Apatinib for the treatment of metastatic or locoregionally recurrent nasopharyngeal carcinoma after failure of chemotherapy: A multicenter, single-arm, prospective phase 2 study

Xiaolan Ruan, Jin-Hui Liang, Yufei Pan, Rui Cai, Rong Jun Zhang, Zhuokai He, Xi Yang, Zhijie Niu, Wei Jiang, Xiaolan Ruan, Jin-Hui Liang, Yufei Pan, Rui Cai, Rong Jun Zhang, Zhuokai He, Xi Yang, Zhijie Niu, Wei Jiang

Abstract

Background: The authors aimed to investigate the efficacy and safety of apatinib in patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma (NPC).

Methods: A multicenter, single-arm, prospective phase 2 study was conducted on patients (18-70 years of age) with metastatic or recurrent NPC who had failed chemotherapy. Patients with recurrent disease involving vascular structure invasion were excluded. All enrolled patients received apatinib (500 mg daily) in continuous 4-week cycles until disease progression or development of unacceptable toxicity. The primary end point of this study was objective response rate (ORR), and the secondary end points were progression-free survival (PFS), overall survival (OS), and toxicity. This study was registered with ClinicalTrials.gov (NCT03130270).

Results: Between January 2017 and June 2018, 33 patients were enrolled. At the end of the data collection (May 20, 2020), the 33 patients had completed a total of 261.2 cycles of apatinib. Although 12 patients achieved a partial response, no patient achieved a complete response; thus, the ORR in the 33 patients was 36.4% (95% CI, 19.0%-53.7%). At the end of follow-up (median, 30 months; 95% CI, 24.9-35.1), median OS and median PFS were 16 months (95% CI, 14.6-17.4 months) and 5.0 months (95% CI, 3.6-6.4 months), respectively. The most common adverse events (grade 1/2) were hand-foot syndrome (18 [54.5%]), hypertension (14 [42.4%]), oral ulcer (8 [24.2%]), and proteinuria (4 [12.1%]). Two patients (1 with diabetes and 1 with hypertension) developed cerebral infarction. Grade 3/4 toxicities were uncommon.

Conclusions: Apatinib shows promising activity, with manageable toxicities, in patients with metastatic or locoregionally recurrent NPC. Further evaluation of apatinib in large-scale studies is warranted.

Lay summary: Clinical studies on vascular endothelial growth factor receptor (VEGFR)-targeted therapy for recurrent or metastatic nasopharyngeal carcinoma (NPC) are limited. A recent preclinical study that evaluated apatinib in models of NPC showed a high objective response rate and a favorable safety profile. Our data further confirmed good efficacy in patients with lung metastasis. Further studies of the efficacy and safety of apatinib combined with immune checkpoint inhibitors or chemotherapy in NPC is warranted.

Keywords: apatinib; locally recurrent; metastasis; nasopharyngeal carcinoma; vascular endothelial growth factor receptor (VEGFR).

© 2021 American Cancer Society.

