Non-small Cell Lung Cancer
Conditions
Keywords
Non-small cell lung cancer (NSCLC), Programmed Cell Death Receptor 1 (PD-1), Programmed Cell Death Receptor Ligand 1 (PD-L1), Programmed Cell Death Receptor Ligand (PDL)
Brief summary
In this study, participants with Stage IB/II-IIIA non-small cell lung cancer (NSCLC) who have undergone surgical resection (lobectomy or pneumonectomy) with or without adjuvant chemotherapy will be treated with pembrolizumab or placebo. The primary study hypothesis is that pembrolizumab will provide improved disease-free survival (DFS) versus placebo.
Interventions
BIOLOGICALPembrolizumab
IV infusion
OTHERPlacebo
IV infusion
Sponsors
Merck Sharp & Dohme LLC
ETOP
European Organisation for Research and Treatment of Cancer - EORTC
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
* Pathological diagnosis of NSCLC confirmed at surgery, any histology. Participants with two synchronous primary non-small cell lung cancers are excluded from the study * Union for International Cancer Control (UICC) v7 Stage IB with T ≥ 4 cm, II-IIIA NSCLC after complete surgical resection with resection margins proved microscopically free of disease (R0). Carcinoma in situ can be present at the bronchial margin * Available tumor sample obtained at surgical resection for programmed cell death ligand-1 (PD-L1) Immunohistochemistry (IHC) expression assessment * Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 * Adequate organ function performed within 10 days of treatment initiation * Female participants of childbearing potential must have a negative urine or serum pregnancy test at screening (within 72 hours of first infusion of study medication). If the urine test cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the participant to be eligible * Female participants of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity starting with the first infusion of study treatment through 120 days after the last infusion of study treatment * Female participants who are breast feeding must discontinue nursing prior to the first infusion of study medication and until 120 days after the last infusion study treatment * Male participants must agree to use an adequate method of contraception starting with the first infusion of study treatment through 120 days after the last infusion of study treatment * Absence of severe comorbidities that in the opinion of the Investigator might hamper the participation to the study and/or the treatment administration * No prior or planned neo-adjuvant or adjuvant radiotherapy and/or neo-adjuvant chemotherapy for the current malignancy is allowed
Exclusion criteria
* Evidence of disease at clinical examination and/or baseline radiological assessment as documented by contrast enhanced chest/upper abdomen CT scan, brain CT/MRI and clinical examination * More than 4 cycles of adjuvant therapy * Prior treatment with anti-programmed cell death (anti-PD)-1, anti-PD ligand-1/2, anti-CD137, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) modulators or any other immune-modulating agents * Live vaccine within 30 days prior to the first infusion of study treatment * Current participation or treatment with an investigational agent or use of an investigational device within 4 weeks of the first infusion of study treatment * History of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive). No known active Hepatitis B or C * Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 3 days prior to the first infusion of study treatment * History of interstitial lung disease or (non-infectious) pneumonitis that required oral or IV steroids (other than COPD exacerbation) or current pneumonitis * Active autoimmune disease that has required systemic treatment in past 2 years * History of a hematologic or primary solid tumor malignancy, unless in remission for at least 5 years with the exception of pT1-2 prostatic cancer Gleason score \< 6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix * Previous allogeneic tissue/solid organ transplant * Active infection requiring therapy * Surgery- or chemotherapy-related toxicity (non-hematological) not resolved to Grade 1 with the exception of alopecia, fatigue, neuropathy and lack of appetite /nausea * Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last infusion of study treatment * Participant will not be eligible if the participant is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial, unless prospective site Review Board approval is given allowing exception to this criterion for a specific participant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-Free Survival (DFS) | Up to approximately 84 months | DFS was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event. |
| DFS in Programmed Death Ligand-1 (PDL-1) Strong Positive Participants With Tumor Proportion Score (TPS) ≥50% | Up to approximately 84 months | DFS in PDL-1 strong positive participants with TPS ≥50% was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 132 months | OS was defined as the time from randomization to the date of death. |
| OS in PDL-1 Strong Positive Participants With TPS ≥50% | Up to approximately 132 months | OS in PDL-1 Strong Positive Participants with TPS ≥50% was defined as the time from randomization to the date of death. |
| OS in PDL-1 Strong Positive Participants With TPS ≥1% | Up to approximately 132 months | OS in PDL-1 Strong Positive Participants with TPS ≥1% was defined as the time from randomization to the date of death. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 22 months | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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. The number of participants who experienced an AE were reported. |
| Lung Cancer Specific Survival (LCSS) | Up to approximately 132 months | LCSS was defined as the time from randomization to the date of death (due to lung cancer specifically). |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 19 months | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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. The number of participants who discontinued study treatment due to an AE were reported. |
| DFS in PDL-1 Strong Positive Participants With TPS ≥1% | Up to approximately 84 months | DFS in PDL-1 strong positive participants with TPS ≥1% was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event. |
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Participants received pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year. | 590 |
