A Multi-center Phase II Study of Combining Cabozantinib and Atezolizumab as the 1st Line Therapy for PD-L1 Negative Advanced/Metastatic NSCLC (Cabatezo-1)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 40
- 试验地点
- 4
- 主要终点
- Objective response rate (ORR)
研究概览
简要总结
NSCLC patients with low expression level of PD-L1, esp. those with its level less than 1%, do not derive much benefit from anti-PD-1/L1 therapy (e.g. atezoilzumab). In this study, investigators hypothesize that the combination of cabozantinib (a multi-kinase inhibitor) and atezolizumab will result in better therapeutic value.
详细描述
For metastatic/advanced non-small cell (NSCLC) patients who do not have targetable mutations, the combination of chemotherapy with immunotherapy targeting the programmed death-1 and its ligand (PD-1/L1) is now a standard of care. In addition, recent studies also demonstrated that immunotherapy doublet using anti-PD-1 agent nivolumab and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agent ipilimumab could be another valid option. However, largely due to the immunosuppressive tumor microenvironment, the therapeutic response remains suboptimal in NSCLC patients with PD-L1 tumor proportion score (TPS) lower than 1% (aka PD-L1 negative). For example, the objective response rate (ORR) in KEYNOTE-189 was 32.3% using pembrolizumab plus chemotherapy, and only 27.3% in Checkmate 227 study using nivolumab and ipilimumab, in the PD-L1 negative population. These observations necessitate the search for novel combinations to benefit our PD-L1 negative NSCLC patients.
The investigators hypothesize that the combination of cabozantinib and atezolizumab is such an innovative strategy based on the following rationales: 1) cabozantinib is a multi-kinase inhibitor, and some of the targets, for example the vascular endothelial growth factor (VEGF) pathway is notorious to confer immune suppressive tumor microenvironment. In fact, our previous study has demonstrated that anti-VEGF synergizes anti-PD-1 in preclinical model. Consistent with this, cabozantinib has been shown to increase tumor infiltrative cytotoxic CD8+ T cells, reduce immune suppressive T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs), as well as activate anti-tumor innate immunity in multiple solid tumors; 2) at the animal level, cabozantinib was found synergistic with anti-PD-1 agents to elicit anti-tumor immune response; and 3) more importantly, at the human level, the combination of cabozantinib with atezolizumab was found safe in Cohort 7 of the phase 1b COSMIC-021 study and achieved 27% ORR in previously immunotherapy-treated NSCLC - suggesting a potentially higher efficacy if such combination is to be used in the 1st line setting.
The investigators therefore propose here the combination of cabozantinib and atezolizumab to be used as the 1st line treatment for advanced/metastatic NSCLC with negative PD-L1 expression.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Cabozantinib and Atezolizumab
Cabozantinib 40mg po daily + Atezolizumab 1200mg iv on day 1; 1 cycle = 21 days
干预措施: Cabozantinib (Drug)
Cabozantinib and Atezolizumab
Cabozantinib 40mg po daily + Atezolizumab 1200mg iv on day 1; 1 cycle = 21 days
干预措施: Atezolizumab (Drug)
结局指标
主要结局
Objective response rate (ORR)
时间窗: through study completion, an average of 1 year
From baseline to End of Treatment (EOT) due to disease progression using RECIST criteria 1.1
次要结局
- Overall survival (OS)(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
- Drug Safety(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
- Duration of response (DOR)(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
- Progression-free survival (PFS)(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
研究者
Jun Zhang, MD, PhD
Associate Professor
University of Kansas Medical Center