References

    1. Chua M, Wee J, Hui E, Chan A. Nasopharyngeal carcinoma. Lancet. 2016;387:1012-1024.
    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.
    1. Chen YP, Tang LL, Yang Q, et al. Induction chemotherapy plus concurrent chemoradiotherapy in endemic nasopharyngeal carcinoma: individual patient data pooled analysis of four randomized trials. Clin Cancer Res. 2018;24:1824-1833.
    1. Colevas AD, Yom SS, Pfister DG, et al. NCCN guidelines insights: head and neck cancers, version 1.2018. J Natl Compr Canc Netw. 2018;16:479-490.
    1. Pan JJ, Ng WT, Zong JF, et al. Prognostic nomogram for refining the prognostication of the proposed 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy. Cancer. 2016;122:3307-3315.
    1. Tang X-R, Li Y-Q, Liang S-B, et al. Development and validation of a gene expression-based signature to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma: a retrospective, multicentre, cohort study. Lancet Oncol. 2018;19:382-393.
    1. Jin Y, Shi YX, Cai XY, et al. Comparison of five cisplatin-based regimens frequently used as the first-line protocols in metastatic nasopharyngeal carcinoma. J Cancer Res Clin Oncol. 2012;138:1717-1725.
    1. Zhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet. 2016;388:1883-1892.
    1. Prawira A, Oosting SF, Chen TW, et al. Systemic therapies for recurrent or metastatic nasopharyngeal carcinoma: a systematic review. Br J Cancer. 2017;117:1743-1752.
    1. Chen Y-P, Chan ATC, Le Q-T, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394:64-80.
    1. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002;2:795-803.
    1. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13:871-882.
    1. Jain R. Molecular regulation of vessel maturation. Nat Med. 2003;9:685-693.
    1. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8:579-591.
    1. Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 2016;15:385-403.
    1. Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol. 2007;25:3766-3773.
    1. Hui EP, Ma BBY, King AD, et al. Hemorrhagic complications in a phase 2 study of sunitinib in patients of nasopharyngeal carcinoma who has previously received high-dose radiation. Ann Oncol. 2011;22:1280-1287.
    1. Hui EP, Ma BBY, Loong HHF, et al. Efficacy, safety, and pharmacokinetics of axitinib in nasopharyngeal carcinoma: a preclinical and phase II correlative study. Clin Cancer Res. 2018;24:1030-1037.
    1. Lim WT, Ng QS, Ivy P, et al. A phase II study of pazopanib in Asian patients with recurrent/metastatic nasopharyngeal carcinoma. Clin Cancer Res. 2011;17:5481-5489.
    1. Tian S, Quan H, Xie C, et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci. 2011;102:1374-1380.
    1. Peng Q, Han Y, Zhang Y, et al. In vivo apatinib inhibits VEGFR-2 and angiogenesis in an murine model of nasopharyngeal carcinoma. Oncotarget. 2017;8:52813-52822.
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
    1. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1-10.
    1. Lee AW, Ma BB, Ng WT, Chan AT. Management of nasopharyngeal carcinoma: current practice and future perspective. J Clin Oncol. 2015;33:3356-3364.
    1. Fountzilas G, Fragkoulidi A, Kalogera-Fountzila A, et al. A phase II study of sunitinib in patients with recurrent and/or metastatic non-nasopharyngeal head and neck cancer. Cancer Chemother Pharmacol. 2010;65:649-660.
    1. Zou X, You R, Liu H, et al. Establishment and validation of M1 stage subdivisions for de novo metastatic nasopharyngeal carcinoma to better predict prognosis and guide treatment. Eur J Cancer. 2017;77:117-126.
    1. Gounder M, Mahoney M, Van Tine B, et al. Sorafenib for advanced and refractory desmoid tumors. N Engl J Med. 2018;379:2417-2428.
    1. Gross-Goupil M, Kwon T, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol. 2018;29:2371-2378.
    1. Staehler M, Motzer R, George D, et al. Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial. Ann Oncol. 2018;29:2098-2104.
    1. Yang R, Pedersen N, Bao C, et al. Type 2 diabetes in midlife and risk of cerebrovascular disease in late life: a prospective nested case-control study in a nationwide Swedish twin cohort. Diabetologia. 2019;62:1403-1411.
    1. Li W, Jin C, Vaidya A, et al. Blood pressure trajectories and the risk of intracerebral hemorrhage and cerebral infarction: a prospective study. Hypertension. 2017;70:508-514.
    1. Zechariah A, El Ali A, Hagemann N, et al. Hyperlipidemia attenuates vascular endothelial growth factor-induced angiogenesis, impairs cerebral blood flow, and disturbs stroke recovery via decreased pericyte coverage of brain endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33:1561-1567.
    1. Xue C, Huang Y, Huang P, et al. Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma. Ann Oncol. 2013;24:1055-1061.
    1. Choong NW, Kozloff M, Taber D, et al. Phase II study of sunitinib malate in head and neck squamous cell carcinoma. Invest New Drugs. 2010;28:677-683.
    1. Machiels JP, Henry S, Zanetta S, et al. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01. J Clin Oncol. 2010;28:21-28.
    1. Crane CH, Ellis LM, Abbruzzese JL, et al. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol. 2006;24:1145-1151.
    1. Lordick F, Geinitz H, Theisen J, Sendler A, Sarbia M. Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases. Int J Radiat Oncol Biol Phys. 2006;64:1295-1298.
    1. Peters NA, Richel DJ, Verhoeff JJ, Stalpers LJ. Bowel perforation after radiotherapy in a patient receiving sorafenib. J Clin Oncol. 2008;26:2405-2406.
    1. Zips D, Eicheler W, Geyer P, et al. Enhanced susceptibility of irradiated tumor vessels to vascular endothelial growth factor receptor tyrosine kinase inhibition. Cancer Res. 2005;65:5374-5379.
    1. Je Y, Schutz F, Choueiri T. Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol. 2009;10:967-974.
    1. Li J, Qin S, Xu J, 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;31:3219-3225.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться