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ORIGINAL ARTICLE
Year : 2020  |  Volume : 57  |  Issue : 1  |  Page : 13-17
 

Efficacy and safety of apatinib monotherapy in elderly patients with advanced metastatic non-small cell lung cancer


1 Department of Cardiothoracic Surgery, Huanggang Central Hospital, Huanggang, Hubei, China
2 Department of Oncology, The First People's Hospital of Jingzhou, Jingzhou, China

Date of Submission16-Sep-2018
Date of Decision27-Feb-2019
Date of Acceptance25-Apr-2019
Date of Web Publication26-Feb-2020

Correspondence Address:
Hongtao Li
Department of Oncology, The First People's Hospital of Jingzhou, Jingzhou
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_614_18

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 » Abstract 


Objective: No effective and definitive chemotherapeutic regimen has been established in patients with non-small cell lung cancer (NSCLC) who failed second-line treatment. The aim of this study was to evaluate apatinib, a VEGFR-2 inhibitor, as monotherapy in elderly patients with advanced metastatic NSCLC.
Methods: We evaluated the efficacy and safety of apatinib in elderly patients (≥65 years old) with advanced metastatic NSCLC who failed second-line treatment from 2015 to 2016 in Huanggang Central Hospital. Survival analysis was performed by the Kaplan–Meier method. Toxicities were evaluated according to the National Cancer Institute Common Toxicity Criteria version 4.0.
Results: Twenty patients were included in the present study. Two patients achieved partial response, and 9 achieved stable disease, representing a response rate of 10% and a disease control rate of 55%. Median progression-free survival and overall survival were 2.8 and 6.0 months, respectively. The toxicities associated with apatinib were generally acceptable with a total grade 3/4 toxicity of 50%.
Conclusion: Apatinib is an optional choice as salvage treatment in elderly patients with advanced metastatic NSCLC, with modest efficacy and acceptable toxicities.


Keywords: Antiangiogenic agents, apatinib, elderly patients, non-small cell lung cancer, targeted therapy


How to cite this article:
Li J, Tong X, Li H. Efficacy and safety of apatinib monotherapy in elderly patients with advanced metastatic non-small cell lung cancer. Indian J Cancer 2020;57:13-7

How to cite this URL:
Li J, Tong X, Li H. Efficacy and safety of apatinib monotherapy in elderly patients with advanced metastatic non-small cell lung cancer. Indian J Cancer [serial online] 2020 [cited 2020 Apr 1];57:13-7. Available from: http://www.indianjcancer.com/text.asp?2020/57/1/13/279176

Jian Li and Xiwen Tong contributed equally to the study.





 » Introduction Top


Lung cancer is one of the leading causes of cancer-related death worldwide.[1] For patients with advanced or metastatic non-small cell lung cancer (NSCLC), chemotherapy in patients without treatable genetic mutations or targeted therapy in patients with corresponding genetic mutations is regarded as the standard treatment, resulting in prolonged survival. However, the overall survival (OS) of advanced or metastatic NSCLC is still gloomy, as most patients progressed after standard systemic therapy.[2] Exploring effective treatments for NSCLC patient who fail standard therapy is imperative.

Angiogenesis is one of the hallmarks of cancer, rendering anti-angiogenesis treatment an attractive and reasonable approach to eradicate cancer.[3] Although bevacizumab, which is a recombinant monoclonal antibody targeting vascular endothelial growth factor (VEGF), and ramucirumab, which is a recombinant monoclonal antibody targeting vascular endothelial growth factor receptor 2 (VEGFR2), were approved by FDA in suitable NSCLC patients, the benefits of these anti-angiogenesis treatments in NSCLC are dismal, warranting alternative anti-angiogenesis approaches.[4]

Apatinib is a small molecule tyrosine kinase inhibitor (TKI) that selectively binds to VEGFR2, inhibiting VEGF-mediated endothelial cell migration, proliferation and tumor microvascular density. Both in vitro and in vivo studies suggest that apatinib may serve as a powerful anti-tumor agent.[5] Phase III clinical trial in patients with chemotherapy-refractory advanced or metastatic gastric cancer demonstrated that apatinib treatment significantly improved OS and progression free survival (PFS), and apatinib has been approved as a third or later-line therapy for advanced or metastatic gastric cancer in China since 2014.[6] Although a few studies have investigated the efficacy and safety of apatinib in NSCLC, showing promising results,[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19] its role in elderly patients remains unclear.

In this study, we focused on elderly NSCLC patients, and explored the efficacy and safety of apatinib as monotherapy when patients had failed two lines of systemic therapy.


 » Patients and Methods Top


Patient eligibility

Since 2015, apatinib was available for the patients in our hospital; some patients with NSCLC were treated with apatinib when their disease progressed after standard chemotherapy or targeted therapy. Patients with advanced or metastatic NSCLC between 2015 and 2016 were screened for this retrospective study. Included patients met the following criteria: Age ≥65 years; histologically or cytologically confirmed adenocarcinoma or squamous NSCLC; stage IV; disease progression after two lines of chemotherapy or targeted therapy. The study was approved by the institutional review board of Huanggang Central Hospital.

