Study of Pembrolizumab Versus Docetaxel in Participants Previously Treated for Non-Small Cell Lung Cancer (MK-3475-033/KEYNOTE-033)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy of pembrolizumab (MK-3475) versus docetaxel in participants with non-small cell lung cancer (NSCLC) with programmed cell death ligand 1 (PD-L1) positive tumors who have experienced disease progression after platinum-containing systemic therapy. The primary hypotheses of this study are that pembrolizumab (MK-3475) prolongs overall survival (OS) and that pembrolizumab prolongs progression-free survival (PFS), compared to docetaxel in participants with PD-L1 positive tumors.

Official Title
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A Multinational, Multicenter, Phase III, Randomized Open-label Trial of Pembrolizumab Versus Docetaxel in Previously Treated Subjects With Non-Small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chinese participants must be born, raised, and reside in China Has a histologically or cytologically confirmed diagnosis of stage IIIB/IV or recurrent NSCLC and have at least one measurable lesion as defined by RECIST 1.1 Has a life expectancy of ≥3 months Has progression of disease (investigator determined) per RECIST 1.1 after treatment with at least two cycles of a platinum-containing doublet Has documentation of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation status Participants with an EGFR sensitizing mutation tumor will be excluded Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 10 days prior to study start Has provided archival tumor tissue sample or newly obtained formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated Has a PD-L1 positive tumor as determined by immunohistochemistry at a central laboratory Has resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia) Has recovered from the toxicity and/or complications of any recent major surgery or radiation therapy Females must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours prior to receiving the first dose of study medication) Female and male participants of reproductive potential must agree to use adequate contraception starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab (MK-3475) or 180 days after the last dose of docetaxel Exclusion Criteria: Has received prior therapy with docetaxel for NSCLC Is currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study treatment Is receiving systemic steroid therapy within 3 days prior to the first dose of study treatment or receiving any other form of immunosuppressive Is expected to require any other form of systemic or localized antineoplastic therapy while on study including maintenance therapy with another agent for NSCLC or radiation therapy Has received prior systemic cytotoxic chemotherapy, antineoplastic biological therapy (e.g., cetuximab), any other agents used as systemic treatment for cancer, or major surgery within 3 weeks of the first dose of study treatment; received thoracic radiation therapy of > 30 Gray Units (Gy) within 6 months of the first dose of study treatment; received prior ALK-directed tyrosine kinase inhibitor therapy or completed palliative radiotherapy of 30 Gy or less within 7 days of the first dose of study treatment Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-PD-L1, anti-PD-L2, with an agent directed to an agonist or antagonist T-cell check point receptor, or if the participant has previously participated in Merck sponsored clinical trials evaluating pembrolizumab (MK-3475) Has a known additional malignancy that is progressing or requires active treatment, with the exception of early stage cancers, treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy Has known active central nervous system metastases and/or carcinomatous meningitis Has active autoimmune disease that has required systemic treatment in past 2 years Has had an allogeneic tissue/solid organ transplant Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis Has received or will receive a live vaccine within 30 days prior to the first administration of study medication Has an active infection requiring intravenous systemic therapy Has known history of Human Immunodeficiency Virus (HIV) (HIV ½ antibodies) Has known active Hepatitis B or C Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Is, at the time of signing informed consent, a regular user (including recreational use) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol) Is pregnant or breastfeeding, or expecting to conceive or father children starting with the screening visit (Visit 1) through 120 days after the last dose of pembrolizumab (MK-3475) or 180 days after the last dose of docetaxel Requires treatment with a strong inhibitor of Cytochrome P450 3A4

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab<br>Participants with NSCLC receive pembrolizumab 2 mg/kg intravenously (IV) over 30 minutes every 3 weeks (Q3W) for up to 35 doses (approximately 24 months). | Biological: Pembrolizumab<br>* Pembrolizumab administered IV at 2 mg/kg on Day 1 of each 21-day cycle for up to 35 doses (approximately 24 months).<br>* Other names: MK-3475;|
| Experimental: Docetaxel<br>Participants with NSCLC receive Docetaxel 75 mg/m^2 IV over 1 hour Q3W until disease progression, toxicity, investigator's decision to discontinue, or consent withdrawal. | Drug: Docetaxel<br>* Docetaxel administered IV at 75 mg/m^2 on Day 1 of each 21-day cycle as per the approved product label.<br>* Other names: TAXOTERE®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Positive (Tumor Proportion Score [TPS] ≥50%) Tumors | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS was reported by treatment arm for participants in the TPS ≥50% stratum of PD-L1 expression. | Up to approximately 36 months (through Final Analysis cut-off date of 09-Sep-2019) | 
| OS in Participants With PD-L1 Positive (TPS ≥1%) Tumors (All Participants) | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS was reported by treatment arm for participants in the TPS ≥1% stratum of PD-L1 expression (all participants). | Up to approximately 36 months (through Final Analysis cut-off date of 09-Sep-2019) | 
| Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With PD-L1 Positive (TPS ≥50%) Tumors | PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, PFS was reported by treatment arm for participants in the TPS ≥50% stratum of PD-L1 expression. | Up to approximately 36 months (through Final Analysis cut-off date of 09-Sep-2019) | 
| PFS Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 Positive (TPS ≥1%) Tumors (All Participants) | PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the SOD of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, PFS was reported by treatment arm for participants in the TPS ≥1% stratum of PD-L1 expression (all participants). | Up to approximately 36 months (through Final Analysis cut-off date of 09-Sep-2019) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 Positive (TPS ≥50%) Tumors | 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: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. as assessed by BICR. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for participants in the TPS ≥50% stratum of PD-L1 expression. | Up to approximately 36 months (through Final Analysis cut-off date of 09-Sep-2019) | 
| ORR Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 Positive (TPS ≥1%) Tumors (All Participants) | ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. as assessed by BICR. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for participants in the TPS ≥1% stratum of PD-L1 expression (all participants). | Up to approximately 36 months (through Final Analysis cut-off date of 09-Sep-2019) | 
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 Positive (TPS ≥50%) Tumors | For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD 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 had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The appearance of one or more new lesions was also considered PD. Response duration was calculated using the Kaplan-Meier method for censored data. Per protocol, DOR was reported by treatment arm for participants in the TPS ≥50% stratum of PD-L1 expression. | Up to approximately 36 months (through Final Analysis cut-off date of 09-Sep-2019) | 
| DOR Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 Positive (TPS ≥1%) Tumors (All Participants) | For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD 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 had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Response duration was calculated using the Kaplan-Meier method for censored data. Per protocol, DOR was reported by treatment arm for participants in the TPS ≥1% stratum of PD-L1 expression (all participants). | Up to approximately 36 months (through Final Analysis cut-off date of 09-Sep-2019) | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. Per protocol, MedDRA preferred terms Neoplasm progression, Malignant neoplasm progression and Disease progression not related to the study intervention are excluded. Per protocol, the number of participants who experienced an AE was reported by treatment arm for all participants as part of the pre-specified safety analysis at study completion (Final AE collection cut-off date of 14-Oct-2022). | Up to approximately 66 months | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. Per protocol, the number of participants who discontinued study treatment due to an AE was reported by treatment arm for all participants as part of the pre-specified safety analysis at study completion (Final AE collection cut-off date of 14-Oct-2022). | Up to approximately 45 months | 
| Number of Participants Who Experienced an Adverse Event of Special Interest (AEOSI) | An AEOSI was defined as any AE that is immune-mediated or potentially immune-mediated. An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. Per protocol, the number of participants who experienced an AE was reported by treatment arm for all participants as part of the pre-specified safety analysis at study completion (Final AE collection cut-off date of 14-Oct-2022). | Up to approximately 66 months | 
| Number of Participants Who Experienced a Grade 3-5 AE | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. Per protocol, MedDRA preferred terms Neoplasm progression, Malignant neoplasm progression and Disease progression not related to the study intervention are excluded. Per protocol, the number of participants who experienced an AE was reported by treatment arm for all participants as part of the pre-specified safety analysis at study completion (Final AE collection cut-off date of 14-Oct-2022). | Up to approximately 66 months | 
| Number of Participants Who Experienced an AE That Was Experienced by ≥10% of Participants in Either Arm | An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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. Any worsening of a pre-existing condition temporally associated with the use of the Sponsor's product was also an AE. Per protocol, MedDRA preferred terms Neoplasm progression, Malignant neoplasm progression and Disease progression not related to the study intervention are excluded. Per protocol, the number of participants who experienced an AE was reported by treatment arm for all participants (TPS ≥1% stratum of PD-L1 expression) as part of the pre-specified safety analysis at study completion (Final AE collection cut-off date of 14-Oct-2022). | Up to approximately 66 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)