A Phase 3 Study of Pembrolizumab in Combination With Pemetrexed/Platinum (Carboplatin or Cisplatin) Followed by Pembrolizumab and Maintenance Olaparib vs Maintenance Pemetrexed in the First-Line Treatment of Participants With Metastatic Nonsquamous Non-Small-Cell Lung Cancer (NSCLC)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,003
- 试验地点
- 290
- 主要终点
- Progression-free Survival (PFS)
研究概览
简要总结
The current study will compare pembrolizumab (MK-3475) plus maintenance olaparib, versus (vs) pembrolizumab plus maintenance pemetrexed for the treatment of non-squamous NSCLC. The study's 2 primary hypotheses are: 1. Pembrolizumab plus maintenance olaparib is superior to pembrolizumab plus maintenance pemetrexed with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent clinical review (BICR) and 2. Pembrolizumab plus maintenance olaparib is superior to pembrolizumab plus maintenance pemetrexed with respect to overall survival (OS).
详细描述
This study has 2 phases: an Induction Phase of up to ~4 Cycles (up to ~12 weeks [cycle =3 weeks]) and a Maintenance Phase of up to ~31 cycles of pembrolizumab (cycle = 3 weeks]); total pembrolizumab treatment duration will be up to ~35 cycles (up to ~2 years). In the Induction Phase, participants receive pembrolizumab plus pemetrexed plus platinum (carboplatin or cisplatin, at the investigator's discretion). 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 pemetrexed. In the Maintenance Phase, participants receive pembrolizumab for up to 31 cycles (cycle = 3 weeks) plus maintenance olaparib OR maintenance pemetrexed until progressive disease (PD), intolerable toxicities, or physician decision.
Qualified participants in each study arm of the maintenance phase (Pembrolizumab plus Olaparib and Pembrolizumab plus Pemetrexed) who complete up to ~35 cycles of pembrolizumab (up to ~2 years [cycle =3 weeks]) may be eligible to receive a second course of pembrolizumab for up to ~17 cycles (up to ~1 additional year). Per protocol, response or progression during the second pembrolizumab course will not be counted towards patient reported outcomes (PROs) or efficacy outcome measures and adverse events during the second pembrolizumab course will not be counted towards safety outcome measures.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Have a histologically or cytologically confirmed diagnosis nonsquamous NSCLC.
- •Have stage IV nonsquamous NSCLC.
- •Have confirmation that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or Proto-oncogene tyrosine-protein kinase (ROS1)-directed therapy is not indicated.
- •Have measurable disease based on RECIST 1.
- •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 start the induction phase. 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 life expectancy of at least 3 months.
- •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 not received prior systemic treatment for their advanced/metastatic NSCLC.
- •Have 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, and female participants must refrain from donating eggs to others or freeze/store for her own use during the treatment period and for 180 days afterwards.
排除标准
- •Has predominantly squamous cell 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 (CNS) metastases and/or carcinomatous meningitis.
- •Has a severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
- •Has a known hypersensitivity to any components or excipients of cisplatin, carboplatin, pemetrexed, or olaparib.
- •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.
- •Has history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
- •Has completed palliative radiotherapy within 7 days of the first dose. Participants must have recovered from all radiation-related toxicities and not require corticosteroids.
研究组 & 干预措施
Pembrolizumab + Pemetrexed + Platinum Therapy + Olaparib
For the Induction Phase, participants receive 4 cycles (up to ~12 weeks [cycle = 3 weeks]): pembrolizumab 200 mg intravenous (IV) on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin area under the curve (AUC) 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m^2 IV on Day 1 of each cycle (Cycles 1 through 4).
If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. The participant can continue to receive maintenance olaparib until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to ~35 cycles (up to ~2 years [cycle = 3 weeks]).
干预措施: Olaparib (Drug)
Pembrolizumab + Pemetrexed + Platinum Therapy + Olaparib
For the Induction Phase, participants receive 4 cycles (up to ~12 weeks [cycle = 3 weeks]): pembrolizumab 200 mg intravenous (IV) on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin area under the curve (AUC) 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m^2 IV on Day 1 of each cycle (Cycles 1 through 4).
If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. The participant can continue to receive maintenance olaparib until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to ~35 cycles (up to ~2 years [cycle = 3 weeks]).
干预措施: Pembrolizumab (Biological)
Pembrolizumab + Pemetrexed + Platinum Therapy + Pemetrexed
For the Induction Phase, participants receive 4 cycles (up to ~12 weeks [cycle = 3 weeks]): pembrolizumab 200 mg IV on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin AUC 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m^2 IV on Day 1 of each cycle (Cycles 1 through 4).
If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance pemetrexed 500 mg/m^2 IV on Day 1 of each 3-week cycle. The participant can continue to receive maintenance pemetrexed until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to ~35 cycles (up to ~2 years [cycle = 3 weeks]).
干预措施: Cisplatin (Drug)
Pembrolizumab + Pemetrexed + Platinum Therapy + Olaparib
For the Induction Phase, participants receive 4 cycles (up to ~12 weeks [cycle = 3 weeks]): pembrolizumab 200 mg intravenous (IV) on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin area under the curve (AUC) 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m^2 IV on Day 1 of each cycle (Cycles 1 through 4).
If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. The participant can continue to receive maintenance olaparib until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to ~35 cycles (up to ~2 years [cycle = 3 weeks]).
干预措施: Pemetrexed (Drug)
Pembrolizumab + Pemetrexed + Platinum Therapy + Olaparib
For the Induction Phase, participants receive 4 cycles (up to ~12 weeks [cycle = 3 weeks]): pembrolizumab 200 mg intravenous (IV) on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin area under the curve (AUC) 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m^2 IV on Day 1 of each cycle (Cycles 1 through 4).
If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. The participant can continue to receive maintenance olaparib until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to ~35 cycles (up to ~2 years [cycle = 3 weeks]).
干预措施: Carboplatin (Drug)
Pembrolizumab + Pemetrexed + Platinum Therapy + Olaparib
For the Induction Phase, participants receive 4 cycles (up to ~12 weeks [cycle = 3 weeks]): pembrolizumab 200 mg intravenous (IV) on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin area under the curve (AUC) 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m^2 IV on Day 1 of each cycle (Cycles 1 through 4).
If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. The participant can continue to receive maintenance olaparib until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to ~35 cycles (up to ~2 years [cycle = 3 weeks]).
干预措施: Cisplatin (Drug)
Pembrolizumab + Pemetrexed + Platinum Therapy + Pemetrexed
For the Induction Phase, participants receive 4 cycles (up to ~12 weeks [cycle = 3 weeks]): pembrolizumab 200 mg IV on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin AUC 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m^2 IV on Day 1 of each cycle (Cycles 1 through 4).
If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance pemetrexed 500 mg/m^2 IV on Day 1 of each 3-week cycle. The participant can continue to receive maintenance pemetrexed until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to ~35 cycles (up to ~2 years [cycle = 3 weeks]).
干预措施: Pembrolizumab (Biological)
Pembrolizumab + Pemetrexed + Platinum Therapy + Pemetrexed
For the Induction Phase, participants receive 4 cycles (up to ~12 weeks [cycle = 3 weeks]): pembrolizumab 200 mg IV on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin AUC 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m^2 IV on Day 1 of each cycle (Cycles 1 through 4).
If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance pemetrexed 500 mg/m^2 IV on Day 1 of each 3-week cycle. The participant can continue to receive maintenance pemetrexed until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to ~35 cycles (up to ~2 years [cycle = 3 weeks]).
干预措施: Pemetrexed (Drug)
Pembrolizumab + Pemetrexed + Platinum Therapy + Pemetrexed
For the Induction Phase, participants receive 4 cycles (up to ~12 weeks [cycle = 3 weeks]): pembrolizumab 200 mg IV on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin AUC 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m^2 IV on Day 1 of each cycle (Cycles 1 through 4).
If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance pemetrexed 500 mg/m^2 IV on Day 1 of each 3-week cycle. The participant can continue to receive maintenance pemetrexed until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to ~35 cycles (up to ~2 years [cycle = 3 weeks]).
干预措施: Carboplatin (Drug)
结局指标
主要结局
Progression-free Survival (PFS)
时间窗: Up to ~31 months
PFS was defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) based on blinded independent central review (BICR) or death due to any cause, whichever occurs first. 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. The appearance of one or more new lesions was also considered PD. PFS was analyzed by the non-parametric Kaplan-Meier (K-M) method. The protocol specified final analysis of PFS is presented here for the first pembrolizumab course in the Maintenance Phase. Per protocol, analysis for this outcome measure was not planned or conducted in the Induction Phase.
Overall Survival (OS)
时间窗: Up to ~51 months
OS was defined as the time from randomization to death due to any cause. OS was analyzed by the non-parametric K-M method. Participants without documented death at the time of analyses were censored at the date of last known to be alive. The protocol specified final analysis of OS is presented here for the first pembrolizumab course in the Maintenance Phase. Per protocol, analysis for this outcome measure was not planned or conducted in the Induction Phase.
次要结局
- Number of Participants Who Experience One or More Adverse Events (AEs)(Up to ~5 years)
- Number of Participants Who Discontinue Study Treatment Due to an AE(Up to ~5 years)
- Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status / Quality of Life (Items 29 and 30) Scale Score(Baseline and Week 24)
- Time to True Deterioration (TTD) in EORTC QLQ-C30 Global Health Status / Quality of Life (Items 29 & 30) Scale Score(Up to ~24 months)
- Change From Baseline in EORTC Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Cough (Item 1) Scale Score(Baseline and Week 24)
- TTD in EORTC QLQ-LC13 Cough (Item 1) Scale Score(Up to ~24 months)
- Change From Baseline in EORTC QLQ-LC13 Chest Pain (Item 10) Scale Score(Baseline and Week 24)
- TTD in EORTC QLQ-LC13 Chest Pain (Item 10) Scale Score(Up to ~24 months)
- Change From Baseline in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score(Baseline and Week 24)
- TTD in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score(Up to ~24 months)
- Change From Baseline in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score(Baseline and Week 24)
- TTD in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score(Up to ~24 months)