Efficacy and safety of apatinib as second or later-line therapy in extensive-stage small cell lung cancer: a prospective, exploratory, single-arm, multi-center clinical trial

Abstract

Background: A paucity of strategies exist for extensive-stage small cell lung cancer (ES-SCLC) patients who fail the first-line chemotherapy. Apatinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), which has been demonstrated to have active antitumor activity in ES-SCLC when used only or combined with PD-1 inhibitors or chemotherapy with good tolerance. However, the efficacy and safety of apatinib monotherapy is unclear in second-line or beyond treatment of ES-SCLC.Methods: In this prospective, exploratory, single-arm, multi-center study, eligible patients were aged 18 years or older with histologically confirmed ES-SCLC, and had progressed on, or were intolerant to previous systemic treatment. Patients received apatinib 500 mg (orally qd, every 4 weeks a cycle). The efficacy was assessed after 1 cycle and then every 2 cycles based on computed tomography imaging per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). The primary endpoint was progressionfree survival (PFS). The adverse events (AEs) were assessed per the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0 (NCI-CTCAE 4.0). This study is registered in the Chinese Clinical Trial Registry, number ChiCTR-OPC-17013964.Results: From 28 July 2017 to 21 June 2019, 62 patients were screened for eligibility, among whom 57 patients were available for efficacy and safety analysis. The objective response rate (ORR) was 14.3% and disease control rate (DCR) was 79.6%. The median PFS was 5.6 months [95% confidence interval (CI): 3.3-8.0 months] and the median overall survival (OS) was 11.2 months (95% CI: 7.5-24.0 months). Among the participants who received apatinib as second-line treatment, the median PFS and OS were 6.1 months (95% CI: 2.6-7.6 months) and 12.0 months (95% CI: 7.9 months to not reached), respectively. The most common AEs of all grades were anemia (36.8%), hypertension (33.3%), fatigue (31.6%), blood bilirubin increased (22.8%), elevated transaminase (19.3%), and hand-foot syndrome (17.54%). Grade 3 AEs included 2 (3.5%) cases of hypertension and 1 (1.8%) case of fatigue. No grade 4/5 AEs were observed.Conclusions: Apatinib showed encouraging anti-tumor activity in pretreated ES-SCLC patients with tolerable toxicities. Further larger scale studies are warranted to demonstrate the efficacy of apatinib.

Efficacy and safety of apatinib in patients with recurrent uterine malignancy: a prospective, single-center, single-arm, phase 2 study

“…The overall toxicity profile reported in this study was consistent with that of previous studies on apatinib (28,(30)(31)(32), and no new safety signals were identified. The severity of most TRAEs were mild to moderate, and relatively few (2/33, 6.1%) patients discontinued treatment because of these events.…”

“…Apatinib (also known as rivoceranib) is a small-molecule tyrosine kinase inhibitor (TKI) that targets the adenosine triphosphate binding site in VEGFR-2 cells, has a high binding affinity and inhibits VEGFR-2, which may decrease the tumor micro-vessel density and thus slow down or even stop tumor development (28,29). Recent studies have shown that apatinib has a promising clinical efficacy and a manageable safety profile in the treatment of patients with untreated or chemotherapy-refractory soft tissue sarcoma, advanced non-small cell lung cancer, or recurrent/advanced gynecological cancers, including cervical and ovarian cancer (28,(30)(31)(32). Currently, anlotinib (a multi-kinase angiogenesis inhibitor) has been approved for soft-tissue sarcoma in China (33,34), which suggests that angiogenesis inhibitors might have good efficacy in the treatment of US.…”

The inhibitory effect of apatinib on different small cell lung cancer cells and in lung cancer‐bearing mice and patients

“…In these 20 patients with SCLC, ORR and DCR were 5% and 85%, and the PFS and OS are 3.3 and 5.6 months. Among the near‐term efficacy ORR and DCR were similar to the results reported in the literature, but the results of long‐term prognostic indicators PFS and OS were lower than the results reported in the literature, which was related to the inclusion of the patients in poorer physical condition and higher PS scores related 29 . Studies have confirmed that apatinib can not only inhibit tumor growth by blocking neovascularization but also directly act on SCLC cells with high expression of VEGFR2, and inhibit tumor growth by promoting apoptosis and inducing cell cycle arrest.…”

“…Among the near‐term efficacy ORR and DCR were similar to the results reported in the literature, but the results of long‐term prognostic indicators PFS and OS were lower than the results reported in the literature, which was related to the inclusion of the patients in poorer physical condition and higher PS scores related. 29 Studies have confirmed that apatinib can not only inhibit tumor growth by blocking neovascularization but also directly act on SCLC cells with high expression of VEGFR2, and inhibit tumor growth by promoting apoptosis and inducing cell cycle arrest. Future clinical studies can further expand the sample size and conduct randomized controlled studies to further confirm the efficacy and safety of apatinib in patients with SCLC.…”

Combination of Arsenic trioxide and Apatinib Synergistically Inhibits Small Cell Lung Cancer by Down-Regulating VEGFR2/mTOR and Akt/c-Myc Signaling Pathway via GRB10

“…The in-vivo assessments have been made using xenograft mouse models with acknowledgement of the limitations of mouse models in SCLC. It has previously been shown that ATO [18][19][20] and APA [21,22], independently, inhibit angiogenic activity in cancer stem cells (CSCs) of SCLC. While ATO mediates its action by down regulating stem-cell maintenance factors [18]; APA inhibits vascular endothelial growth factor receptor-2 (VEGFR2) [13].…”