Non-small Cell Lung Carcinoma
Conditions
Keywords
PD-1, PD1, Programmed Cell Death-1, Programmed Cell Death 1, Chemotherapy, Pemetrexed, Paclitaxel, Bevacizumab, Erlotinib, Gefitinib, Ipilimumab, Carboplatin
Brief summary
The purpose of this study is to determine the safety, tolerability, and efficacy of pembrolizumab (MK-3475) in combination with chemotherapy or immunotherapy in participants with unresectable or metastatic non-small cell lung cancer (NSCLC).
Interventions
BIOLOGICALPembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
DRUGPaclitaxel
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
DRUGCarboplatin
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
BIOLOGICALBevacizumab
IV on Day 1 of each 3-week cycle
DRUGPemetrexed
IV on Day 1 of each 3-week cycle
BIOLOGICALIpilimumab
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
DRUGErlotinib
Orally tablet once daily
DRUGGefitinib
Oral tablet once daily
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Stage IIIb/IV NSCLC * Disease progression \>1 year after completing adjuvant therapy for Stage I-IIIA disease and no systemic therapy for the recurrent disease * Resolution of any toxic effects (excepting alopecia) of the most recent therapy * At least one radiographically measurable lesion * Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status scale * Female participants of reproductive potential must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start) * Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 120 days after the last dose of study therapy and for up to 180 days after the last dose of chemotherapeutic agents or tyrosine kinase inhibitors
Exclusion criteria
* Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of administration of pembrolizumab * Expected to require any other form of antineoplastic therapy while on study * Is on chronic systemic steroid therapy or on any other form of immunosuppressive medication * Has received a live-virus vaccination within 30 days of planned treatment start * Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation) * History of a hematologic malignancy, primary brain tumor or sarcoma, or of another primary solid tumor, unless the participant has undergone potentially curative therapy with no evidence of that disease for 5 years * Active central nervous system (CNS) metastases and/or carcinomatous meningitis * Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb) * Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapies for hormone deficiencies are allowed) * Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent or an antibody targeting other immuno-regulatory receptors or mechanisms * Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 3 weeks of the first dose of study medication * Radiation therapy to lung \>30 Gy within 6 months of first dose of study medication * Prior tyrosine kinase inhibitor therapy or palliative radiation within 7 days of first dose of study medication * Active infection requiring therapy * History of Human Immunodeficiency Virus (HIV) * Active Hepatitis B or C * Symptomatic ascites or pleural effusion * Interstitial lung disease or pneumonitis requiring oral or IV glucocorticoids * Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study * Psychiatric disorders and substance (drug/alcohol) abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 2 Cohorts G+ and G-: Objective Response Rate (ORR) | Up to approximately 2 years | ORR was defined as the percentage of participants in the analysis population 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) per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR). |
| Part 2 Cohorts D4 and H: Objective Response Rate (ORR) | Up to approximately 2 years | For participants who demonstrated a confirmed response (Complete Response \[CR\]: Disappearance of all target lesions or Partial Response \[PR\]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was assessed by BICR. |
| All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | Cycle 1 (Up to 21 days) | DLTs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. A DLT was defined as any of the following events: Grade 4 non-hematologic toxicity (not laboratory); Grade 4 hematologic toxicity lasting ≥7 days; Grade 3 non-hematologic toxicity (not laboratory, specifically nausea, vomiting and diarrhea) lasting \>3 days despite optimal supportive care; Any Grade 3 or Grade 4 non-hematologic laboratory value requiring treatment or hospitalization, or persisting for \>1 week; Febrile neutropenia Grade 3 or Grade 4; Qualifying thrombocytopenia \<25,000/mm\^3; Prolonged delay (\>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; Missing \>10% of erlotinib or gefitinib doses as a result of adverse events (AEs) during the DLT window of observation; or Grade 5 toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2 Cohorts G+ and G-: Progression-Free Survival (PFS) | Up to approximately 2 years | PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. PFS was assessed by BICR. |
| Part 2 Cohorts G+ and G-: Overall Survival (OS) | Up to approximately 2 years | OS was defined as the time from randomization to death due to any cause. |
| Part 2 Cohorts G+ and G-: Duration of Response (DOR) | Up to approximately 2 years | For participants who demonstrated a confirmed response (Complete Response \[CR\]: Disappearance of all target lesions or Partial Response \[PR\]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was assessed by BICR. |
Participant flow
Recruitment details
This results disclosure is based on efficacy data cutoff dates of 08-Aug-2016 for Cohorts C and G (primary endpoint); 07-Nov-2016 for Cohorts A, B, D, E, F and H; and 19-Aug-2019 for Cohort G (secondary endpoints).
