Safety and Tolerability of Pembrolizumab (MK-3475) + Pegylated Interferon Alfa-2b and Pembrolizumab+ Ipilimumab in Participants With Advanced Melanoma or Renal Cell Carcinoma (MK-3475-029/KEYNOTE-29)

Participants in Part 1A were analyzed for DLTs. DLTs included all adverse experiences that were clearly not related to disease progression or intercurrent illness if judged by the investigator to be possibly, probably, or definitely related to study intervention. Reported adverse experiences used the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.0. DLTs were analyzed and reported separately for protocol specified clinical indications of metastatic melanoma (MEL) and renal cell carcinoma (RCC) in Part 1A: Part 1A Pembrolizumab + IPI 1mg/kg (MEL), Part 1A Pembrolizumab + IPI 1 mg/kg (RCC), Part 1A Pembrolizumab + PEG-IFN 1 µg/kg (MEL), Part 1A Pembrolizumab + PEG-IFN 1 µg/kg (RCC), Part 1A Pembrolizumab + PEG-IFN 2 µg/kg (RCC). Per protocol, DLT outcome analysis did not include Parts 1B and 1C.

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. Reported adverse experiences used the Common Terminology for Adverse Events (CTCAE) Version 4.0.The number of participants who experienced at least one AE was reported.

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. Reported adverse experiences used the CTCAE Version 4.0. The percentage of participants who discontinued study treatment due to an AE was reported.

AEOSIs consist of immune-mediated events, infusion reactions and depression. Events include Pneumonitis, Colitis, Hepatitis, Nephritis, Adrenal Insufficiency, Hypophysitis, Hyperthyroidism, Hypothyroidism, Thyroiditis, Type 1 Diabetes Mellitus, Skin Disorders, Uveitis, Pancreatitis, Myositis, Guillain-Barre Syndrome, Myocarditis, Encephalitis, Sarcoidosis, Infusion Reactions, Myasthenic Syndrome, Myelitis, Vasculitis, and Cholangitis Sclerosing. Per protocol Part 1B and Part 1C are reported. Part 1A was not included in the AEOIs outcome analysis, per protocol.

Participants in Part 1C who experienced grade 3-5 drug-related AEs (DRAEs) using CTCAE Version 4.0 are presented. Grade 3-5 DRAEs for Parts 1A and 1B was a secondary outcome analysis, per protocol and reported later in the record.

ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The percentage of participants who experienced a CR or PR is presented. Per protocol, ORR in Part 1C was planned and conducted as a pre-specified primary outcome analysis. ORR in Part 1B was planned and conducted as a protocol-specified secondary outcome analysis and has been reported later in the record. Outcome analysis of ORR in Part 1A was not planned or conducted in this study, per protocol.

PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS was to be assessed by independent central review per RECIST 1.1. Part 2 of the study was not conducted, based on protocol specified criteria and this Part 2 specific outcome measure could not be reported.

ORR was defined as the percentage of participants who had a CR: Disappearance of all target lesions or a PR: At least a 30% decrease in the sum of diameters of target lesions as assessed using RECIST 1.1. The percentage of participants who experienced a CR or PR is presented. Per protocol, ORR in Part 1B was planned and conducted as a pre-specified secondary outcome analysis. ORR in Part 1C was planned and conducted as a protocol-specified primary outcome analysis and has been reported earlier in the record. Outcome analysis of ORR in Part 1A was not planned or conducted in this study, per protocol.

ORR was defined as the percentage of participants who had a CR: Disappearance of all target lesions or a PR: At least a 30% decrease in the sum of diameters of target lesions as assessed using RECIST 1.1. The percentage of participants that experienced a CR or PR by PD-L1 status is presented. PD-L1 positivity was defined as ≥1% staining in tumor and inflammatory cells, while PD-L1 negativity is defined as <1% staining. ORR for participants in Parts 1B and 1C with measurable disease at baseline based on central independent review, who had ORR data available for PD-L1+ and PD-L1- participants are presented. Outcome analysis of ORR in Part 1A was not planned or conducted in this study, per protocol.

Ordinal response, per RECIST 1.1 included the best overall responses of Very Good Partial Response ([VGPR]>60% tumor reduction) as well as Moderate Partial Response ([MPR]>30%- ≤60% tumor reduction). The percentage of participants in Part 1B and 1C who experienced a MPR or VGPR (based on the degree of tumor shrinkage) in participants with advanced melanoma is presented. Outcome analysis of ordinal response in Part 1A was not planned or conducted in this study, per protocol.

DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on central imaging review with confirmation. The DOR as assessed using RECIST 1.1 for participants with measurable disease at baseline based on central independent review in Parts 1B and 1C who experienced a confirmed CR or PR with DOR data available is presented. Outcome analysis of DOR in Part 1A was not planned or conducted in this study, per protocol.

PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS as assessed by independent central review per RECIST 1.1 for all participants who received at least one dose of study treatment in Part 1B and all randomized participants in Part 1C, who had PFS data available is presented. Outcome analysis of PFS in Part 1A was not planned or conducted in this study, per protocol.

OS was defined as the time from randomization to death due to any cause. OS for all participants who received at least one dose of study treatment in Part 1B and all randomized participants in Part 1C, who had OS data available is presented. Outcome analysis of OS in Part 1A was not planned or conducted in this study, per protocol.

PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PD-L1 positivity was defined as ≥1% staining in tumor and inflammatory cells, while PD-L1 negativity is defined as <1% staining. PFS for all participants who received at least one dose of study treatment in Part 1B and all randomized participants in Part 1C, who had PFS data available for PD-L1+ and PD-L1- participants is presented. Outcome analysis of PFS in Part 1A was not planned or conducted in this study, per protocol.

OS was defined as the time from randomization to death due to any cause. PD-L1 positivity was defined as ≥1% staining in tumor and inflammatory cells, while PD-L1 negativity is defined as <1% staining. OS for all participants who received at least one dose of study treatment in Part 1B and all randomized participants in Part 1C, who had OS data available for PD-L1+ and PD-L1- participants is presented. Outcome analysis of OS in Part 1A was not planned or conducted in this study, per protocol.

Participants in Parts 1A and 1B who experienced DRAEs using CTCAE Version 4.0 are presented. Grade 3-5 DRAEs for Part 1C was a primary outcome analysis, per protocol and reported earlier in the record.

ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. Part 2 of the study was not conducted, based on protocol specified criteria and this Part 2 specific outcome measure was not reported.