Treatment methods

Apatinib was administered at a dose of 500 mg once daily. One treatment cycle was defined as 28 days. Dose reduction to 250 mg for drug-related toxicity or treatment interruption less than 14 days was allowed.

Responses and toxicity

Tumor responses were assessed every two cycles until disease progression, or were evaluated early when progression was suspected. Objective tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Objective tumor responses included complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The disease control rate (DCR) was defined as the addition of objective response and stabilization rates (CR + PR + SD). Toxicities were evaluated according to the National Cancer Institute Common Toxicity Criteria version 4.0 (CTC4.0).

Follow-up

All the patients were followed-up for the assessment of PFS and OS. PFS was defined as the time from the first day of apatinib treatment to documented progression or death from any cause. OS was defined as the time from the first day of apatinib treatment to death or last follow-up. The last follow-up was December 30, 2017.

Statistical analysis

Survival analysis was conducted using the Kaplan–Meier analysis and comparison by the log-rank test. The survival curves were calculated according to the Kaplan–Meier method. Statistical analysis was performed using SPSS version 19.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 was regarded as statistically significant.


 » Results Top


Patient characteristics

A total of 20 patients were included in this retrospective study [Table 1], 12 patients were female and 8 were male, with a median age of 67.5 years. Six patients had smoking history and 14 were never-smokers. Ten patients had ECOG performance status (PS) of 1 and 10 had PS of 2. 13 patients had adenocarcinoma and 7 had squamous cell carcinoma. Among patients with adenocarcinoma, 6 patients had EGFR mutation.
Table 1: Clinical characteristics of the study population (n=20)

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Treatment before apatinib monotherapy

For adenocarcinoma with EGFR sensitizing mutation, patients were routinely treated with gefitinib as first-line treatment, and then pemetrexate with cisplatin or carboplation (PP) as second-line treatment. For adenocarcinoma without EGFR sensitizing mutation, patients were treated with PP as first-line treatment, and then docetaxel as second-line treatment. For squamous cell carcinoma, patients were routinely treated with gemcitabine and cisplatin (GP), and then docetaxel as second-line treatment.

Clinical efficacy

After apatinib monotherapy, no patients achieved CR, 2 patients had PR (10%), 9 patients had SD (45%), and 9 patients had PR (45%). The ORR and DCR were 10% and 55%, respectively.

At the time of the last follow-up, all patients had died. The median PFS was 2.8 months (95%CI, 1.7-3.9; [Figure 1]). The median OS was 6 months (95%CI, 3.8-8.2; [Figure 2]). There was no significant association of PFS and OS with gender, PS, smoking history and histology [Table 2].
Figure 1: Kaplan–Meier estimates of progression-free survival of apatinib treatment

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Figure 2: Kaplan–Meier estimates of overall survival of apatinib treatment

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Table 2: Univariate analysis of PFS and OS

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Toxicities

All patients were assessed for toxicities [Table 3]. The rate of grade 3/4 toxicities was 50%, grade 5 toxicities were not observed. The most common grade 3/4 toxicities are nonhematologic, including hypertension, proteinuria and hand-foot syndrome. There were no patients who experienced grade 3/4 hematologic toxicities. Four patients discontinued apatinib and 6 patients took reduced dose of apatinib (250 mg) because of severe toxicities.
Table 3: The main toxicities of apatinib in advanced metastatic NSCLC patients (n=20)

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 » Discussion Top


As the population ages, the number of elderly patients with NSCLC increases. For elderly patients, the possibility of comorbidities increases, which renders these patients inappropriate for more aggressive treatments, especially when they experience progression after first and second line treatments. Less toxic and more convenient drugs are needed in this set of patients. In this study, apatinib monotherapy was used in elderly patients with advanced metastatic NSCLC to assess the efficacy and safety of apatinib. To our best knowledge, this is the first study to investigate the efficacy and safety of apatinib exclusively in elderly NSCLC patients.

Apatinib is a novel small-molecule oral agent that strongly and selectively inhibits VEGFR-2 activation.[5] With the hopeful results of apatinib in the treatment of gastric cancer in a phase III trial, the potential benefits of apatinib were widely investigated in many other solid tumors, including NSCLC.[20] In this study, we investigated the potential role of apatinib in NSCLC patients aged no less than 65 years. In this group of patients with PS of 1-2, most of the patients refused further intravenous chemotherapy after disease progression, and preferred oral anti-cancer drugs. Thus, apatinib was suggested when patients completely understood the potential benefits and toxicities of it. The ORR and DCR were 10% and 55%, respectively, and the median PFS and OS were 2.8 months and 6.0 months, respectively. 10 (50%) patients experienced grade 3/4 toxicities, and no patients experienced grade 5 toxicities. Hypertension and proteinuria were the most common toxicities, and no grade 3/4 bleeding was observed.

Two phase II trials were conducted to determine the efficacy and safety of apatinib in previously heavily treated advanced non-squamous NSCLC.[17],[19] Zhang et al. applied daily apatinib of 750 mg, showing a PFS of 4.7 months, ORR of 20% and DCR of 68.9%;[19] while Wu et al. administrated daily apatinib of 500 mg in most of patients, showing a PFS of 3.06 months, ORR of 13.2% and DCR of 63.2%.[17] Both studies suggested that apatinib could be a choice as salvage therapy in previously treated patients with non-squamous NSCLC with acceptable toxicity.

Many retrospective studies have also investigated the efficacy and safety of apatinib in previously treated advanced NSCLC.[11],[12],[13],[16],[18] Most of these studies administrated apatinib of 500 mg as standard dose. The reported ORR and DCR ranged from 5.88% to 26% and 61.76% to 93%, respectively. The reported PFS and OS ranged from 3 to 5.2 months and 6 to 8.2 months, respectively. A recent retrospective study analyzed the efficacy and safety of apatinib in 34 patients with advanced NSCLC after the failure of chemotherapy or targeted therapy.[16] The median PFS was 4 months, and the ORR and DCR were 5.88% and 61.76%, respectively. As only 250 mg daily dose of apatinib was used no grade 3/4 adverse effects were observed.

In conclusion, apatinib is an optional choice as salvage treatment in elderly patients with advanced metastatic NSCLC, with modest efficacy and acceptable toxicities. However, more effective treatment approaches are urgently needed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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3.
Sitohy B, Nagy JA, Dvorak HF. Anti-VEGF/VEGFR therapy for cancer: Reassessing the target. Cancer Res 2012;72:1909-14.  Back to cited text no. 3
    
4.
Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, et al. Non-small cell lung cancer, version 5.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2017;15:504-35.  Back to cited text no. 4
    
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6.
Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol 2016;34:1448-54.  Back to cited text no. 6
    
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Ding L, Li QJ, You KY, Jiang ZM, Yao HR. The use of apatinib in treating nonsmall-cell lung cancer: Case report and review of literature. Medicine (Baltimore) 2016;95:e3598.  Back to cited text no. 7
    
8.
Fang S, Zhang M, Wei G, Lu KH. Apatinib as a third- or further- line treatment in patients with advanced NSCLC harboring wild-type EGFR. Oncotarget 2018;9:7175-81.  Back to cited text no. 8
    
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Fang SC, Zhang HT, Zhang YM, Xie WP. Apatinib as post second-line therapy in EGFR wild-type and ALK-negative advanced lung adenocarcinoma. Onco Targets Ther 2017;10:447-52.  Back to cited text no. 9
    
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Peng Y, Cui H, Liu Z, Liu D, Liu F, Song Y, et al. Apatinib to combat EGFR-TKI resistance in an advanced non-small cell lung cancer patient with unknown EGFR status: A case report. Onco Targets Ther 2017;10:2289-95.  Back to cited text no. 10
    
11.
Song Z, Yu X, Lou G, Shi X, Zhang Y. Salvage treatment with apatinib for advanced non-small-cell lung cancer. Onco Targets Ther 2017;10:1821-5.  Back to cited text no. 11
    
12.
Wu D, Liang L, Nie L, Nie J, Dai L, Hu W, et al. Efficacy, safety and predictive indicators of apatinib after multilines treatment in advanced nonsquamous nonsmall cell lung cancer: Apatinib treatment in nonsquamous NSCLC. Asia Pac J Clin Oncol 2018;14:446-52.  Back to cited text no. 12
    
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Xu J, Liu X, Yang S, Zhang X, Shi Y. Clinical response to apatinib monotherapy in advanced non-small cell lung cancer. Asia Pac J Clin Oncol 2018;14:264-9.  Back to cited text no. 13
    
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Zeng DX, Wang CG, Huang JA, Jiang JH. Apatinib in the treatment of advanced lung adenocarcinoma with KRAS mutation. Onco Targets Ther 2017;10:4269-72.  Back to cited text no. 14
    
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Zeng DX, Wang CG, Lei W, Huang JA, Jiang JH. Efficiency of low dosage apatinib in post- first-line treatment of advanced lung adenocarcinoma. Oncotarget 2017;8:66248-53.  Back to cited text no. 15
    
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Liu Z, Ou W, Li N, Wang SY. Apatinib monotherapy for advanced non-small cell lung cancer after the failure of chemotherapy or other targeted therapy. Thorac Cancer 2018;9:1285-90.  Back to cited text no. 16
    
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Wu F, Zhang S, Xiong A, Gao G, Li W, Cai W, et al. A phase II clinical trial of apatinib in pretreated advanced non-squamous non-small-cell lung cancer. Clin Lung Cancer 2018;19:e831-42.  Back to cited text no. 17
    
18.
Li X, Le L, Han L, Zhang Y, Sun S. Short-term efficacy and safety of apatinib in advanced squamous cell carcinoma of the lung. Indian J Cancer 2017;54:547-9.  Back to cited text no. 18
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Zhang L, Shi M, Huang C, Liu X, Xiong JP, 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 (Suppl 15).  Back to cited text no. 19
    
20.
Scott AJ, Messersmith WA, Jimeno A. Apatinib: A promising oral antiangiogenic agent in the treatment of multiple solid tumors. Drugs Today (Barc) 2015;51:223-9.  Back to cited text no. 20
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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