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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 159-162

Apatinib for advanced nonsmall-cell lung cancer: A retrospective case series analysis


1 Oncology Department, Lianyungang Affiliated Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, China
2 Graduate Student of Xuzhou Medical University, Lianyungang, Jiangsu, China

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Wen Feng
Obstetrics and Gynecology Department, Lianyungang Affiliated Hospital of Xuzhou Medical University, Lianyungang, Jiangsu
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_258_17

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 > Abstract 

Objectives: Apatinib, a tyrosine kinase inhibitor which selectively inhibits vascular endothelial growth factor receptor-2, has been shown to be beneficial to patients with a variety of cancers, including advanced nonsmall-cell lung cancer (NSCLC). Thus, this study was aimed to retrospectively assess the efficacy and safety of apatinib in patients with advanced/metastatic NSCLC who failed more than two lines of treatment.
Methods: Twenty-three NSCLC patients were involved in this study, who received oral apatinib at a daily dose of 250/500/750 mg, with the progression after the failure of second-line therapy. Treatment was continued until disease progression. The tumor assessments were determined according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Safety was evaluated with adverse reactions and toxicities based on the Common Terminology Criteria for Adverse Events (version 4.0). Response and safety for the included patients were evaluated every 8 weeks.
Results: In this study, 23 NSCLC patients were followed from January 2015 to December 2016. Available image efficacy was obtained in 22 patients, including 4 identified as partial responses, 17 stable disease, and 1 progressive disease; no complete responses was observed. The objective response rate was 18.2%, and the disease control rate was 95.5%. Median progression free survival and overall survival for apatinib were 203 days (95% CI, 120–269) and 227 days (95% CI, 146–294), respectively. The most frequent treatment-related adverse events were hypertension, gastrointestinal reactions, and hand-foot skin reaction.
Conclusion: Apatinib exhibited modest activity and acceptable toxicity for advanced NSCLC after the failure of chemotherapy or other targeted therapy.

Keywords: Advanced nonsmall-cell lung cancer, antiangiogenic agent, apatinib


How to cite this article:
Yang C, Feng W, Wu D. Apatinib for advanced nonsmall-cell lung cancer: A retrospective case series analysis. J Can Res Ther 2018;14:159-62

How to cite this URL:
Yang C, Feng W, Wu D. Apatinib for advanced nonsmall-cell lung cancer: A retrospective case series analysis. J Can Res Ther [serial online] 2018 [cited 2019 Nov 14];14:159-62. Available from: http://www.cancerjournal.net/text.asp?2018/14/1/159/226738


 > Introduction Top


Lung cancer remains the leading cause of cancer death in China.[1] Nonsmall-cell lung cancer (NSCLC) accounted for over 70% of all cases of lung cancer.[2] Antiangiogenesis therapy has been confirmed to make an antitumor effect on advanced/metastatic NSCLC.[3],[4] A number of platinum-based regimens (with or without bevacizumab) have been standard for the first-line therapy. The second-line therapies have included docetaxel (with or without ramucirumab), pemetrexed (nonsquamous only), gemcitabine, and erlotinib. Treatment options were limited for advanced NSCLC patients who failed to respond to two or more conventional chemotherapy regimens.[5]

Apatinib is an oral, small molecular tyrosine kinase inhibitor (TKI), which mainly targeted the intracellular downstream pathways of vascular endothelial growth factor receptor-2 (VEGFR-2) within the cell and also inhibited the receptor tyrosine kinase such as PDGFR, c-Kit, and c-src. On October 17, 2014, apatinib was approved by the China Food and Drug Administration for the application as a single agent in patients with metastatic gastric or gastroesophageal junction adenocarcinoma after second-line chemotherapy.[6] VEGFR-2 was predominantly expressed in endothelial and hematopoietic cells, and it would be overexpressed in the vasculature of many human solid tumors.[7] The Phase II trials of apatinib for advanced NSCLC, hepatocellular carcinoma, breast cancer, and colorectal cancer have been conducted and completed. All of them have shown the substantial clinical activity of apatinib.[8],[9],[10],[11] A Phase II, open-label, single-armed, prospective study (NCT02515435) was performed to investigate the safety of apatinib for heavily treated, advanced nonsquamous NSCLC patients. All patients received apatinib with a dose of 500 mg, qd, po. A Phase III, open-label, single-armed, prospective study (NCT02332512) was also performed to investigate the safety of apatinib for heavily treated, advanced nonsquamous NSCLC patients. All patients received apatinib with a dose of 750 mg, qd, po. Apatinib has been known for its simplicity and compliance, as well as less side effects. Until now, couples of clinical trials investigating the efficacy of apatinib on patients with NSCLC are still ongoing.

Some NSCLC patients with Stage-IIIB and Stage-IV disease did not respond to conventional first-, second-, and third-line therapy. Other ones may be not suitable for chemotherapy due to their age, poor performance status (PS), and/or concurrent conditions. They may have suffered severe adverse reactions from the previous therapies. In addition, many NSCLC patients are not “eligible” for protocols due to their diffusely disseminated “not-measurable” diseases or tumor recidivation in previously resected or irradiated sites. Here, the retrospective series analysis was performed on advanced/metastatic NSCLC patients treated with apatinib after two previous treatment regimens.


 > Methods Top


Patient population

This observational study was approved by the Ethics Committee of the First People's Hospital of Lianyungang (Jiangsu, China). The enrolled patients were ≥18 years with histologically confirmed advanced/metastatic NSCLC (squamous or nonsquamous) and at least two lines of prior systemic therapies had failed. Additional eligibility criteria included as follows: (1) one or more measurable target lesions documented by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1; (2) an Eastern Cooperative Oncology Group PS of 0, 1, or 2; (3) life expectancy of ≥3 months; (4) adequate renal, hematologic, and hepatic functions.

Study drug

Patients received oral apatinib with a daily dose of 250 or 500 or 750 mg, depending on individual tolerance and/or concurrent condition. The cycle was repeated every 4 weeks (28 days) until observed progression or unacceptable toxicity.

Assessments

After the first dose, the variations in tumor size in posttreatment tumor assessments were analyzed by CT or MRI every 8 weeks until documented disease progression. The complete responses (CR), partial responses (PR), stable disease (SD), and progressive disease (PD) were assessed with RECIST version 1.1 criteria.[12]

Adverse events related to apatinib were graded according to Common Terminology Criteria for Adverse Events, version 4.0.[13]

Statistical analysis

Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan–Meier method. Statistical analysis was performed with SAS version 9.3.


 > Results Top


Patients' characteristics

Between January 2015 and December 2016, 23 NSCLC patients were consecutively treated. Hereinto, there were 22 patients available for efficacy and safety evaluation. Baseline patient characteristics were summarized [Table 1].
Table 1: Baseline demographic and clinical characteristics in the patients

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Efficacy

The results of the tumor response analysis were shown [Table 2]. Within 22 patients with available image efficacy, no CR was observed, and 4 were identified as PR, giving an objective response rate (ORR) of 18.2%. SD was observed in 17 patients (77.3%). Therefore, the overall disease control rate (DCR) was 95.5%. Among them, 7 patients had received the treatment of apatinib for more than 6 months.
Table 2: Overall tumor response in the patients

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In 23 patients, the initial dose of 5 patients (21.74%) was 250 mg, 1 was identified as PR, 1 was SD, and 1 was unidentified; the dose of 8 patients (34.78%) was 500 mg, 1 was identified as PR, and 7 was SD; the dose of 10 patients (43.48%) was 750 mg, 2 was identified as PR, 7 was SD, and 1 was PD. There was no significantly different efficacy between groups of different doses.

PFS was defined as the time from the first dose to PD or death. The PFS of the patients ranged from 39 to 497 days, with a median PFS of 203 days (95% CI, 120–269 days) [Figure 1].
Figure 1: Progression free survival

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OS was defined as the time from the first dose to death from any cause. The OS ranged from 87 to 623 days, with a median of 227 days (95% CI, 146–294 days) [Figure 2].
Figure 2: Overall survival

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Toxicity

The most frequent treatment-related adverse events were hypertension (50%, 11/22), gastrointestinal reaction (36.4%, 8/22), and hand-foot skin reaction (22.7%, 5/22) [Table 3]. Main Grade 3 toxicities were hand-foot skin reaction (9.1%, 2/22) and proteinuria (9.1%, 2/22). There were no reported Grade 4 hematological and nonhematological toxicities.
Table 3: Treatment-related adverse events in the patients

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For the 23 patients, the initial dose of 5 patients (21.74%) was 250 mg, the rate of overall adverse events was 60% (3/5), and the major adverse events were hypertension (40%, 2/5); the initial dose of 8 patients (34.78%) was 500 mg, with the rate of overall adverse events of 62.5% (5/8), and the major adverse events were hypertension (37.5%, 3/8); the initial dose of 10 patients (43.48%) was 750 mg, the rate of overall adverse events was 80% (8/10), and the major adverse events were hypertension (60%, 6/10). The rate of overall adverse events in dose group of 750 mg was higher than that of in dose group of 500 or 250 mg.


 > Discussion Top


The VEGF/VEGFR pathway activated a complex cascade of downstream signaling pathways, leading to neovascularization, vasodilation, increased vascular permeability, and migration of bone marrow endothelial cells.[14] VEGF/VEGFR blockade inhibited these pathways and thereby made effects on tumor survival, migration, and invasion. Bevacizumab, a humanization monoclonal antibody, the first FDA approved antiangiogenic agent worked by specifically binding to VEGF and preventing its interaction with VEGFR. For patients with nonsquamous NSCLC and PS 0–1 who were negative for either ALK gene rearrangements or sensitizing EGFR mutations, the combination of bevacizumab and platinum-based chemotherapy was recommended in the NCCN Guidelines. Moreover, ramucirumab was a humanization monoclonal antibody that specifically inhibited VEGFR-2 on the cell membrane. It has been approved by the FDA for application in combination with docetaxel for the treatment of patients with metastatic NSCLC suffering disease progression or after platinum-based chemotherapy. This approval was based on an improvement in OS with an acceptable toxicity profile in the Phase III REVEL study, comprising of 1,253 patients with metastatic NSCLC previously treated with a platinum-based combination therapy.[15] Benefit in terms of OS and PFS could also be obtained in patients with squamous cell histology with the addition of ramucirumab. Therefore, patients with (or without) ALK rearrangements or sensitizing EGFR mutations would be eligible for ramucirumab/docetaxel if they have progressed after receiving the appropriate-targeted therapy.

Apatinib, a small molecular TKI targeting VEGFR-2 within the cell, has been the first generation of oral antiangiogenesis agent invented in China. Acting as the highly selective and intensive inhibitors of VEGFR-2, a high degree of consistency was obtained in the results of two trial on apatinib [6] and ramucirumab [16] for metastatic gastric cancer. Considering the improvement of antiangiogenesis agents in the treatment of advanced/metastatic NSCLC, this study was aimed to assess the efficacy and safety of apatinib in Chinese patients who progressed after second-line therapy. Herein, the cases for the advanced/metastatic NSCLC treated with apatinib in our hospital were analyzed.

Within 22 patients with available image efficacy, the ORR and DCR were18.2% and 95.5%, respectively. Median PFS was 203 days, which was consistent with that of established in the Phase II trial of apatinib.[8] Overall, the safety profile of apatinib appeared to be acceptable relative to the benefits. The most common side effect of apatinib was hypertension, which was as expected in antiangiogenesis therapy.


 > Conclusion Top


This retrospective series confirmed previously reported data on clinical activity of apatinib in advanced NSCLC. Apatinib may be an option for advanced NSCLC after the failure of chemotherapy or other targeted therapy. The efficacy of apatinib has being evaluated with an ongoing Phase III study, which compared apatinib monotherapy with placebo as 3rd/4th setting in advanced nonsquamous NSCLC (NCT02332512).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Langer CJ, Mok T, Postmus PE. Targeted agents in the third-/fourth-line treatment of patients with advanced (stage III/IV) non-small cell lung cancer (NSCLC). Cancer Treat Rev 2013;39:252-60.  Back to cited text no. 5
    
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Smith NR, Baker D, James NH, Ratcliffe K, Jenkins M, Ashton SE,et al. Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarily to the vasculature in human primary solid cancers. Clin Cancer Res 2010;16:3548-61.  Back to cited text no. 7
    
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Zhang L, Shi M, Huang C, Liu X, Xiong J, Chen G,et al. A phase II, multicenter, placebo-controlled trial of apatinib in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after two previous treatment regimens. J Clin Oncol 2012;30:7548.  Back to cited text no. 8
    
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Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol 2013;31:3219.  Back to cited text no. 9
    
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Hu X, Cao J, Hu W, Wu C, Pan Y, Cai L,et al. Multicenter phase II study of apatinib in non-triple-negative metastatic breast cancer. BMC Cancer 2014;14:820.  Back to cited text no. 10
    
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Watanabe H, Okada M, Kaji Y, Satouchi M, Sato Y, Yamabe Y,et al. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Gan To Kagaku Ryoho 2009;36:2495-501.  Back to cited text no. 12
    
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Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Available from: http://www.evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. [Last accessed on 2016 Jan 01; Last updated on 2015 Apr 02].  Back to cited text no. 13
    
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Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: Therapeutic perspective. Clin Cancer Res 2006;12:5018-22.  Back to cited text no. 14
    
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Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T,et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): A multicentre, double-blind, randomised phase 3 trial. Lancet 2014;384:665-73.  Back to cited text no. 15
    
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Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C,et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014;383:31-9.  Back to cited text no. 16
    


    Figures

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