Apatinib Plus Gefitinib as First-Line Treatment in Advanced EGFR-Mutant NSCLC: The Phase III ACTIVE Study (CTONG1706)

Zhao, Hongyun; Yao, Wenxiu; Min, Xuhong; Gu, Kangsheng; Yang, Guohua; Zhang, Zhonghan; Cui, Jiuwei; Miao, Liyun; Zhang, Li; Yuan, Xia; Fang, Yong; Fu, Xue Jun; Hu, Chengping; Zhu, Xiaoyun; Fan, Yun; Qin, Yu; Wu, Gang; Jiang, Ou; Du, Xiaohui; Liu, Jiwei; Gu, Wei; Hou, Zhiguo; Wang, Quanren; Zheng, Rongrong; Zhou, Xianfeng

doi:10.1016/j.jtho.2021.05.006

Cited by 86 publications

(131 citation statements)

References 53 publications

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“…In addition, phase II and III trials have shown that apatinib plus gefitinib as first-line therapy resulted in superior PFS to placebo plus gefitinib in advanced EGFR-mutant NSCLC. Combination therapy resulted in more adverse events but did not interfere with the quality of life of patients (39,42).…”

Section: Lung Cancermentioning

confidence: 91%

Efficacy and Response Biomarkers of Apatinib in the Treatment of Malignancies in China: A Review

2021

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Apatinib is a multitarget tyrosine kinase inhibitor marketed in China for the treatment of advanced gastric cancer (GC) and hepatocellular carcinoma (HCC). It has also been used off-label for the treatment of many other malignancies. To comprehensively evaluate the efficacy of apatinib as a targeted therapy in the treatment of malignancies, we conducted systematic online and manual searches of the literature on apatinib in the treatment of malignancies. In this review, we first summarized the efficacy of apatinib against various malignancies based on clinical trials where results have been reported. In prospectively registered trials, apatinib has been proven to be effective against GC, HCC, lung cancer, breast cancer, sarcoma, esophageal cancer, colorectal cancer, ovarian cancer, cervical cancer, cholangiocarcinoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, and differentiated thyroid cancer. The response biomarkers for apatinib were also reviewed. This review will serve as a good reference for the application of apatinib in clinical studies and the design of clinical trials.

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Section: Lung Cancermentioning

confidence: 91%

Efficacy and Response Biomarkers of Apatinib in the Treatment of Malignancies in China: A Review

2021

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“…Several studies demonstrated that apatinib plus EGFR-TKIs (gefitinib) exhibited a tolerable safety profile and encouraging antitumor activity for advanced EGFRmutant NSCLC [52][53][54]. Thus, the efficacy of apatinib in EGFR-mutant NSCLC might be related with the inactivation of STAT3.…”

Section: Discussionmentioning

confidence: 99%

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Xie

Zhou

Liang

et al. 2021

J Exp Clin Cancer Res

114

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Background Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear. Methods MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors. Results We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo. Conclusion Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling.

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“…However, the above-mentioned studies were conducted without knowing EGFR mutation status. For patients with EGFR mutation, multiple studies had demonstrated that antiangiogenic agents plus EGFR-TKIs significantly improved PFS compared with EGFR-TKIs alone ( 80 – 84 ). Were similar results obtained in EGFR-mutated patients with TP53 concurrent mutations?…”

Section: Clinical Implications In Advanced Egfr-mutated Nsclc Patient...mentioning

confidence: 99%

TP53 Co-Mutations in Advanced EGFR-Mutated Non–Small Cell Lung Cancer: Prognosis and Therapeutic Strategy for Cancer Therapy

Liu

Zhang

et al. 2022

Front. Oncol.

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Lung cancer is the leading cause of cancer-related deaths worldwide. As the most prevalent molecular mutation subtypes in non-small cell lung cancer (NSCLC), EGFR-TKIs are currently a standard first-line therapy for targeting the mutated EGFR in advanced NSCLC patients. However, 20-30% of this subset of patients shows primary resistance to EGFR-TKIs. Patients with co-mutations of EGFR and several other genes have a poor response to EGFR-TKIs, whereas the prognostic and predictive significance of EGFR/TP53 co-mutation in NSCLC patients remains controversial. Meanwhile, little is known about how to choose an optimal therapeutic strategy for this subset of patients. Presently, no drugs targeting TP53 mutations are available on the market, and some p53 protein activators are in the early stage of clinical trials. A combination of EGFR-TKIs with antiangiogenic agents or chemotherapy or other agents might be a more appropriate strategy to tackle the problem. In this review, we describe the prognostic and predictive value of EGFR/TP53 co-mutation in NSCLC patients, investigate the mechanisms of this co-mutation affecting the response to EGFR-TKIs, and further explore optimal regimens effectively to prolong the survival time of the NSCLC patients harboring this co-mutation.

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Apatinib Plus Gefitinib as First-Line Treatment in Advanced EGFR-Mutant NSCLC: The Phase III ACTIVE Study (CTONG1706)

Abstract: are two individuals with the same name.

Cited by 86 publications

References 53 publications

Efficacy and Response Biomarkers of Apatinib in the Treatment of Malignancies in China: A Review

Efficacy and Response Biomarkers of Apatinib in the Treatment of Malignancies in China: A Review

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

TP53 Co-Mutations in Advanced EGFR-Mutated Non–Small Cell Lung Cancer: Prognosis and Therapeutic Strategy for Cancer Therapy

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