pearson method.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=31 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status n=28 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status n=1 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status n=170 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Objective Response Rate (ORR) for All Treated Participants by Investigator Per RECIST 1.1	29.0 Percent of Participants Interval 14.2 to 48.0	39.3 Percent of Participants Interval 21.5 to 59.4	0 Percent of Participants Interval 0.0 to 97.5	29.4 Percent of Participants Interval 22.7 to 36.9	—

SECONDARY outcome

Population: All treated participants in Part 1. Endpoint pre-specified only for participants treated in Part 1.

Disease control rate (DCR) is the percent of treated participants with a best overall response of a complete response (CR), partial response (PR), or stable disease (SD), assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). PR is at least a 30% decrease in the sum of diameters of target lesions, using the baseline sum diameters as reference. CR is disappearance of all target lesions and a reduction in short axis to \<10 mm of any pathological lymph nodes (target or non-target). SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking smallest sum diameters as reference. PD is at least a 20% increase in the sum of diameters of target lesions, taking the smallest sum as reference. The sum must also demonstrate an absolute increase of at least 5 mm. (one or more new lesions is also considered progression). CR+PR, confidence interval based on the Clopper and Pearson method.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=31 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status n=28 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status n=1 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Disease Control Rate (DCR) for Part 1	58.1 Percent of Participants Interval 39.1 to 75.5	64.3 Percent of Participants Interval 44.1 to 81.4	100.0 Percent of Participants Interval 2.5 to 100.0	—	—

SECONDARY outcome

Timeframe: From first dose to the date of the first documented tumor progression or death due to any cause (Up to approximately 67 months)

Population: All treated participants in Part 1 who had complete or partial response. Endpoint pre-specified only for participants treated in Part 1.

DOR is the time between first confirmed response (Complete/Partial Response) and first documented tumor progression (per RECIST 1.1) or death due to any cause. Participants who don't progress or die are censored on the date of their last evaluable tumor assessment. Participants who started subsequent anti-cancer therapy without prior reported progression were censored at the last evaluable tumor assessment prior to or on the date of subsequent anti-cancer therapy. PR is at least 30% decrease in the sum of diameters of target lesions, using baseline sum diameters as reference. CR is disappearance of all target lesions and reduction in short axis to \<10 mm of any pathological lymph nodes (target or non-target). Progressive Disease (PD) is at least 20% increase in the sum of diameters of target lesions, taking the smallest sum as reference. The sum must also show an overall increase of \> 5 mm. (one or more new lesions is also progression). Median computed using Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=9 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status n=11 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Duration of Response (DOR) for Part 1	24.56 Months Interval 1.9 to 61.7	29.57 Months Interval 2.8 to 48.9	—	—	—

SECONDARY outcome

Timeframe: From first dose to the time the criteria for Complete Response/Partial Response are first met (Up to approximately 67 months)

Population: All treated participants in Part 1 who had complete or partial response. Endpoint pre-specified only for participants treated in Part 1.

TTR is the time taken from first dosing date to the time the criteria for Complete Response (CR)/Partial Response (PR) are first met. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=9 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status n=11 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Time to Response (TTR) for Part 1	1.84 Months Interval 1.6 to 3.7	5.26 Months Interval 1.7 to 18.5	—	—	—

SECONDARY outcome

Timeframe: From first dose to the date of the first documented tumor progression or death due to any causes (Assessed up to approximately 67 months)

Population: All treated Part 1 and Part 2 participants

PFS is defined as the time from first dosing date to the date of the first documented tumor progression (per RECIST 1.1) or death due to any cause. Participants who neither progress nor die will be censored on the date of their last evaluable tumor assessment. Participants who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last evaluable tumor assessment prior to or on the date of initiation of subsequent anti-cancer therapy. Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking the smallest sum on study as reference. The sum must also show an overall increase of \> 5 mm. (one or more new lesions is also progression). Median calculated using Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=31 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status n=28 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status n=1 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status n=170 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Progression Free Survival (PFS)	3.71 Months Interval 1.97 to 8.9	4.30 Months Interval 1.84 to 13.6	3.61 Months Insufficient number of participants with events	6.28 Months Interval 5.09 to 7.56	—

SECONDARY outcome

Timeframe: From first dose to the date of death (Assessed up to approximately 67 months)

Population: All treated Part 1 and Part 2 participants

OS is defined as the time from first dosing date to the date of death. If a participant didn't die, OS will be censored on the last date the participant was known to be alive. Median based on Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=31 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status n=28 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status n=1 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status n=170 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Overall Survival (OS)	9.63 Months Interval 4.47 to 20.57	22.29 Months Interval 11.56 to 25.23	9.23 Months Insufficient number of participants with events	14.78 Months Interval 11.99 to 20.6	—

SECONDARY outcome

Timeframe: From first dose to 30 days after last dosing date (assessed up to approximately 27 months)

Population: All treated Part 2 participants. Endpoint pre-specified only for participants treated in Part 2.

An Adverse Event (AE) is any new untoward medical occurrence or worsening preexisting medical condition in a treated participant and that does not necessarily have a causal relationship with treatment. An AE can be any unfavorable, unintended sign, symptom, or disease temporally associated with the use of treatment, whether or not related to the treatment.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=170 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Number of Participants With Adverse Events (AEs) for Study Part 2	169 Participants	—	—	—	—

SECONDARY outcome

Timeframe: From first dose to 30 days after last dosing date (assessed up to approximately 27 months)

Population: All treated Part 2 participants. Endpoint pre-specified only for participants treated in Part 2.

A Serious Adverse Event (SAE) results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), or requires inpatient hospitalization or causes prolongation of existing hospitalization.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=170 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Number of Participants With Serious Adverse Events (SAEs) for Study Part 2	102 Participants	—	—	—	—

SECONDARY outcome

Timeframe: From first dose to 30 days after last dosing date (up to approximately 27 months)

Population: All treated Part 2 participants. Endpoint pre-specified only for participants treated in Part 2.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=170 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Number of Participants With Select Adverse Events (AEs) for Study Part 2 Gastrointestinal Adverse Events	68 Participants	—	—	—	—
Number of Participants With Select Adverse Events (AEs) for Study Part 2 Hepatic Adverse Events	49 Participants	—	—	—	—
Number of Participants With Select Adverse Events (AEs) for Study Part 2 Pulmonary Adverse Events	17 Participants	—	—	—	—
Number of Participants With Select Adverse Events (AEs) for Study Part 2 Renal Adverse Events	28 Participants	—	—	—	—
Number of Participants With Select Adverse Events (AEs) for Study Part 2 Skin Adverse Events	73 Participants	—	—	—	—
Number of Participants With Select Adverse Events (AEs) for Study Part 2 Hypersensitivity/Infusion Reaction	12 Participants	—	—	—	—

POST_HOC outcome

Population: All treated PD-L1 and bTMB evaluable Part 1 and 2 participants (Blood TMB Cut-point = 16 mutations/MB). Non-evaluable PD-L1 status means that PD-L1 status could not be determined, thus the Arm population did not meet this criteria. Not all participants were bTMB evaluable. To be analyzed participants had to be both PD-L1 evaluable and bTMB evaluable.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=36 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status n=131 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Extended Collection of Objective Response Rate (ORR) Per Investigator by Blood TMB (bTMB) (TMB Cut-point = 16 Mutations/MB) bTMB High (Cut-point = 16-mutations)	40.0 Percent of Participants Interval 19.1 to 63.9	—	34.4 Percent of Participants Interval 22.9 to 47.3	—	—
Extended Collection of Objective Response Rate (ORR) Per Investigator by Blood TMB (bTMB) (TMB Cut-point = 16 Mutations/MB) bTMB Low (Cut-point = 16-mutations)	25.0 Percent of Participants Interval 7.3 to 52.4	—	26.9 Percent of Participants Interval 16.8 to 39.1	—	—

POST_HOC outcome

Population: All treated PD-L1 and bTMB evaluable Part 1 and Part 2 participants (Blood TMB Cut-point = 21-mutations/MB). Non-evaluable PD-L1 status means that PD-L1 status could not be determined, thus the Arm population did not meet this criteria. Not all participants were bTMB evaluable. To be analyzed participants had to be both PD-L1 evaluable and bTMB evaluable.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=36 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status n=131 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Extended Collection of Objective Response Rate (ORR) Per Investigator by Blood TMB (bTMB) (Blood TMB Cut-point = 21-mutations/MB) bTMB High (Cut-point = 21-mutations)	50.0 Percent of Participants Interval 21.1 to 78.9	—	44.4 Percent of Participants Interval 29.6 to 60.0	—	—
Extended Collection of Objective Response Rate (ORR) Per Investigator by Blood TMB (bTMB) (Blood TMB Cut-point = 21-mutations/MB) bTMB Low (Cut-point = 21-mutations)	25.0 Percent of Participants Interval 9.8 to 46.7	—	23.3 Percent of Participants Interval 14.8 to 33.6	—	—

POST_HOC outcome

Population: All treated PD-L1 and bTMB evaluable Part 1 and Part 2 participants (Blood TMB Cut-point = 10-mutations/MB). Non-evaluable PD-L1 status means that PD-L1 status could not be determined, thus the Arm population did not meet this criteria. Not all participants were bTMB evaluable. To be analyzed participants had to be both PD-L1 evaluable and bTMB evaluable.

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to \<10 mm. Tissue tumor mutational burden (tTMB) is the total number of nonsynonymous somatic mutations produced by a tumor that are detected in tumor tissue samples. CR+PR, confidence interval based on the Clopper and Pearson method.

Outcome measures

Outcome measures
Measure	PART 1: PD-L1 + Status n=35 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 1: Not Evaluable/Indeterminate PD-L1 Status n=101 Participants Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.	PART 2: PD-L1+ Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first	PART 2: PD-L1- Status Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first
Extended Collection of Objective Response Rate (ORR) Per Investigator by Tissue TMB (Tissue TMB Cut-point = 10-mutations/MB) tTMB High (Cut-point = 10-mutations)	46.7 Percent of Participants Interval 21.3 to 73.4	—	50.0 Percent of Participants Interval 32.4 to 67.6	—	—
Extended Collection of Objective Response Rate (ORR) Per Investigator by Tissue TMB (Tissue TMB Cut-point = 10-mutations/MB) tTMB Low (Cut-point = 10-mutations	20.0 Percent of Participants Interval 5.7 to 43.7	—	19.4 Percent of Participants Interval 10.8 to 30.9	—	—

Adverse Events

PART 1: PD-L1+ Status

Serious events: 24 serious events

Other events: 31 other events

Deaths: 27 deaths

PART 1: PD-L1- Status

Serious events: 14 serious events

Other events: 27 other events

Deaths: 22 deaths

PART 1: Not Evaluable/Indeterminate PD-L1 Status

Serious events: 0 serious events

Other events: 1 other events

Deaths: 1 deaths

PART 2: PD-L1 Status Independent

Serious events: 113 serious events

Other events: 161 other events

Deaths: 134 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