A Study of Nivolumab Combined With Ipilimumab and Nivolumab Alone in Patients With Advanced or Metastatic Solid Tumors of High Tumor Mutational Burden (TMB-H)

ORR was defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) based on Blinded Independent Central Review (BICR) assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.

Time frame: From date of randomization up to 42 months

Population: All participants randomized in a salvage setting to arm A by TMB-High status

CBR is defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) or stable disease (SD) per Blinded Independent Central Review (BICR) assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm PR= ≥ 30% decrease in the sum of diameters of target lesions SD= does not qualify for PR or progressive disease RANO Criteria: CR= Disappearance of all enhancing disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; stable or improved clinically SD= does not qualify for CR, PR, or progression; stable nonenhancing T2/FLAIR lesions

Time frame: From date of randomization up to 57 months

Population: All participants randomized in a salvage setting by TMB-High status

CBR is defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) or stable disease (SD) based on investigator assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm PR= ≥ 30% decrease in the sum of diameters of target lesions SD= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD RANO Criteria: CR= Disappearance of all enhancing disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; stable or improved clinically SD= does not qualify for CR, PR, or progression; stable nonenhancing T2/FLAIR lesions

Time frame: From date of randomization up to 57 months

Population: All participants randomized in a salvage setting by TMB-High status

DoR was defined as the time from first confirmed complete or partial response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Calculated using KM method. RECIST Criteria: CR= Disappearance of all target lesions. PR= ≥ 30% decrease in the sum of diameters of target lesions. PD= ≥ 20% increase in the sum of diameters of target lesions. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable/improved T2/FLAIR; off corticosteroids; stable/improved clinically PR= ≥ 50% decrease in the sum of diameters of all measurable enhancing lesions; no progression of nonmeasurable disease; no new lesions; stable/improved T2/FLAIR; stable/improved clinically. PD= ≥ 25% increase in sum of diameters of enhancing lesions, on stable/increasing doses of corticosteroids; significant increase in T2/FLAIR; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease.

Time frame: From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)

Population: All responders (CR or PR) randomized in a salvage setting by TMB-High status

DoR was defined as the time from first confirmed complete or partial response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Calculated using KM method. RECIST Criteria: CR= Disappearance of all target lesions. PR= ≥ 30% decrease in the sum of diameters of target lesions. PD= ≥ 20% increase in the sum of diameters of target lesions. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable/improved T2/FLAIR; off corticosteroids; stable/improved clinically PR= ≥ 50% decrease in the sum of diameters of all measurable enhancing lesions; no progression of nonmeasurable disease; no new lesions; stable/improved T2/FLAIR; stable/improved clinically. PD= ≥ 25% increase in sum of diameters of enhancing lesions, on stable/increasing doses of corticosteroids; significant increase in T2/FLAIR; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease.

Time frame: From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)

Population: All responders (CR or PR) randomized in a salvage setting by TMB-High status

Number of participants with any grade adverse events (AEs), serious adverse events (SAEs), drug-related AEs, and drug-related SAEs by Tumor Mutational Burden- High (TMB-H) status using worst grade per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) v5 criteria. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. TMB-H = ≥ 10 mutations per megabase bTMB-H and tTMB-H are not mutually exclusive

Time frame: From first dose to 30 days post last dose (Up to 25 months)

Population: All treated participants by TMB-High status

Number of participants with grade 3-4 on-treatment laboratory parameters. Parameters include hematology, chemistry, liver function, and renal function using worst grade per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) v5 criteria. Grade 3=Severe event Grade 4=Life threatening event TMB-H = ≥ 10 mutations per megabase bTMB-H and tTMB-H are not mutually exclusive

Time frame: From first dose to 30 days post last dose (Up to 25 months)

Population: All treated participants with on-treatment laboratory measures by TMB-H status

ORR was defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) based on Blinded Independent Central Review (BICR) assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.

Time frame: From date of randomization up to 57 months

Population: All participants randomized in a salvage setting to arm B by TMB-High status

ORR was defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) based on investigator assessment. Calculated using Clopper-Pearson method. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.

Time frame: From date of randomization up to 57 months

Population: All participants randomized in a salvage setting by TMB-High status

OS is defined as the time between the date of randomization and the date of death due to any cause. Participants who did not have a date of death were censored on the last date for which a participant was known to be alive. Calculated using KM method.

Time frame: From date of randomization to date of death (Up to 57 months)

Population: All participants randomized in a salvage setting by TMB-High status

PFS is defined as the time from randomization date to the date of the first documented tumor progression, determined by Blinded Independent Central Review (BICR) assessment, or death due to any cause, whichever occurs first. Calculated using KM method. RECIST Criteria: Progressive Disease (PD)= ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of ≥ 5 mm. RANO Criteria: PD= ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline or best response, on stable or increasing doses of corticosteroids; significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease.

Time frame: From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)

Population: All participants randomized in a salvage setting by TMB-High status

PFS is defined as the time from randomization date to the date of the first documented tumor progression, determined by investigator assessment, or death due to any cause, whichever occurs first. Calculated using KM method. RECIST Criteria: Progressive Disease (PD)= ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of ≥ 5 mm. RANO Criteria: PD= ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline or best response, on stable or increasing doses of corticosteroids; significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease.

Time frame: From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)

Population: All participants randomized in a salvage setting by TMB-High status

TTR is defined as the time from randomization date to the date of the first confirmed response (complete response (CR) or partial response (PR)), based on Blinded Independent Central Review (BICR) assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.

Time frame: From date of randomization to date of first confirmed response (CR or PR) (Up to 57 months)

Population: All responders (CR or PR) randomized in a salvage setting by TMB-High status

TTR is defined as the time from randomization date to the date of the first confirmed response (complete response (CR) or partial response (PR)), based on investigator assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.

Time frame: From date of randomization to date of first confirmed response (CR or PR) (Up to 57 months)

Population: All responders (CR or PR) randomized in a salvage setting by TMB-High status