Top

Cancer Chemotherapy and Pharmacology

Published in:

01-08-2014 | Original Article

Hypothyroidism as a potential biomarker of efficacy of famitinib, a novel VEGFR-2 inhibitor in metastatic breast cancer

Authors: Jun Cao, Jian Zhang, Zhonghua Wang, Biyun Wang, Fangfang Lv, Leiping Wang, Xichun Hu

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2014

Abstract

Purpose

Hypothyroidism is a common adverse event in patients treated with anti-VEGFR-2 targeting agents and may be a valuable predictive factor of efficacy. Famitinib is an inhibitor of multiple tyrosine kinases mainly targeting VEGFR-2. The objectives of this study were to assess the efficacy and safety of famitinib in patients with pretreated HER2-negative metastatic breast cancer (MBC) and to explore potential of famitinib-induced hypothyroidism and serum vascular endothelial growth factor (VEGF) level for efficacy prediction.

Materials and methods

The primary end point was objective response rate (ORR). Famitinib was administered 25 mg/d. Thyroid function assessments were done at baseline and then every 4 weeks. Plasma levels of VEGF were determined at baseline and 2 cycles after treatment.

Results

A total of 28 patients were enrolled. ORR was 14.3 %. The most common grade 3/4 AEs were hand–foot syndrome (25.0 %), proteinuria (21.4 %) and hypertension (17.9 %). 64.0 % patients were observed with elevated thyroid-stimulating hormone (TSH) (>4.94 mIU/L) at any time during the entire treatment period. Sixteen patients with an elevated TSH had a significantly longer PFS than nine patients with no TSH elevation (107 vs. 53 days, respectively, P = 0.002). TSH elevation was also an independent predictor of PFS in a Cox regression model. Plasma VEGF levels did not correlate significantly with clinical outcomes.

Conclusions

Famitinib did show substantial anti-tumor activities with a good safety profile in heavily pretreated patients with HER2-negative MBC. Famitinib-related TSH increase may be an early indicator of its efficacy. Serial monitoring of serum TSH may help define VEGFR-2-dependent or VEGFR-2-independent drug resistance.

Banerjee S, Dowsett M, Ashworth A, Martin LA (2007) Mechanisms of disease: angiogenesis and the management of breast cancer. Nat Clin Pract Oncol 4(9):536–550PubMedCrossRef

Ferrara N (2004) Vascular endothelial growth factor basic science and clinical progress. Endocr Rev 25(4):581–611PubMedCrossRef

Seymour L, Dajee D, Bezwoda WR (1993) Tissue platelet derived-growth factor (PDGF) predicts for shortened survival and treatment failure in advanced breast cancer. Breast Cancer Res Treat 26(3):247–252PubMedCrossRef

Hines SJ, Organ C, Kornstein MJ, Krystal GW (1995) Coexpression of the c-kit and stem cell factor genes in breast carcinomas. Cell Growth Differ 6(6):769–779PubMed

Miles DW, Chan A, Dirix LY et al (2010) Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28(20):3239–3247PubMedCrossRef

Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–2676PubMedCrossRef

Robert NJ, Diéras V, Glaspy J et al (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor r 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29(10):1252–1260PubMedCrossRef

Brufsky AM, Hurvitz S, Perez E et al (2011) RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 29(32):4286–4293PubMedCrossRef

Miles DW, de Haas SL, Dirix LY et al (2013) Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J Cancer 108(5):1052–1060PubMedCentralPubMedCrossRef

10.

Van Cutsem E, de Haas S, Kang YK et al (2012) Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol 30(17):2119–2127PubMedCrossRef

11.

Mendel DB, Laird AD, Xin X et al (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascularendothelial growth factor and platelet-derived growth factor receptors: determination of apharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9(1):327–337PubMed

12.

Wilhelm S, Carter C, Lynch M et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 5(10):835–844PubMedCrossRef

13.

