Cytokine and angiogenic factors associated with efficacy and toxicity of pazopanib in advanced soft-tissue sarcoma: an EORTC-STBSG study

S Sleijfer, T Gorlia, C Lamers, H Burger, J-Y Blay, A Le Cesne, M Scurr, F Collin, L Pandite, S Marreaud, P Hohenberger, S Sleijfer, T Gorlia, C Lamers, H Burger, J-Y Blay, A Le Cesne, M Scurr, F Collin, L Pandite, S Marreaud, P Hohenberger

Abstract

Background: Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in soluble vascular endothelial growth factor receptor-2 (sVEGFR2) or placental-derived growth factor (PlGF) levels during treatment were explored for their association with outcome.

Methods: Twenty-three baseline CAFs, and sVEGFR2 and PlGF changes were measured in 85 and 32 patients, respectively. Associations between baseline CAF levels and efficacy parameters, plus between-week 12 sVEGFR2 and PlGF levels and pazopanib-specific toxicities were investigated.

Results: At baseline, low interleukin (IL)-12 p40 subunit and MPC3 levels were associated with better progression-free survival (PFS) at 12 weeks (PFS(12wks)), low basic nerve growth factor and hepatocyte growth factor with a better PFS, and low inter-cellular adhesion molecule-1 and IL-2 receptor alpha with prolonged overall survival (OS; all P<0.05). Pazopanib decreased sVEGFR2 and increased PlGF levels. Low sVEGFR2 and high PlGF levels at week 12 were associated with higher-grade hypertension, with TSH elevations and with poorer PFS(12wks), and OS (both P<0.05).

Conclusion: Several baseline CAFs were related to outcome parameters. Low sVEGFR2 and high PlGF at week 12 associate with several pazopanib-specific toxicities and poorer efficacy. If confirmed, these factors may be used as early markers for response to and toxicity from pazopanib, enabling further individualisation of STS treatment.

Figures

Figure 1
Figure 1
Progression-free survival by baseline bNGF (A) and baseline HGF (B), together with overall survival by baseline ICAM-1 (C) and IL2ra (D). For this analysis, marker levels have been categorised, according to ‘rounded’ quartiles of their distribution. Results therefore slightly differ from those of the Cox regression analysis.
Figure 2
Figure 2
Scatterplot of PlGF and sVEGFR2 levels at week 12.
Figure 3
Figure 3
Associations with grade hypertension with sVEGR2 and PlGF levels at week 12.
Figure 4
Figure 4
Association of sVEGFR2 and PlGF levels at week 12, with success rate at week 12 (A), OS by PlGF levels at week 12 (B), and by sVEGFR2 levels at week 12 (C).

References

    1. Bass MB, Sherman SI, Schlumberger MJ, Davis MT, Kivman L, Khoo HM, Notari KH, Peach M, Hei YJ, Patterson SD (2010) Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer. J Clin Endocrinol Metab 95: 5018–5027
    1. Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, Hande KR, Keohan ML, Samuels BL, Schuetze S, Lebedinsky C, Elsayed YA, Izquierdo MA, Gomez J, Park YC, Le Cesne A (2009) Efficacy and safety of trabectidin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol 27: 4188–4196
    1. Drevs J, Zirrgiebel U, Schmidt-Gersbach CI, Mross K, Medinger M, Lee L, Pinheiro J, Wood J, Thomas AL, Unger C, Henry A, Steward WP, Laurent D, Lebwohl D, Dugan M, Marme D (2005) Soluble markers for the assessment of biological activity with PTK787/ZK222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials. Ann Oncol 16: 558–565
    1. Ebos JM, Lee CR, Christensen JG, Mutsaerts AJ, Kerbel RS (2007) Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci USA 104: 17069–17074
    1. Fata F, O’Reilly E, Ilson D, Pfister D, Leffel D, Kelsen DP, Schwartz GK, Casper ES (1999) Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer 86: 2034–2037
    1. Fischer C, Mazzone M, Jonckx B, Carmeliet P (2008) FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 8: 942–956
    1. Hamberg P, Verweij J, Sleijfer S (2010) (Pre)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. Oncologist 15: 539–547
    1. Hanrahan EO, Lin HY, Kim ES, Yan S, Du DZ, McKee KS, Tran HT, Lee JJ, Ryan AJ, Langmuir P, Johnson BE, Heymach JV (2009a) Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/or chemotherapy in patients with non-small cell lung cancer. J Clin Oncol 28: 193–201
    1. Hanrahan EO, Ryan AJ, Mann H, Kennedy SJ, Langmuir P, Natale RB, Herbst RS, Johnson BE, Heymach JV (2009b) Baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from vandetanib in non-small lung cancer. Clin Cancer Res 15: 3600–3609
    1. Kiura K, Nakagawa K, Shinkai T, Eguchi K, Ohe Y, Yamamoto N, Tsuboi M, Yokota S, Seto T, Jiang H, Nishio K, Saijo N, Fukuoka M (2008) A randomized, double-blind, phase IIa dose-finding study of vandetanib (ZD6474) in Japanese patients with non-small cell lung cancer. J Thorac Oncol 3: 386–393
    1. Murukesh N, Dive C, Jayson GC (2010) Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer 102: 8–18
    1. Nikolanikos PG, Altorki N, Yankelevitz D, Tran HT, Yan S, Rajagopalan D, Bordogna W, Ottesen LH, Heymach JV (2010) Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Res 70: 2171–2179
    1. Rini BI, Michaelson MD, Rosenberg JE, Bukowski RM, Sosman JA, Stadler WM, Hutson TE, Margolin K, Harmon CS, DePrimo SE, Kim ST, Chen I, George DJ (2008) Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 26: 3743–3748
    1. Rosen LS, Kurzrock R, Mulay M, Van Vugt A, Purdom M, Ng C, Silverman J, Koutsoukos A, Sun YN, Bass MB, Xu RY, Polverino A, Wiezorek JS, Chang DD, Benjamin R, Herbst RS (2007) Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 25: 2369–2376
    1. Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schöffski P, Collin F, Pandite L, Marreaud S, De Brauwer A, van Glabbeke M, Verweij J, Blay JY (2009) Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma group (EORTC 62043). J Clin Oncol 27: 3126–3132
    1. Sleijfer S, Seynaeve C, Verweij J (2005) Using single-agent therapy in adult patients with advanced soft tissue sarcoma can still be considered standard care. Oncologist 10: 833–841
    1. Tascilar M, Loos WJ, Seynaeve C, Verweij J, Sleijfer S (2007) The pharmacologic basis of ifosfamide use in adult patients with advanced soft tissue sarcomas. Oncologist 12: 1351–1360
    1. Tran HT, Liu Y, Lin Y, Martin A-M, Baker KL, Fritsche HA, Zurita A, Pandite LN, Heymach JV (2010) Use of multiplatform analysis of plasma cytokines and angiogenic factors (CAFs) to identify baseline CAFs associated with pazopanib response and tumor burden in renal cell carcinoma (RCC) patients. J Clin Oncol 28, (suppl 15s): abstr 4522
    1. Van der Graaf WT, Blay JY, Chawla SP, Kim D, Bui Nguyen B, Casali PG, Schöffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji M, Dei Tos AP, Hohenberger P (2011) PALETTE: a randomized, double-blind, phase III trial of pazopanib versus placebo in patients (pts) with soft-tissue sarcoma (STS) whose disease has progressed during or following prior chemotherapy—an EORTC STBSG Global Network Study (EORTC 62072). J Clin Oncol 29, (suppl): abstr LBA10002
    1. Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: a randomised trial. Lancet 364: 1127–1134

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit