A Randomized, Open Label, Multicenter Phase II Study Evaluating the Efficacy and Safety of Capmatinib (INC280) Plus Pembrolizumab Versus Pembrolizumab Alone as First Line Treatment for Locally Advanced or Metastatic Non-small Cell Lung Cancer With PD-L1≥ 50%
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 76
- 试验地点
- 1
- 主要终点
- Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1
研究概览
简要总结
The purpose was to evaluate the efficacy and safety of the combination of capmatinib with pembrolizumab compared to pembrolizumab alone as first-line treatment for subjects with locally advanced or metastatic NSCLC who have PD-L1 expression ≥ 50% and have no EGFR mutation or ALK rearrangement. Capmatinib has demonstrated immunomodulatory activities when combined with an anti-PD1 antibody in preclinical tumor models irrespective of MET dysregulation. The combination of capmatinib with checkpoint inhibitors has been established to be tolerable and could provide additional clinical benefit to the subjects.
详细描述
This was a randomized, open-label, multicenter, phase II study evaluating the efficacy and safety of capmatinib plus pembrolizumab in comparison to pembrolizumab alone as first line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) with programmed cell death ligand-1 (PD-L1) expression ≥ 50%, mesenchymal epithelial transition (MET) unselected, epidermal growth factor receptor (EGFR) wild type and anaplastic lymphoma kinase (ALK) negative.
All eligible subjects were randomized to one of the treatment arms in a 2:1 (capmatinib plus pembrolizumab: pembrolizumab alone) ratio. Participants in both treatment arms were to receive up to 35 cycles (approximately 24 months) of study treatment. The study enrollment was halted on 21-Jan-2021 per sponsor's decision. The enrollment halt decision was based on lack of tolerability observed in the capmatinib plus pembrolizumab arm.
Immediately following the enrollment halt, the below procedural changes were performed:
- Capmatinib treatment was discontinued in subjects on the combination arm. All ongoing subjects were allowed to continue receiving pembrolizumab single agent treatment as per investigator's discretion until unacceptable toxicity, or disease progression, or up to 35 cycles of treatment, whichever occurred first.
- Termination of capmatinib pharmacokinetics (PK) sample collection.
- Termination of pembrolizumab PK/immunogenicity (IG) sample collection. After the enrollment halt, the study protocol was amended (amendment 03) and the collection of efficacy data was stopped. As pembrolizumab is a registered and commercialized treatment for the study indication, the efficacy and safety assessments were to be performed as per each institution's standard of care and no longer captured in the electronic Case Report Form (eCRF) (except reporting of adverse events). Additionally, as single-agent pembrolizumab is a well-established standard treatment for the study indication, the requirement for post-treatment disease progression follow-up and survival follow-up were removed.
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
- •Histologically confirmed and documented locally advanced stage III (not candidates for surgical resection or definitive chemo-radiation) or stage IV (metastatic) NSCLC (per AJCC/IASLC v.8) for treatment in the first-line setting
- •Histologically or cytologically confirmed diagnosis of NSCLC that is both EGFR wild type status and ALK- negative rearrangement statu
- •Have an archival tumor sample or newly obtained tumor biopsy with high PD-L1 expression (TPS ≥ 50%)
- •ECOG performance status score ≤ 1
- •Have at least 1 measurable lesion by RECIST 1.1
- •Have adequate organ function
排除标准
- •Prior treatment with a MET inhibitor or HGF-targeting therapy
- •Prior immunotherapy (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways)
- •Have untreated symptomatic central nervous system (CNS) metastases
- •Clinically significant, uncontrolled heart diseases
- •Prior palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment
研究组 & 干预措施
Capmatinib 400mg BID + pembrolizumab 200mg Q3W
Capmatinib (INC280) 400 mg orally twice daily (BID) in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W)
干预措施: Capmatinib (Drug)
Capmatinib 400mg BID + pembrolizumab 200mg Q3W
Capmatinib (INC280) 400 mg orally twice daily (BID) in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W)
干预措施: Pembrolizumab (Biological)
Pembrolizumab 200mg Q3W
Pembrolizumab 200 mg intravenously every 3 weeks (Q3W)
干预措施: Pembrolizumab (Biological)
结局指标
主要结局
Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1
时间窗: Up to 1.3 years
PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. Tumor response was based on investigator assessment per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment, the start of a subsequent anti-neoplastic therapy (if any) or the date of sponsor's decision to discontinue capmatinib (applicable only to subjects on the combination arm). Due to the discontinuation of one of the investigational drugs (capmatinib) in all subjects in the combination arm, PFS was censored on the 21-Jan-2021 or the last adequate tumor assessment prior to that date for the capmatinib plus pembrolizumab arm. PFS was analyzed using Kaplan-Meier estimates.
次要结局
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(From first dose of study treatment to 30 days after last dose, up to 2.1 years)
- Maximum Observed Plasma Concentration (Cmax) of Capmatinib(pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 2 Day 1. The duration of one cycle was 21 days.)
- Disease Control Rate (DCR) by Investigator Assessment as Per RECIST 1.1(Up to 1.3 years)
- Overall Response Rate (ORR) by Investigator Assessment as Per RECIST 1.1(Up to 1.3 years)
- Duration of Response (DOR) by Investigator Assessment as Per RECIST 1.1(Up to 1.3 years)
- Overall Survival (OS)(Up to 2.1 years)
- Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib(pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 2 Day 1. The duration of one cycle was 21 days.)
- Trough Serum Concentration (Ctrough) of Pembrolizumab(pre-dose on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 6 Day 1 and Cycle 12 Day 1. The duration of one cycle was 21 days.)
- Time to Response (TTR) by Investigator Assessment as Per RECIST 1.1(Up to 1.3 years)
- Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib(pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 2 Day 1. The duration of one cycle was 21 days.)
- Number of Participants With Anti-pembrolizumab Antibodies(Baseline (pre-dose), up to 8 months)