Lung Cancer
Conditions
Keywords
Non-small cell lung cancer, programmed cell death 1 (PD-1) inhibitor, indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor, chemotherapy
Brief summary
The purpose of this study was to evaluate the efficacy and safety of pembrolizumab plus epacadostat with platinum-based chemotherapy versus pembrolizumab plus platinum-based chemotherapy plus placebo as first-line therapy in participants with metastatic non-small cell lung cancer (NSCLC).
Interventions
DRUGPembrolizumab
Pembrolizumab administered intravenously every 3 weeks.
DRUGEpacadostat
Epacadostat administered orally twice daily.
Investigator selected one of the following regimens: pemetrexed + cisplatin, pemetrexed + carboplatin, or paclitaxel + carboplatin, depending on histology.
DRUGPlacebo
Matching placebo administered orally twice daily.
Sponsors
Merck Sharp & Dohme LLC
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of stage IV NSCLC without epidermal growth factor receptor (EGFR)-sensitizing mutation, ROS1 and/or anaplastic lymphoma kinase (ALK) translocation * Measurable disease based on RECIST 1.1 * Life expectancy of at least 3 months. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Adequate organ function per protocol-defined criteria. * Provide tumor tissue sample.
Exclusion criteria
* Known untreated central nervous system metastases and/or carcinomatous meningitis * History of (non-infectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease. * Symptomatic ascites or pleural effusion. * Known history of an additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy. * Active autoimmune disease that has required systemic treatment in past 2 years. * Has had an allogeneic tissue/solid organ transplant. * Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by the local health authority. * Has known history of or is positive for active Hepatitis B (HBsAg reactive) or has active Hepatitis C (HCV RNA). Note: Testing must be performed to determine eligibility. * History or presence of an abnormal electrocardiogram (ECG) that, in the Investigator's opinion, is clinically meaningful. * Use of protocol-defined prior/concomitant therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | Assessed every 12 weeks up to 24 months | ORR is defined as the percentage of participants who have a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) based on blinded independent central review (BICR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | Up to 24 months | Defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurs first. |
| Overall Survival of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | Up to 24 months | Defined as the time from randomization to death due to any cause. |
| Duration of Response of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | Up to 24 months | Defined as the time from the earliest date of qualifying response until earliest date of disease progression, per RECIST v1.1, or death from any cause, whichever comes first. |
| Safety and Tolerability of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo as Measured by the Number of Participants Experiencing Adverse Events (AEs) | Up to 25 months | An AE is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. |
| Safety and Tolerability of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo as Measured by the Number of Participants Discontinuing Study Drug Due to AEs | Up to 25 months | An AE is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of any study drug, whether or not considered related to the study drug. |
Countries
Australia, Canada, Hungary, Ireland, Israel, Italy, Mexico, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 65 investigative sites in 14 countries from 09 January 2018 to 13 December 2018.
Pre-assignment details
Phase 3 design of the study has been amended soon after it had started to a prospectively randomized phase 2 study. At the time of amendment existing participants were given a choice to move/participate in the new phase 2 study, and some participants who chose to discontinue the study at phase 3 were assigned to study terminated by sponsor as the reason for not completing the study in disposition table. The results posted are combined in the prospectively redesigned phase 2 trial.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Chemotherapy + Epacadostat Participant received pembrolizumab 200 mg intravenous (IV) infusion, every 3 weeks (Q3W) on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat 100 mg tablets, orally, twice daily (BID) in each 21 day cycle for up to 35 cycles + platinum-doublet chemotherapy (pemetrexed 500 mg/m\^2 IV infusion, Q3W + cisplatin 75 mg/m\^2 IV infusion, Q3W or carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles followed by pemetrexed maintenance; or paclitaxel 200 mg /m\^2 IV infusion, Q3W + carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles). | 91 |
| Pembrolizumab + Chemotherapy + Placebo Participant received pembrolizumab 200 mg IV infusion, Q3W on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat matching placebo tablets, orally, BID in each 21 day cycle for up to 35 cycles + platinum-doublet chemotherapy (pemetrexed 500 mg/m\^2 IV infusion, Q3W + cisplatin 75 mg/m\^2 IV infusion, Q3W or carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles followed by pemetrexed maintenance; or paclitaxel 200 mg /m\^2 IV infusion, Q3W + carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles). | 87 |
| Pembrolizumab + Epacadostat Participant received pembrolizumab 200 mg IV infusion, Q3W on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat 100 mg tablets, orally, BID in each 21 day cycle for up to 35 cycles. | 55 |
| Total | 233 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 34 | 35 | 23 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Physician Decision | 6 | 7 | 2 |
| Overall Study | Study terminated by sponsor | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 3 | 6 |
Baseline characteristics
| Characteristic | Pembrolizumab + Chemotherapy + Epacadostat | Total | Pembrolizumab + Epacadostat | Pembrolizumab + Chemotherapy + Placebo |
|---|---|---|---|---|
| Age, Continuous | 63.0 years STANDARD_DEVIATION 11.7 | 63.2 years STANDARD_DEVIATION 9.9 | 62.8 years STANDARD_DEVIATION 8.4 | 63.6 years STANDARD_DEVIATION 8.8 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 3 Participants | 5 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 86 Participants | 223 Participants | 52 Participants | 85 Participants |
| Race/Ethnicity, Customized Ethnicity Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Unknown | 2 Participants | 4 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race American Indian Or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 11 Participants | 23 Participants | 2 Participants | 10 Participants |
| Race/Ethnicity, Customized Race Black Or African American | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Missing | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 78 Participants | 206 Participants | 53 Participants | 75 Participants |
| Sex: Female, Male Female | 33 Participants | 79 Participants | 16 Participants | 30 Participants |
| Sex: Female, Male Male | 58 Participants | 154 Participants | 39 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 38 / 90 | 35 / 86 | 26 / 52 | 99 / 228 |
| other Total, other adverse events | 87 / 90 | 81 / 86 | 51 / 52 | 219 / 228 |
| serious Total, serious adverse events | 47 / 90 | 41 / 86 | 20 / 52 | 108 / 228 |
Outcome results
Primary
Objective Response Rate (ORR) of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo
ORR is defined as the percentage of participants who have a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) based on blinded independent central review (BICR).
Time frame: Assessed every 12 weeks up to 24 months
Population: ITT population consisted of all participants randomized in treatment arm Pembrolizumab+Epacadostat+Chemotherapy and treatment arm Pembrolizumab+Chemothrapy. This is not a primary outcome measure for treatment arm Pembrolizumab+Epacadostat per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Chemotherapy + Epacadostat | Objective Response Rate (ORR) of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | 26.4 percentage of participants |
| Pembrolizumab + Chemotherapy + Placebo | Objective Response Rate (ORR) of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | 44.8 percentage of participants |
p-value: 0.994895% CI: [-32, -4.3]Stratified Miettinen and Nurminen method
Secondary
Duration of Response of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo
Defined as the time from the earliest date of qualifying response until earliest date of disease progression, per RECIST v1.1, or death from any cause, whichever comes first.
Time frame: Up to 24 months
Population: ITT population consisted of all participants randomized in treatment arm Pembrolizumab+Epacadostat+Chemotherapy and treatment arm Pembrolizumab+Chemothrapy. This is not a secondary outcome measure for treatment arm Pembrolizumab+Epacadostat per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy + Epacadostat | Duration of Response of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | NA months |
| Pembrolizumab + Chemotherapy + Placebo | Duration of Response of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | 7.0 months |
Secondary
Overall Survival of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo
Defined as the time from randomization to death due to any cause.
Time frame: Up to 24 months
Population: ITT population consisted of all participants randomized in treatment arm Pembrolizumab+Epacadostat+Chemotherapy and treatment arm Pembrolizumab+Chemothrapy. This is not a secondary outcome measure for treatment arm Pembrolizumab+Epacadostat per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy + Epacadostat | Overall Survival of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | NA months |
| Pembrolizumab + Chemotherapy + Placebo | Overall Survival of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | NA months |
p-value: 0.9627295% CI: [0.93, 3.9]Regression, Cox
Secondary
Progression-free Survival of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo
Defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurs first.
Time frame: Up to 24 months
Population: ITT population consisted of all participants randomized in treatment arm Pembrolizumab+Epacadostat+Chemotherapy and treatment arm Pembrolizumab+Chemothrapy. This is not a secondary outcome measure for treatment arm Pembrolizumab+Epacadostat per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy + Epacadostat | Progression-free Survival of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | 8.0 months |
| Pembrolizumab + Chemotherapy + Placebo | Progression-free Survival of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo | 8.2 months |
p-value: 0.9430595% CI: [0.91, 2.36]Regression, Cox
Secondary
Safety and Tolerability of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo as Measured by the Number of Participants Discontinuing Study Drug Due to AEs
An AE is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of any study drug, whether or not considered related to the study drug.
Time frame: Up to 25 months
Population: All Subjects as Treated consists of all randomized participants who received at least one dose of study treatment. This is not a secondary outcome measure for treatment arm Pembrolizumab+Epacadostat per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Chemotherapy + Epacadostat | Safety and Tolerability of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo as Measured by the Number of Participants Discontinuing Study Drug Due to AEs | 37 Participants |
| Pembrolizumab + Chemotherapy + Placebo | Safety and Tolerability of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo as Measured by the Number of Participants Discontinuing Study Drug Due to AEs | 35 Participants |
Secondary
Safety and Tolerability of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo as Measured by the Number of Participants Experiencing Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Time frame: Up to 25 months
Population: All Subjects as Treated consists of all randomized participants who received at least one dose of study treatment. This is not a secondary outcome measure for treatment arm Pembrolizumab+Epacadostat per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Chemotherapy + Epacadostat | Safety and Tolerability of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo as Measured by the Number of Participants Experiencing Adverse Events (AEs) | 89 Participants |
| Pembrolizumab + Chemotherapy + Placebo | Safety and Tolerability of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo as Measured by the Number of Participants Experiencing Adverse Events (AEs) | 82 Participants |