Bianchi G, Loibl S, Zamagni C et al (2009) Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs 20(7):616–624PubMedCrossRef

14.

Moreno-Aspitia A, Morton RF, Hillman DW et al (2009) Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336. J Clin Oncol 27(1):11–15PubMedCentralPubMedCrossRef

15.

Burstein HJ, Elias AD, Rugo HS et al (2008) Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 26(11):1810–1816PubMedCrossRef

16.

Crown JP, Diéras V, Staroslawska E et al (2013) Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol 31(23):2870–2878PubMedCrossRef

17.

Zhu AX, Sahani DV, Duda DG et al (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 27(18):3027–3035

18.

Hanrahan EO, Ryan AJ, Mann H et al (2009) Baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from vandetanib in non-small cell lung cancer. Clin Cancer Res 15(10):3600–3609

19.

Murukesh N, Dive C, Jayson GC (2010) Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer 102(1):8–18PubMedCentralPubMedCrossRef

20.

Deprimo SE, Bello CL, Smeraglia J et al (2007) Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 5:32PubMedCentralPubMedCrossRef

21.

Beuselinck B, Karadimou A, Lambrechts D et al (2013) Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib. Br J Cancer 108(4):887–900PubMedCentralPubMedCrossRef

22.

Schneider BP, Wang M, Radovich M et al (2008) Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26(28):4672–4678PubMedCentralPubMedCrossRef

23.

Cameron D, Brown J, Dent R et al (2013) Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol. 4(10):933–942CrossRef

24.

Van Cutsem E, Jayson G, Dive C et al (2011) Analysis of blood plasma factors in the AVITA phase III randomized study of bevacizumab (bev) with gemcitabine-erlotinib (GE) in patients (pts) with metastatic pancreatic cancer (mPC) European Multidisciplinary Cancer Congress, 23–27 September 2011Stockholm, Sweden; (abstract 803)

25.

Fan M, Zhang J, Wang Z et al (2014) Phosphorylated VEGFR-2 and hypertension: potential biomarkers to indicate VEGF-dependency of advanced breast cancer in anti-angiogenic therapy. Breast Cancer Res Treat 143(1):141–151

26.

Rini BI, Schiller JH, Fruehauf JP et al (2011) Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res 17(11):3841–3849PubMedCrossRef

27.

Rini BI, Cohen DP, Lu DR et al (2011) Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 103(9):763–773PubMedCentralPubMedCrossRef

28.

Schmidinger M, Vogl UM, Bojic M et al (2011) Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 117(3):534–544PubMedCrossRef

29.

Riesenbeck LM, Bierer S, Hoffmeister I et al (2011) Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib. World J Urol 29(6):807–813PubMedCrossRef

30.

Baldazzi V, Tassi R, Lapini A, Santomaggio C, Carini M, Mazzanti R (2012) The impact of sunitinib-induced hypothyroidism on progression-free survival of metastatic renal cancer patients: a prospective single-center study. Urol Oncol. 30(5):704–710PubMedCrossRef

31.

Zhou A, Zhang W, Chang C et al (2013) Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib. Cancer Chemother Pharmacol 72(5):1043–1053PubMedCrossRef

32.

Ross DS (2001) Serum thyroid-stimulating hormone measurement for assessment of thyroid function and disease. Endocrinol Metab Clin North Am 30(2): 245–264, vii

33.

Llovet JM, Ricci S, Mazzaferro V, SHARP Investigators Study Group et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390PubMedCrossRef

34.

Escudier B, Eisen T, Stadler WM, TARGET Study Group et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134PubMedCrossRef

35.

Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345PubMedCrossRef

36.

Lenz HJ, Van Cutsem E, Khambata-Ford S et al (2006) Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24(30):4914–4921PubMedCrossRef

37.

Douillard J, Cassidy J, Jassem J et al (2010) Randomized, open-label, phase III study of panitumumab with FOLFOX4 versus FOLFOX4 alone as first-line treatment for metastatic colorectal cancer: efficacy by skin toxicity. J Clin Oncol 28(15 suppl):Abstract 3528

38.

Price TJ, Sobrero AF, Wilson G et al (2010) Randomized, open-label, phase III study of panitumumab with FOLFIRI versus FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer: Efficacy by skin toxicity. J Clin Oncol 28(15 suppl): Abstract 3529

39.

Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL (2004) Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin 22(1):77–85CrossRef

40.

Bonner JA, Harari PM, Giralt J et al (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11(1):21–28PubMedCrossRef

41.

Pérez-Soler R, Chachoua A, Hammond LA et al (2004) Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 22(16):3238–3247PubMedCrossRef

42.

Rini BI, Tamaskar I, Shaheen P et al (2007) Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 99(1):81–83PubMedCrossRef

43.

Tamaskar I, Bukowski R, Elson P et al (2008) Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol 19(2):265–268PubMedCrossRef

44.

Shinohara N, Takahashi M, Kamishima T et al (2011) The incidence and mechanism of sunitinib-induced thyroid atrophy in patients with metastatic renal cell carcinoma. Br J Cancer 104(2):241–247PubMedCentralPubMedCrossRef

45.

Wolter P, Stefan C, Decallonne B et al (2008) The clinical implications of sunitinib-induced hypothyroidism:a prospective evaluation. Br J Cancer 99(3):448–454PubMedCentralPubMedCrossRef

46.

Makita N, Iiri T (2013) Tyrosine kinase inhibitor-induced thyroid disorders: a review and hypothesis. Thyroid. 23(2):151–159PubMedCrossRef

47.

Aparicio-Gallego G, Blanco M, Figueroa A et al (2011) New insights into molecular mechanisms of sunitinib-associated side effects. Mol Cancer Ther 10(12):2215–2223PubMedCrossRef

48.

Foekens JA, Peters HA, Grebenchtchikov N et al (2001) High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res 61(14):5407–5414PubMed

49.

Berns EM, Klijn JG, Look MP, Grebenchtchikov N, Vossen R, Peters H, Geurts-Moespot A, Portengen H, van Staveren IL, Meijer-van Gelder ME, Bakker B, Sweep FC, Foekens JA (2003) Combined vascular endothelial growth factor and TP53 status predicts poor response totamoxifen therapy in estrogen receptor-positive advanced breast cancer. Clin Cancer Res 9(4):1253–1258PubMed

50.

Jayson GC, de Haas S, Delmar P et al (2011) Evaluation of plasma VEGFA as a potential predictive pan-tumour biomarker for bevacizumab. European Multidisciplinary Cancer Congress, 23–27 September 2011 Stockholm, Sweden; (abstract 804)

Title: Hypothyroidism as a potential biomarker of efficacy of famitinib, a novel VEGFR-2 inhibitor in metastatic breast cancer
Authors: Jun Cao
Jian Zhang
Zhonghua Wang
Biyun Wang
Fangfang Lv
Leiping Wang
Xichun Hu
Publication date: 01-08-2014
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2014
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2505-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Materials and methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2014

Differential regulation of bladder cancer growth by various glucocorticoids: corticosterone and prednisone inhibit cell invasion without promoting cell proliferation or reducing cisplatin cytotoxicity

Impact of patient ethnicity on the metabolic and immunologic effects of PI3K–mTOR pathway inhibition in patients with solid tumor malignancies

Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates

Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001)

A phase II study of metronomic paclitaxel/cyclophosphamide/capecitabine followed by 5-fluorouracil/epirubicin/cyclophosphamide as preoperative chemotherapy for triple-negative or low hormone receptor expressing/HER2-negative primary breast cancer

Frontline treatment with gemcitabine, oxaliplatin and erlotinib for the treatment of advanced or metastatic pancreatic cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer