A Study of Pembrolizumab (MK-3475) With or Without Maintenance Olaparib in First-line Metastatic Squamous Non-small Cell Lung Cancer (NSCLC, MK-7339-008/KEYLYNK-008)

Phase 3

Active, not recruiting

Conditions: Carcinoma, Squamous Cell, Non-small-cell Lung

Interventions: Biological: Pembrolizumab
Drug: Carboplatin
Drug: Paclitaxel
Drug: Nab-paclitaxel
Drug: Placebo
Drug: Olaparib

Registration Number: NCT03976362

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: The current study will compare pembrolizumab (MK-3475) plus maintenance olaparib, vs. pembrolizumab plus maintenance olaparib placebo for the treatment of squamous NSCLC. The study's 2 primary hypotheses are:

1. Pembrolizumab plus maintenance olaparib is superior to pembrolizumab plus maintenance olaparib placebo with respect to progression-free survival (PFS) per RECIST 1.1 by blinded independent clinical review (BICR).

2. Pembrolizumab plus maintenance olaparib is superior to pembrolizumab plus maintenance olaparib placebo with respect to overall survival (OS).

As of Amendment 07, there will be no further analyses for OS and patient-reported outcome assessments.

Detailed Description: This study has 2 phases: an Induction Phase (4 Cycles) and a Maintenance Phase (Up to 31 cycles of pembrolizumab). In the Induction Phase, participants receive pembrolizumab plus carboplatin plus a taxane (paclitaxel or nab-paclitaxel). In the Maintenance Phase, participants with a partial or complete disease response or with stable disease after completing four cycles of induction therapy and who meet eligibility criteria will be randomly assigned to receive pembrolizumab plus maintenance olaparib OR pembrolizumab plus maintenance olaparib placebo. In the Maintenance Phase, participants randomly assigned to receive pembrolizumab for up to 31 cycles plus maintenance olaparib OR maintenance olaparib placebo until centrally verified progressive disease (PD), intolerable toxicities, or physician decision.

As of Amendment 07, participants actively taking placebo will discontinue taking the placebo intervention and continue in the study.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 851

Inclusion Criteria

Have a histologically or cytologically confirmed diagnosis squamous NSCLC.
Have Stage IV squamous NSCLC.
Have measurable disease based on RECIST 1.1.
Have not received prior systemic treatment for their advanced/metastatic NSCLC.
Have provided archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated.

Note: Adequacy of biopsy specimen for the above analyses must be confirmed by the central laboratory before the participant can receive study intervention(s). Submission of another tumor specimen may be required prior to enrolling the participant, if adequate tumor tissue was not provided the first time.
Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status assessed within 7 days prior to the administration of study intervention
Have a life expectancy of at least 3 months.
Has adequate organ function.
Male and female participants who are not pregnant and of childbearing potential must follow contraceptive guidance during the treatment period and for 180 days afterwards.
Male participants must refrain from donating sperm during the treatment period and for 180 days afterwards.

Exclusion Criteria

Has non-squamous histology NSCLC.
Has a known additional malignancy that is progressing or has progressed within the past 3 years requiring active treatment.
Has known active central nervous system metastases and/or carcinomatous meningitis.
Has a known hypersensitivity to any components or excipients of carboplatin, paclitaxel or nab-paclitaxel, or olaparib.
Has a severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
Has an active autoimmune disease that has required systemic treatment in past 2 years.
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy.
Has a known history of human immunodeficiency virus (HIV) infection, a known history of hepatitis B infection, or known active hepatitis C virus infection.
Has interstitial lung disease, or history of pneumonitis requiring systemic steroids for treatment.
Has received prior therapy with olaparib or with any other polyadenosine 5' diphosphoribose (polyADP ribose) polymerization (PARP) inhibitor.
Has received prior therapy with an agent directed to programmed cell death ligand 1 (PD-L1), anti PD-L2, or directed to a stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137).
Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pembrolizumab + Carboplatin + Taxane + Olaparib	Nab-paclitaxel	For the Induction Phase, participants receive 4 cycles: Pembrolizumab 200 mg, intravenous (IV) on Day 1 of each 21-day cycle PLUS carboplatin PLUS a taxane (either paclitaxel or nab-paclitaxel) for 4 cycles (21-day cycles). If the participant has a complete or partial response or stable disease to induction therapy, the participant is randomized to maintenance therapy. For the Maintenance Phase, participants receive pembrolizumab IV on Day 1 of each 21-day for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. In the Maintenance Phase, the participant continues to receive maintenance olaparib until centrally verified progressive disease, physician decision or intolerable toxicity.
Pembrolizumab + Carboplatin + Taxane + Olaparib Placebo	Nab-paclitaxel	For the Induction Phase, participants receive 4 cycles: Pembrolizumab 200 mg, intravenous (IV) on Day 1 of each 21-day cycle PLUS carboplatin PLUS a taxane (either paclitaxel or nab-paclitaxel) for 4 cycles (21-day cycles). If the participant has a complete or partial response or stable disease to induction therapy, the participant is randomized to maintenance therapy. For the Maintenance Phase, participants receive pembrolizumab IV on Day 1 of each 21-day for up to 31 cycles PLUS matching maintenance olaparib placebo twice daily. In the Maintenance Phase, the participant continues to receive maintenance olaparib placebo until centrally verified progressive disease, physician decision or intolerable toxicity.
Pembrolizumab + Carboplatin + Taxane + Olaparib	Carboplatin	For the Induction Phase, participants receive 4 cycles: Pembrolizumab 200 mg, intravenous (IV) on Day 1 of each 21-day cycle PLUS carboplatin PLUS a taxane (either paclitaxel or nab-paclitaxel) for 4 cycles (21-day cycles). If the participant has a complete or partial response or stable disease to induction therapy, the participant is randomized to maintenance therapy. For the Maintenance Phase, participants receive pembrolizumab IV on Day 1 of each 21-day for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. In the Maintenance Phase, the participant continues to receive maintenance olaparib until centrally verified progressive disease, physician decision or intolerable toxicity.
Pembrolizumab + Carboplatin + Taxane + Olaparib Placebo	Pembrolizumab	For the Induction Phase, participants receive 4 cycles: Pembrolizumab 200 mg, intravenous (IV) on Day 1 of each 21-day cycle PLUS carboplatin PLUS a taxane (either paclitaxel or nab-paclitaxel) for 4 cycles (21-day cycles). If the participant has a complete or partial response or stable disease to induction therapy, the participant is randomized to maintenance therapy. For the Maintenance Phase, participants receive pembrolizumab IV on Day 1 of each 21-day for up to 31 cycles PLUS matching maintenance olaparib placebo twice daily. In the Maintenance Phase, the participant continues to receive maintenance olaparib placebo until centrally verified progressive disease, physician decision or intolerable toxicity.
Pembrolizumab + Carboplatin + Taxane + Olaparib Placebo	Placebo	For the Induction Phase, participants receive 4 cycles: Pembrolizumab 200 mg, intravenous (IV) on Day 1 of each 21-day cycle PLUS carboplatin PLUS a taxane (either paclitaxel or nab-paclitaxel) for 4 cycles (21-day cycles). If the participant has a complete or partial response or stable disease to induction therapy, the participant is randomized to maintenance therapy. For the Maintenance Phase, participants receive pembrolizumab IV on Day 1 of each 21-day for up to 31 cycles PLUS matching maintenance olaparib placebo twice daily. In the Maintenance Phase, the participant continues to receive maintenance olaparib placebo until centrally verified progressive disease, physician decision or intolerable toxicity.
Pembrolizumab + Carboplatin + Taxane + Olaparib	Olaparib	For the Induction Phase, participants receive 4 cycles: Pembrolizumab 200 mg, intravenous (IV) on Day 1 of each 21-day cycle PLUS carboplatin PLUS a taxane (either paclitaxel or nab-paclitaxel) for 4 cycles (21-day cycles). If the participant has a complete or partial response or stable disease to induction therapy, the participant is randomized to maintenance therapy. For the Maintenance Phase, participants receive pembrolizumab IV on Day 1 of each 21-day for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. In the Maintenance Phase, the participant continues to receive maintenance olaparib until centrally verified progressive disease, physician decision or intolerable toxicity.
Pembrolizumab + Carboplatin + Taxane + Olaparib Placebo	Carboplatin	For the Induction Phase, participants receive 4 cycles: Pembrolizumab 200 mg, intravenous (IV) on Day 1 of each 21-day cycle PLUS carboplatin PLUS a taxane (either paclitaxel or nab-paclitaxel) for 4 cycles (21-day cycles). If the participant has a complete or partial response or stable disease to induction therapy, the participant is randomized to maintenance therapy. For the Maintenance Phase, participants receive pembrolizumab IV on Day 1 of each 21-day for up to 31 cycles PLUS matching maintenance olaparib placebo twice daily. In the Maintenance Phase, the participant continues to receive maintenance olaparib placebo until centrally verified progressive disease, physician decision or intolerable toxicity.
Pembrolizumab + Carboplatin + Taxane + Olaparib Placebo	Paclitaxel	For the Induction Phase, participants receive 4 cycles: Pembrolizumab 200 mg, intravenous (IV) on Day 1 of each 21-day cycle PLUS carboplatin PLUS a taxane (either paclitaxel or nab-paclitaxel) for 4 cycles (21-day cycles). If the participant has a complete or partial response or stable disease to induction therapy, the participant is randomized to maintenance therapy. For the Maintenance Phase, participants receive pembrolizumab IV on Day 1 of each 21-day for up to 31 cycles PLUS matching maintenance olaparib placebo twice daily. In the Maintenance Phase, the participant continues to receive maintenance olaparib placebo until centrally verified progressive disease, physician decision or intolerable toxicity.
Pembrolizumab + Carboplatin + Taxane + Olaparib	Paclitaxel	For the Induction Phase, participants receive 4 cycles: Pembrolizumab 200 mg, intravenous (IV) on Day 1 of each 21-day cycle PLUS carboplatin PLUS a taxane (either paclitaxel or nab-paclitaxel) for 4 cycles (21-day cycles). If the participant has a complete or partial response or stable disease to induction therapy, the participant is randomized to maintenance therapy. For the Maintenance Phase, participants receive pembrolizumab IV on Day 1 of each 21-day for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. In the Maintenance Phase, the participant continues to receive maintenance olaparib until centrally verified progressive disease, physician decision or intolerable toxicity.
Pembrolizumab + Carboplatin + Taxane + Olaparib	Pembrolizumab	For the Induction Phase, participants receive 4 cycles: Pembrolizumab 200 mg, intravenous (IV) on Day 1 of each 21-day cycle PLUS carboplatin PLUS a taxane (either paclitaxel or nab-paclitaxel) for 4 cycles (21-day cycles). If the participant has a complete or partial response or stable disease to induction therapy, the participant is randomized to maintenance therapy. For the Maintenance Phase, participants receive pembrolizumab IV on Day 1 of each 21-day for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. In the Maintenance Phase, the participant continues to receive maintenance olaparib until centrally verified progressive disease, physician decision or intolerable toxicity.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	Up to approximately 39 months	Progression-free Survival was defined as the time from the date of randomization until either documented disease progression or death due to any cause, whichever occurred first. Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, progressive disease (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 have also demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS as assessed by Blinded Independent Central Review (BICR) per RECIST 1.1 is presented. PFS is reported based on the non-parametric Kaplan-Meier method. Per protocol this outcome measure was not planned for the Induction Phase.
Overall Survival (OS)	Up to approximately 46 months	Overall survival was the time from the date of randomization to death due to any cause. OS is reported based on the non-parametric Kaplan-Meier method. Per protocol this outcome measure was not planned for the Induction Phase.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With One or More Adverse Events (AEs)	Up to approximately 4 years	An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. The number of participants who reported 1 or more AEs is presented. Per protocol this outcome measure was not planned for the Induction Phase.
Number of Participants Who Discontinued Study Intervention Due to an AE	Up to approximately 4 years	An AE was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. The number of participants who discontinued study intervention due to an AE is presented. Per protocol this outcome measure was not planned for the Induction Phase.
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/ Quality of Life (QoL) (Items 29 and 30) Combined Scale Score	Baseline and Week 24	EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the Global Health Status GHS question "How would you rate your overall health during the past week?" (Item 29) and the QoL question "How would you rate your overall quality of life during the past week?" (Item 30) were each scored on a 7-point scale (1=Very Poor to 7=Excellent), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score was assessed using a constrained longitudinal data analysis (cLDA) model with the patient-reported outcome (PRO) score as the response variable, and treatment, time, treatment-by-time interaction, and clinical study stratification factors as covariates. Per protocol this outcome measure was not planned for the Induction Phase.
Time to True Deterioration (TTD) in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QoL) (Items 29 and 30) Scale Score	Up to approximately 2 years	TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline in GHS (EORTC QLQ-C30 Item 29) and QoL score (EORTC QLQ-C30 Item 30). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10- point negative change (decrease) from Baseline in GHS score, will be presented. A longer TTD indicates a better outcome. TTD is reported based on the non-parametric Kaplan-Meier method. Per protocol this outcome measure was not planned for the Induction Phase.
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Cough (Item 1) Scale Score	Baseline and Week 24	The EORTC QLQ-LC13 is a lung cancer specific supplemental questionnaire used in combination with the EORTC QLQ-C30 questionnaire. Participant responses to the question "How much did you cough?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. The change from baseline in EORTC QLQ-LC13 cough (Item 1) score is presented. Change from baseline score was assessed using a cLDA model with the PRO score as the response variable, and treatment, time, treatment-by-time interaction, and clinical study stratification factors as covariates. Per protocol this outcome measure was not planned for the Induction Phase.
Time to True Deterioration (TTD) in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Cough (Item 1) Scale Score	Up to approximately 2 years	The EORTC QLQ-LC13 is a lung cancer specific supplemental questionnaire used in combination with the EORTC QLQ-C30 questionnaire. Participant responses to the question "How much did you cough?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. TTD was defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in cough scale score. The TTD for cough (Item 1) is presented. TTD is reported based on the non-parametric Kaplan-Meier method. Per protocol this outcome measure was not planned for the Induction Phase.
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Chest Pain (Item 10) Scale Score	Baseline and Week 24	The EORTC QLQ-LC13 is a lung cancer specific supplemental questionnaire used in combination with the EORTC QLQ-C30 questionnaire. Participant responses to the question "Have you had pain in your chest?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. The change from baseline in EORTC QLQ-LC13 chest pain (Item 10) score is presented. Change from baseline score was assessed using a cLDA model with the PRO score as the response variable, and treatment, time, treatment-by-time interaction, and clinical study stratification factors as covariates. Per protocol this outcome measure was not planned for the Induction Phase.
Time to True Deterioration (TTD) in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Chest Pain (Item 10) Scale Score	Up to approximately 2 years	The EORTC QLQ-LC13 is a lung cancer specific supplemental questionnaire used in combination with the EORTC QLQ-C30 questionnaire. Participant responses to the question "Have you had pain in your chest?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. TTD was defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in chest pain scale score. The TTD for chest pain (Item 10) is presented. TTD is reported based on the non-parametric Kaplan-Meier method. Per protocol this outcome measure was not planned for the Induction Phase.
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Dyspnea (Item 8) Scale Score	Baseline and Week 24	The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question "Were you short of breath?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in EORTC QLQ-C30 dyspnea (Item 8) score will be presented. A lower score indicates a better outcome. The change from baseline in EORTC QLQ-C30 dyspnea (Item 8) score is presented. Change from baseline score was assessed using a cLDA model with the PRO score as the response variable, and treatment, time, treatment-by-time interaction, and clinical study stratification factors as covariates. Per protocol this outcome measure was not planned for the Induction Phase.
Time to True Deterioration (TTD) in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Dyspnea (Item 8) Scale Score	Up to approximately 2 years	The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question "Were you short of breath?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. TTD was defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in Item 8 scale score. The TTD for dyspnea (Item 8) is presented. TTD is reported based on the non-parametric Kaplan-Meier method. Per protocol this outcome measure was not planned for the Induction Phase.
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Physical Functioning (Items 1 to 5) Scale Score	Baseline and Week 24	The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) score is presented. Change from baseline score was assessed using a constrained longitudinal data analysis (cLDA) model with the patient-reported outcome (PRO) score as the response variable, and treatment, time, treatment-by-time interaction, and clinical study stratification factors as covariates. Per protocol this outcome measure was not planned for the Induction Phase.
Time to True Deterioration (TTD) in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Physical Functioning (Items 1 to 5) Scale Score	Up to approximately 2 years	The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. TTD was defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in physical functioning Items 1 to 5 scale scores. The TTD for physical functioning (Item 1-5) is presented. TTD is reported based on the non-parametric Kaplan-Meier method. Per protocol this outcome measure was not planned for the Induction Phase.

Trial Locations

Locations (178): Alabama Oncology Bruno Cancer Center ( Site 0001)
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Birmingham, Alabama, United States
Disney Family Cancer Center ( Site 0005)
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Burbank, California, United States
Boca Raton Regional Hospital ( Site 0018)
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Boca Raton, Florida, United States
Mid-Florida Cancer Centers ( Site 0022)
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Orange City, Florida, United States
H. Lee Moffitt Cancer Center and Research Institute ( Site 0024)
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Tampa, Florida, United States
Columbus Regional Research Institute ( Site 0099)
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Columbus, Georgia, United States
Mount Sinai Hospital Medical Center ( Site 0035)
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Chicago, Illinois, United States
Oncology of Northshore ( Site 0036)
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Rolling Meadows, Illinois, United States
Methodists Hospitals/Premier Oncology Hematology Associates ( Site 0039)
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Merrillville, Indiana, United States
MedStar Franklin Square Medical Center ( Site 0044)
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Baltimore, Maryland, United States
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Alabama Oncology Bruno Cancer Center ( Site 0001)
🇺🇸Birmingham, Alabama, United States