Lung Cancer
Conditions
Keywords
non-small cell lung cancer, programmed cell death 1 (PD-1) inhibitor, indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor
Brief summary
The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus epacadostat compared to pembrolizumab plus placebo as first-line treatment in participants with metastatic non-small cell lung cancer (NSCLC) expressing high levels of programmed cell death ligand 1 (PD-L1).
Interventions
DRUGPembrolizumab
Pembrolizumab administered intravenously every 3 weeks.
DRUGEpacadostat
Epacadostat administered orally twice daily.
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)
Masking description
With the implementation of Amendment 05 the study is no longer blinded.
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. * Tumor tissue that demonstrates programmed cell death ligand 1 (PD-L1) expression in ≥ 50% of tumor cells (tumor proportion score \[TPS\] ≥ 50%) as assessed by immunohistochemistry at a central laboratory. * 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.
Exclusion criteria
* Known untreated central nervous system metastases and/or carcinomatous meningitis. * History of (noninfectious) 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 Plus Epacadostat Versus Pembrolizumab Plus Placebo | Up to approximately 6 months | ORR is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 based on blinded independent central review (BICR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo | Up to approximately 36 months | OS is defined as the time from randomization to death due to any cause. |
| Progression-free Survival (PFS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo | Up to approximately 36 months | PFS is defined as the time from randomization to the first documented progressive disease per RECIST v1.1 based on BICR or death due to any cause, whichever occurs first. |
| Duration of Response (DOR) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo | Up to approximately 36 months | DOR is 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. |
| Number of Participants With Adverse Events (AEs) | Up to 37 months | AE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. |
| Number of Participants Who Discontinued Study Drug Due to AEs | Up to 37 months | AE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. |
Countries
Australia, Canada, Denmark, Estonia, Ireland, Israel, Italy, Japan, Malaysia, Poland, Russia, South Korea, Spain, Switzerland, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 154 participants were randomized in 1:1 to either combination (Pembrolizumab+Epacadostat) and control (Pembrolizumab+Placebo) groups. As of Amendment 05, study design was changed to unblinded, open-label, and single-arm (epacadostat and placebo were removed).
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 + Epacadostat Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. | 77 |
| Pembrolizumab + Placebo Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05. | 77 |
| Total | 154 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 21 | 28 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 7 | 6 |
| Overall Study | Study terminated by sponsor | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Pembrolizumab + Epacadostat | Pembrolizumab + Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63.7 years STANDARD_DEVIATION 9.5 | 66.9 years STANDARD_DEVIATION 10.1 | 65.3 years STANDARD_DEVIATION 9.9 |
| Race/Ethnicity, Customized Not Hispanic Or Latino Hispanic Or Latino | 7 Participants | 4 Participants | 11 Participants |
| Race/Ethnicity, Customized Not Hispanic Or Latino Not Hispanic Or Latino | 66 Participants | 73 Participants | 139 Participants |
| Race/Ethnicity, Customized Not Hispanic Or Latino Not Reported | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic Or Latino Unknown | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 25 Participants | 23 Participants | 48 Participants |
| Race/Ethnicity, Customized White | 52 Participants | 54 Participants | 106 Participants |
| Sex: Female, Male Female | 24 Participants | 18 Participants | 42 Participants |
| Sex: Female, Male Male | 53 Participants | 59 Participants | 112 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 23 / 75 | 29 / 77 | 52 / 152 |
| other Total, other adverse events | 69 / 75 | 67 / 77 | 136 / 152 |
| serious Total, serious adverse events | 36 / 75 | 35 / 77 | 71 / 152 |
Outcome results
Primary
Objective Response Rate (ORR) of Pembrolizumab Plus Epacadostat Versus Pembrolizumab Plus Placebo
ORR is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 based on blinded independent central review (BICR).
Time frame: Up to approximately 6 months
Population: ITT population consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Epacadostat | Objective Response Rate (ORR) of Pembrolizumab Plus Epacadostat Versus Pembrolizumab Plus Placebo | 32.5 percentage of participants |
| Pembrolizumab + Placebo | Objective Response Rate (ORR) of Pembrolizumab Plus Epacadostat Versus Pembrolizumab Plus Placebo | 39.0 percentage of participants |
p-value: 0.895% CI: [-21.5, 8.7]Stratified Miettinen and Nurminen method
Secondary
Duration of Response (DOR) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo
DOR is 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 approximately 36 months
Population: DOR included all responders in ITT population. Response duration was calculated from product-limit (Kaplan-Meier) method for censored data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Epacadostat | Duration of Response (DOR) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo | 6.2 Months |
| Pembrolizumab + Placebo | Duration of Response (DOR) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo | NA Months |
Secondary
Number of Participants Who Discontinued Study Drug Due to AEs
AE is defined as any untoward medical occurrence in a patient 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 37 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Epacadostat | Number of Participants Who Discontinued Study Drug Due to AEs | 15 Participants |
| Pembrolizumab + Placebo | Number of Participants Who Discontinued Study Drug Due to AEs | 12 Participants |
Secondary
Number of Participants With Adverse Events (AEs)
AE is defined as any untoward medical occurrence in a patient 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 37 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Epacadostat | Number of Participants With Adverse Events (AEs) | 72 Participants |
| Pembrolizumab + Placebo | Number of Participants With Adverse Events (AEs) | 72 Participants |
Secondary
Overall Survival (OS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo
OS is defined as the time from randomization to death due to any cause.
Time frame: Up to approximately 36 months
Population: ITT population consisted of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Epacadostat | Overall Survival (OS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo | NA Months |
| Pembrolizumab + Placebo | Overall Survival (OS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo | NA Months |
Secondary
Progression-free Survival (PFS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo
PFS is defined as the time from randomization to the first documented progressive disease per RECIST v1.1 based on BICR or death due to any cause, whichever occurs first.
Time frame: Up to approximately 36 months
Population: ITT population consisted of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Epacadostat | Progression-free Survival (PFS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo | 6.7 months |
| Pembrolizumab + Placebo | Progression-free Survival (PFS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo | 6.2 months |