| Placebo Participants received placebo, IV, every 3 weeks, for one year. | 587 |
| Total | 1,177 |
Baseline characteristics
| Characteristic | Total | Pembrolizumab | Placebo |
|---|---|---|---|
| Adjuvant Chemotherapy at Baseline No | 167 Participants | 84 Participants | 83 Participants |
| Adjuvant Chemotherapy at Baseline Yes | 1010 Participants | 506 Participants | 504 Participants |
| Age, Continuous | 64.3 Years STANDARD_DEVIATION 8.4 | 64.1 Years STANDARD_DEVIATION 8.5 | 64.5 Years STANDARD_DEVIATION 8.4 |
| Disease Stage at Baseline Stage IB | 172 Participants | 85 Participants | 87 Participants |
| Disease Stage at Baseline Stage II | 668 Participants | 330 Participants | 338 Participants |
| Disease Stage at Baseline Stage IIIA | 335 Participants | 175 Participants | 160 Participants |
| Disease Stage at Baseline Stage IV | 2 Participants | 0 Participants | 2 Participants |
| Geographic region Asia | 211 Participants | 106 Participants | 105 Participants |
| Geographic region Eastern Europe | 229 Participants | 116 Participants | 113 Participants |
| Geographic region Rest of the World | 133 Participants | 65 Participants | 68 Participants |
| Geographic region Western Europe | 604 Participants | 303 Participants | 301 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status at Baseline TPS <1% | 465 Participants | 233 Participants | 232 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status at Baseline TPS 1-49% | 379 Participants | 189 Participants | 190 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status at Baseline TPS ≥50% | 333 Participants | 168 Participants | 165 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 214 Participants | 107 Participants | 107 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 13 Participants | 10 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 41 Participants | 22 Participants | 19 Participants |
| Race (NIH/OMB) White | 905 Participants | 450 Participants | 455 Participants |
| Sex: Female, Male Female | 373 Participants | 189 Participants | 184 Participants |
| Sex: Female, Male Male | 804 Participants | 401 Participants | 403 Participants |
| Smoking status Current smoker | 165 Participants | 75 Participants | 90 Participants |
| Smoking status Former smoker | 859 Participants | 428 Participants | 431 Participants |
| Smoking status Never smoker | 153 Participants | 87 Participants | 66 Participants |
| Tumor Histology Non-squamous | 761 Participants | 398 Participants | 363 Participants |
| Tumor Histology Squamous | 416 Participants | 192 Participants | 224 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 136 / 590 | 154 / 587 |
| other Total, other adverse events | 510 / 580 | 458 / 581 |
| serious Total, serious adverse events | 142 / 580 | 90 / 581 |
Outcome results
Primary
DFS in Programmed Death Ligand-1 (PDL-1) Strong Positive Participants With Tumor Proportion Score (TPS) ≥50%
DFS in PDL-1 strong positive participants with TPS ≥50% was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.
Time frame: Up to approximately 84 months
Population: All randomized PDL-1 strong positive participants with TPS ≥50%. One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | DFS in Programmed Death Ligand-1 (PDL-1) Strong Positive Participants With Tumor Proportion Score (TPS) ≥50% | 67.0 Months |
| Placebo | DFS in Programmed Death Ligand-1 (PDL-1) Strong Positive Participants With Tumor Proportion Score (TPS) ≥50% | 47.6 Months |
p-value: 0.1349995% CI: [0.59, 1.16]Regression, Cox
Primary
Disease-Free Survival (DFS)
DFS was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.
Time frame: Up to approximately 84 months
Population: All randomized participants. One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Disease-Free Survival (DFS) | 53.8 Months |
| Placebo | Disease-Free Survival (DFS) | 43.0 Months |
95% CI: [0.68, 0.96]
Secondary
DFS in PDL-1 Strong Positive Participants With TPS ≥1%
DFS in PDL-1 strong positive participants with TPS ≥1% was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.
Time frame: Up to approximately 84 months
Population: All randomized PDL-1 strong positive participants with TPS ≥1%. One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | DFS in PDL-1 Strong Positive Participants With TPS ≥1% | 58.7 Months |
| Placebo | DFS in PDL-1 Strong Positive Participants With TPS ≥1% | 42.8 Months |
p-value: 0.0132795% CI: [0.62, 0.97]Regression, Cox
Secondary
Lung Cancer Specific Survival (LCSS)
LCSS was defined as the time from randomization to the date of death (due to lung cancer specifically).
Time frame: Up to approximately 132 months
Secondary
Number of Participants Who Discontinued Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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. The number of participants who discontinued study treatment due to an AE were reported.
Time frame: Up to approximately 19 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Discontinued Study Treatment Due to an AE | 116 Participants |
| Placebo | Number of Participants Who Discontinued Study Treatment Due to an AE | 34 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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. The number of participants who experienced an AE were reported.
Time frame: Up to approximately 22 months
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Experienced an Adverse Event (AE) | 556 Participants |
| Placebo | Number of Participants Who Experienced an Adverse Event (AE) | 529 Participants |
Secondary
OS in PDL-1 Strong Positive Participants With TPS ≥1%
OS in PDL-1 Strong Positive Participants with TPS ≥1% was defined as the time from randomization to the date of death.
Time frame: Up to approximately 132 months
Secondary
OS in PDL-1 Strong Positive Participants With TPS ≥50%
OS in PDL-1 Strong Positive Participants with TPS ≥50% was defined as the time from randomization to the date of death.
Time frame: Up to approximately 132 months
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to the date of death.
Time frame: Up to approximately 132 months
Other Pre-specified
DFS at 68 Months
DFS was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.
Time frame: Up to approximately 68 months
Population: All randomized participants. One participant randomized to the study in error did not provide informed consent and was not included. No data was collected on this participant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | DFS at 68 Months | 53.6 Months |
| Placebo | DFS at 68 Months | 42.0 Months |
p-value: 0.0014395% CI: [0.63, 0.91]Regression, Cox