Participants by arm
| Arm | Count |
|---|---|
| Part1CohortA2 (Pembro 2 mg/kg+Paclitaxel [Pa]+Carboplatin [C]) Cohort A2 participants received pembrolizumab (Pembro 2 mg/kg) via intravenous (IV) infusion on Day 1 of each 3-week cycle PLUS paclitaxel (Pa 200 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (C Area Under the Curve \[AUC\] 6 \[6 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle. | 13 |
| Part1CohortA10 (Pembro10mg/kg+Pa+C) Cohort A10 participants received pembrolizumab (Pembro 10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (Pa 200 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (C AUC 6 \[6 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle. | 12 |
| Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B]) Cohort B2 participants received pembrolizumab (Pembro 2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (Pa 200 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (C AUC 6 \[6 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle PLUS bevacizumab (B 15 mg/kg) via IV infusion on Day 1 of each 3-week cycle. | 12 |
| Part 1 Cohort B10 (Pembro 10 mg/kg+Pa+C+B) Cohort B10 participants received pembrolizumab (Pembro 10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (Pa 200 mg/m\^2 via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (C AUC 6 \[6 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle PLUS bevacizumab (B 15 mg/kg) via IV infusion on Day 1 of each 3-week cycle. | 13 |
| Part 1 Cohort C2 (Pembro 2 mg/kg+Pemetrexed [Pe]+C) Cohort C2 participants received pembrolizumab (Pembro 2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (Pe 500 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (C AUC 5 \[5 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle. | 12 |
| Part 1 Cohort C10 (Pembro 10 mg/kg+Pe+C) Cohort C10 participants received pembrolizumab (Pembro 10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (Pe 500 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (C AUC 6 \[6 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle. | 12 |
| Part 1 Cohort D1 (Pembro 10 mg/kg+Ipilimumab [I]) Cohort D1 participants received pembrolizumab (Pembro 10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (I 1 mg/kg) via IV infusion on Day 1 of each 3-week cycle. | 3 |
| Part 1 Cohort D2 (Pembro 10 mg/kg+I) Cohort D2 participants received pembrolizumab (Pembro 10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (I 3 mg/kg) via IV infusion on Day 1 of each 3-week cycle. | 3 |
| Part 1 Cohort D4 (Pembro 2 mg/kg+I) Cohort D4 participants received pembrolizumab (Pembro 2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (I 1 mg/kg) via IV infusion on Day 1 of each 3-week cycle. | 12 |
| Part 1 Cohort E (Pembro 2 mg/kg+Erlotinib) Cohort E participants received pembrolizumab (Pembro 2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS erlotinib (E 150 mg) via oral tablet once a day on every day of each 3-week cycle. | 12 |
| Part 1 Cohort F (Pembro 2 mg/kg+Gefitinib) Cohort F participants received pembrolizumab (Pembro 2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS gefitinib (G 250 mg) via oral tablet once a day on every day of each 3-week cycle. | 7 |
| Part 2 Cohort G+ (Pembro 200 mg+Pe+C) Cohort G+ participants received pembrolizumab (Pembro 200 mg) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (C AUC 5 \[5 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (Pe 500 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle. | 60 |
| Part 2 Cohort G- (Placebo+Pe+C) Cohort G- participants received placebo (normal saline solution) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (Pe 500 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (C AUC 5 \[5 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle. | 63 |
| Part 2 Cohort H (Pembro 2 mg/kg+I) Cohort H participants received pembrolizumab (Pembro 2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (I 1 mg/kg) via IV infusion on Day 1 of each 3-week cycle (at the recommended Phase 2 dose determined in Cohort D). | 33 |
| Total | 267 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 2 | 3 | 1 |
| Overall Study | Clinical Progression | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Death | 2 | 0 | 2 | 3 | 0 | 0 | 1 | 0 | 2 | 0 | 1 | 3 | 2 | 8 |
| Overall Study | Excluded Medication | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 2 | 3 | 5 | 6 | 8 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 1 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Progressive Disease | 8 | 8 | 6 | 7 | 9 | 10 | 1 | 3 | 6 | 4 | 0 | 34 | 34 | 18 |
| Overall Study | Sponsor Decision | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 3 | 0 | 8 | 5 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 3 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1 | 4 | 6 | 2 |
Baseline characteristics
| Characteristic | Part1CohortA2 (Pembro 2 mg/kg+Paclitaxel [Pa]+Carboplatin [C]) | Part1CohortA10 (Pembro10mg/kg+Pa+C) | Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B]) | Part 1 Cohort B10 (Pembro 10 mg/kg+Pa+C+B) | Part 1 Cohort C2 (Pembro 2 mg/kg+Pemetrexed [Pe]+C) | Part 1 Cohort C10 (Pembro 10 mg/kg+Pe+C) | Part 1 Cohort D1 (Pembro 10 mg/kg+Ipilimumab [I]) | Part 1 Cohort D2 (Pembro 10 mg/kg+I) | Part 1 Cohort D4 (Pembro 2 mg/kg+I) | Part 1 Cohort E (Pembro 2 mg/kg+Erlotinib) | Part 1 Cohort F (Pembro 2 mg/kg+Gefitinib) | Part 2 Cohort G+ (Pembro 200 mg+Pe+C) | Part 2 Cohort G- (Placebo+Pe+C) | Part 2 Cohort H (Pembro 2 mg/kg+I) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 64.5 Years STANDARD_DEVIATION 8 | 61.4 Years STANDARD_DEVIATION 9.2 | 61.2 Years STANDARD_DEVIATION 5.1 | 59.5 Years STANDARD_DEVIATION 9.1 | 60.3 Years STANDARD_DEVIATION 11 | 63.3 Years STANDARD_DEVIATION 8.4 | 69.3 Years STANDARD_DEVIATION 6 | 59.3 Years STANDARD_DEVIATION 5.5 | 55.3 Years STANDARD_DEVIATION 14 | 60.2 Years STANDARD_DEVIATION 8 | 62.7 Years STANDARD_DEVIATION 12 | 61.8 Years STANDARD_DEVIATION 9.2 | 63.2 Years STANDARD_DEVIATION 9.6 | 62.2 Years STANDARD_DEVIATION 9.7 | 61.8 Years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 5 Participants | 8 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 2 Participants | 1 Participants | 4 Participants | 6 Participants | 4 Participants | 38 Participants | 37 Participants | 18 Participants | 147 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 6 Participants | 7 Participants | 6 Participants | 6 Participants | 1 Participants | 2 Participants | 8 Participants | 6 Participants | 3 Participants | 22 Participants | 26 Participants | 15 Participants | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 12 | 10 / 13 | 2 / 2 | 11 / 13 | 9 / 12 | 1 / 1 | 11 / 12 | 8 / 12 | 3 / 3 | 3 / 3 | 11 / 12 | 5 / 12 | 7 / 7 | 0 / 1 | 42 / 60 | 47 / 63 | 1 / 2 | 24 / 28 | 31 / 33 |
| other Total, other adverse events | 12 / 12 | 13 / 13 | 0 / 2 | 12 / 13 | 11 / 11 | 0 / 1 | 12 / 12 | 12 / 12 | 3 / 3 | 3 / 3 | 12 / 12 | 12 / 12 | 7 / 7 | 1 / 1 | 58 / 59 | 60 / 62 | 0 / 2 | 24 / 28 | 30 / 33 |
| serious Total, serious adverse events | 5 / 12 | 7 / 13 | 0 / 2 | 8 / 13 | 8 / 11 | 0 / 1 | 7 / 12 | 6 / 12 | 1 / 3 | 1 / 3 | 5 / 12 | 8 / 12 | 5 / 7 | 0 / 1 | 30 / 59 | 21 / 62 | 0 / 2 | 7 / 28 | 12 / 33 |
Outcome results
Primary
All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)
DLTs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. A DLT was defined as any of the following events: Grade 4 non-hematologic toxicity (not laboratory); Grade 4 hematologic toxicity lasting ≥7 days; Grade 3 non-hematologic toxicity (not laboratory, specifically nausea, vomiting and diarrhea) lasting \>3 days despite optimal supportive care; Any Grade 3 or Grade 4 non-hematologic laboratory value requiring treatment or hospitalization, or persisting for \>1 week; Febrile neutropenia Grade 3 or Grade 4; Qualifying thrombocytopenia \<25,000/mm\^3; Prolonged delay (\>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; Missing \>10% of erlotinib or gefitinib doses as a result of adverse events (AEs) during the DLT window of observation; or Grade 5 toxicity.
Time frame: Cycle 1 (Up to 21 days)
Population: The DLT evaluable population consisted of all participants who completed the first cycle of study treatment or who discontinued from the study due to a drug-related AE.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 2 Cohort G+ (Pembro 200 mg+Pe+C) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 2 Cohort G- (Placebo+Pe+C) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B]) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1 Cohort B10 (Pembro 10 mg/kg+Pa+C+B) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1 Cohort C2 (Pembro 2 mg/kg+Pemetrexed [Pe]+C) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1 Cohort C10 (Pembro 10 mg/kg+Pe+C) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1 Cohort D1 (Pembro 10mg/kg+Ipilimumab [I]) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1 Cohort D2 (Pembro 10 mg/kg+I) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1 Cohort D4 (Pembro 2 mg/kg+I) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1 Cohort E (Pembro 2 mg/kg+Erlotinib) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1 Cohort F (Pembro 2 mg/kg+Gefitinib) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 2 Cohort G+ (Pembro 200 mg+Pe+C) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 2 Cohort G- (Placebo+Pe+C) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 2 Cohort H (Pembro 2 mg/kg+I) | All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
Primary
Part 2 Cohorts D4 and H: Objective Response Rate (ORR)
For participants who demonstrated a confirmed response (Complete Response \[CR\]: Disappearance of all target lesions or Partial Response \[PR\]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was assessed by BICR.
Time frame: Up to approximately 2 years
Population: The analysis population consisted of all treated Cohort D4 and Cohort H participants (database cutoff date: 07 November 2016). One Cohort H participant was excluded from the efficacy analysis population due to a protocol violation. This participant did not have non-small cell lung cancer.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 Cohort G+ (Pembro 200 mg+Pe+C) | Part 2 Cohorts D4 and H: Objective Response Rate (ORR) | 29.5 Percentage of Participants |
p-value: 0.0858Exact binomial distribution for testing
Primary
Part 2 Cohorts G+ and G-: Objective Response Rate (ORR)
ORR was defined as the percentage of participants in the analysis population 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) per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR).
Time frame: Up to approximately 2 years
Population: The analysis population consisted of all randomized Cohort G participants (database cutoff date: 08 August 2016).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 Cohort G+ (Pembro 200 mg+Pe+C) | Part 2 Cohorts G+ and G-: Objective Response Rate (ORR) | 55.0 Percentage of Participants |
| Part 2 Cohort G- (Placebo+Pe+C) | Part 2 Cohorts G+ and G-: Objective Response Rate (ORR) | 28.6 Percentage of Participants |
p-value: 0.001695% CI: [8.9, 42.1]Miettinen & Nurminen Method
Secondary
Part 2 Cohorts G+ and G-: Duration of Response (DOR)
For participants who demonstrated a confirmed response (Complete Response \[CR\]: Disappearance of all target lesions or Partial Response \[PR\]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was assessed by BICR.
Time frame: Up to approximately 2 years
Population: The analysis population consisted of all randomized Cohort G participants who experienced a confirmed response (CR or PR); (database cutoff date: 19 August 2019).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2 Cohort G+ (Pembro 200 mg+Pe+C) | Part 2 Cohorts G+ and G-: Duration of Response (DOR) | NA Months |
| Part 2 Cohort G- (Placebo+Pe+C) | Part 2 Cohorts G+ and G-: Duration of Response (DOR) | NA Months |
Secondary
Part 2 Cohorts G+ and G-: Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause.
Time frame: Up to approximately 2 years
Population: The analysis population consisted of all randomized Cohort G participants (database cutoff date: 19 August 2019).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2 Cohort G+ (Pembro 200 mg+Pe+C) | Part 2 Cohorts G+ and G-: Overall Survival (OS) | 34.5 Months |
| Part 2 Cohort G- (Placebo+Pe+C) | Part 2 Cohorts G+ and G-: Overall Survival (OS) | 21.1 Months |
p-value: 0.0676295% CI: [0.45, 1.12]Log Rank
Secondary
Part 2 Cohorts G+ and G-: Progression-Free Survival (PFS)
PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. PFS was assessed by BICR.
Time frame: Up to approximately 2 years
Population: The analysis population consisted of all randomized Cohort G participants (database cutoff date: 19 August 2019).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2 Cohort G+ (Pembro 200 mg+Pe+C) | Part 2 Cohorts G+ and G-: Progression-Free Survival (PFS) | 24.5 Months |
| Part 2 Cohort G- (Placebo+Pe+C) | Part 2 Cohorts G+ and G-: Progression-Free Survival (PFS) | 9.9 Months |
p-value: 0.0025295% CI: [0.35, 0.83]Log Rank