Non-small Cell Lung Cancer
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Brief summary
In this China extension study, carboplatin and paclitaxel with or without pembrolizumab (MK-3475, KEYTRUDA®) will be administered to Chinese adults with first line metastatic squamous non-small cell lung cancer (NSCLC). The primary hypotheses are that treatment with pembrolizumab prolongs: 1) Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by a blinded central imaging vendor compared to placebo, and 2) Overall Survival (OS) in Chinese participants. After analysis of interim results was conducted, the protocol was amended (Amendment 5) to allow participants the option to discontinue placebo in the control arm and to switch to pembrolizumab in the event of documented progressive disease as assessed by central review.
Detailed description
The MK-3475-407-China Extension Study enrolled a total of 125 participants, of which 15 participants have been also previously enrolled in the MK-3475-407 global study (NCT02775435). This China extension study did not include nano particle albumin-bound paclitaxel (nab-paclitaxel) that was an option in the global base study, because nab-paclitaxel it is not yet approved for treatment of NSCLC in China.
Interventions
BIOLOGICALPembrolizumab
IV infusion
DRUGPaclitaxel
IV infusion
DRUGCarboplatin
IV infusion Carboplatin dose should not exceed 900 mg.
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a histologically or cytologically confirmed diagnosis of stage IV (M1a or M1b-American Joint Committee on Cancer \[AJCC\]) squamous NSCLC. * Has measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. * Has not received prior systemic treatment for metastatic NSCLC. * Has provided tumor tissue from locations not radiated prior to biopsy. * Has a life expectancy of at least 3 months. * Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status. * Has adequate organ function. * If female of childbearing potential, is willing to use an adequate method of contraception for the course of the study through 180 days after the last dose of study treatment. * If male with a female partner(s) of child-bearing potential, must agree to use an adequate method of contraception starting with the first dose of study treatment through 95 days after the last dose of study treatment. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
Exclusion criteria
* Has non-squamous histology NSCLC. * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of pembrolizumab. * Before the first dose of study drug: a) Has received prior systemic cytotoxic chemotherapy for metastatic disease; b) Has received other targeted or biological antineoplastic therapy (e.g., erlotinib, crizotinib, cetuximab) for metastatic disease; c) Has had major surgery (\<3 weeks prior to first dose). * Received radiation therapy to the lung that is \>30 Gray (Gy) within 6 months of the first dose of study treatment. * Completed palliative radiotherapy within 7 days of the first dose of study treatment. * Is expected to require any other form of antineoplastic therapy while on study. * Has received a live-virus vaccination within 30 days of planned treatment start. * Has a known history of prior 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. * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. * Has pre-existing peripheral neuropathy that is ≥ Grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) Version 4 criteria. * Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody. * Has a known sensitivity to any component of carboplatin or paclitaxel or nab-paclitaxel. * Has active autoimmune disease that has required systemic treatment in past 2 years. * Is on chronic systemic steroids. * Had prior treatment with any other anti-programmed cell death 1 (anti-PD-1), or programmed cell death ligand 1 (PD-L1) or PD-L2 agent or an antibody or a small molecule targeting other immuno-regulatory receptors or mechanisms. * Has participated in any other pembrolizumab trial and has been treated with pembrolizumab. * Has an active infection requiring therapy. * Has known history of Human Immunodeficiency Virus (HIV). * Has known active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection. * Is, at the time of providing documented informed consent, a regular user (including recreational use) of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol). * Has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 33 months | 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 Response Criteria in Solid Tumors version 1.1 (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. Note: The appearance of ≥1 new lesions was also considered PD. PFS as assessed by blinded independent central review per RECIST 1.1 is presented. Data are from the product-limit (Kaplan-Meier) method for censored data. |
| Overall Survival (OS) | Up to approximately 39 months | OS was defined as the time from randomization to death due to any cause. OS is presented. Data are from the product-limit (Kaplan-Meier) method for censored data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 33 months | 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) as assessed by RECIST 1.1. ORR as assessed by blinded independent central review per RECIST 1.1 is presented. |
| Duration of Response (DOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 30 months | 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, DOR was defined as the time from first documented evidence of CR or PR until disease progression as assessed by RECIST 1.1 or death. DOR as assessed by blinded independent central review per RECIST 1.1 is presented. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 31 months | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented. Data are from the product-limit (Kaplan-Meier) method for censored data. |
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | Up to approximately 29 months | The number of participants who discontinued study treatment due to an AE is presented. |
Countries
China
Participant flow
Recruitment details
The China extension study included participants previously enrolled in China in the global study for MK-3475-407 (NCT02775435) plus those enrolled during the China extension enrollment period.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Chemotherapy Participants received pembrolizumab 200 mg by intravenous (IV) infusion prior to chemotherapy on Day 1 of each 21-day cycle for up to 35 cycles PLUS paclitaxel (200 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) PLUS carboplatin Area Under the Curve (AUC) 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles. | 65 |
| Chemotherapy Participants received normal saline by IV infusion prior to chemotherapy on Day 1 of each 21-day cycle for up to 35 cycles PLUS paclitaxel (200 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) PLUS carboplatin AUC 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles. | 60 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 5 |
| Overall Study | Death | 44 | 51 |
| Overall Study | Participation Was Terminated By Sponsor | 19 | 4 |
Baseline characteristics
| Characteristic | Total | Chemotherapy | Pembrolizumab + Chemotherapy |
|---|---|---|---|
| Age, Continuous | 61.5 Years STANDARD_DEVIATION 8.8 | 61.5 Years STANDARD_DEVIATION 9.1 | 61.6 Years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 125 Participants | 60 Participants | 65 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Geographic Region East Asia | 125 Participants | 60 Participants | 65 Participants |
| Geographic Region Non-East Asia | 0 Participants | 0 Participants | 0 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Level: Tumor Proportion Score (TPS) TPS <1% | 48 Participants | 23 Participants | 25 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Level: Tumor Proportion Score (TPS) TPS ≥1% | 72 Participants | 35 Participants | 37 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Level: Tumor Proportion Score (TPS) Unknown | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 125 Participants | 60 Participants | 65 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 119 Participants | 57 Participants | 62 Participants |
| Taxane Chemotherapy +Nab-paclitaxel | 0 Participants | 0 Participants | 0 Participants |
| Taxane Chemotherapy +Paclitaxel | 125 Participants | 60 Participants | 65 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 | 41 / 65 | 22 / 60 | 34 / 38 | 5 / 6 |
| other Total, other adverse events | 65 / 65 | 60 / 60 | 32 / 38 | 5 / 6 |
| serious Total, serious adverse events | 35 / 65 | 22 / 60 | 10 / 38 | 0 / 6 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. OS is presented. Data are from the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 39 months
Population: The Intent-To-Treat population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment arm to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy | Overall Survival (OS) | 30.1 Months |
| Chemotherapy | Overall Survival (OS) | 12.7 Months |
95% CI: [0.28, 0.7]
Primary
Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
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 Response Criteria in Solid Tumors version 1.1 (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. Note: The appearance of ≥1 new lesions was also considered PD. PFS as assessed by blinded independent central review per RECIST 1.1 is presented. Data are from the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 33 months
Population: The Intent-To-Treat population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment arm to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy | Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 8.3 Months |
| Chemotherapy | Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 4.2 Months |
95% CI: [0.24, 0.52]
Secondary
Duration of Response (DOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
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, DOR was defined as the time from first documented evidence of CR or PR until disease progression as assessed by RECIST 1.1 or death. DOR as assessed by blinded independent central review per RECIST 1.1 is presented.
Time frame: Up to approximately 30 months
Population: The Intent-To-Treat population consisted of all randomized participants, regardless of whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy | Duration of Response (DOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 7.1 Months |
| Chemotherapy | Duration of Response (DOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 3.5 Months |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
The number of participants who discontinued study treatment due to an AE is presented.
Time frame: Up to approximately 29 months
Population: The Safety population consisted of all participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Chemotherapy | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 8 Participants |
| Chemotherapy | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 4 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented. Data are from the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 31 months
Population: The Safety population consisted of all participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Chemotherapy | Number of Participants Who Experienced an Adverse Event (AE) | 65 Participants |
| Chemotherapy | Number of Participants Who Experienced an Adverse Event (AE) | 60 Participants |
Secondary
Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
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) as assessed by RECIST 1.1. ORR as assessed by blinded independent central review per RECIST 1.1 is presented.
Time frame: Up to approximately 33 months
Population: The Intent-To-Treat population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment arm to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Chemotherapy | Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 80.0 Percentage of Participants |
| Chemotherapy | Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 43.3 Percentage of Participants |
95% CI: [19.9, 51.6]