Hypertension (HTN) as a potential biomarker of efficacy in pazopanib-treated patients with advanced non-adipocytic soft tissue sarcoma. A retrospective study based on European Organisation for Research and Treatment of Cancer (EORTC) 62043 and 62072 trials

doi:10.1016/j.ejca.2015.08.002

European Journal of Cancer

Volume 51, Issue 17, November 2015, Pages 2615-2623

https://doi.org/10.1016/j.ejca.2015.08.002 Get rights and content

Highlights

•
Pazopanib is an active agent for metastatic non-adipocytic soft tissue sarcomas.
•
Markers to early identify patients benefiting from treatment are needed.
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Hypertension (HTN) is a specific side-effect of pazopanib.
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In 337 patients the association of occurrence of HTN and outcome was assessed.
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No association was found between the occurrence of HTN and outcome.

Abstract

Background

Reliable biomarkers of pazopanib’s efficacy in soft tissue sarcoma (STS) are lacking. Hypertension (HTN) is an on-target effect of vascular endothelial growth factor (VEGF)-receptor inhibitors such as pazopanib. We evaluated the association of pazopanib-induced HTN with antitumour efficacy in patients with metastatic non-adipocytic STS.

Methods

Associations between pazopanib-induced-HTN and antitumour efficacy were retrospectively assessed across 2 prospective studies (European Organisation for Research and Treatment of Cancer (EORTC) study 62043 and 62072) in metastatic STS patients who received pazopanib 800 mg daily. Only patients with baseline blood pressure (BP) < 150/90 mmHg, were included. BP was measured monthly. HTN was reported according to National Cancer Institute-Common Toxicity Criteria Adverse Events (NCI-CTC AE) grading (v3.0), and as absolute differences compared to baseline. The effect of HTN developing in patients without baseline anti-hypertensive medication was assessed on progression-free (PFS) and overall survival (OS) using a landmark analysis stratified by study; univariately using the Kaplan–Meier method and a log-rank test, and in a multivariate Cox regression model after adjustment for important prognostic factors.

Results

Of the 337 patients eligible for this analysis, 21.7% received anti-hypertensive medication at baseline and had a similar PFS and OS compared to those who did not. In patients without baseline anti-hypertensive medication, 38.6% developed HTN. As the majority of patients developing HTN did so within 5 weeks after initiation of pazopanib (68.6%), this time point was used as landmark. Univariately, there was no effect on PFS or OS from occurrence of HTN within 5 weeks of treatment expressed either in NCI-CTC AE criteria or as maximal differences from baseline in systolic and diastolic BP. Also in multivariate analysis, after adjusting for important prognostic factors, the occurrence of HTN expressed in the different parameters was not associated with PFS and OS.

Conclusions

In this retrospective analysis, pazopanib-induced HTN did not correlate with outcome in pazopanib-treated STS patients. The occurrence of HTN cannot serve as biomarker in this setting.

Section snippets

Background

Pazopanib is a tyrosine-kinase inhibitor (TKI) targeting several factors, including vascular endothelial growth factor (VEGF) receptors, platelet derived growth factor (PDGF) receptors, and c-kit. As VEGF-driven angiogenesis is involved in the tumour biology of many soft tissue sarcomas (STS) subtypes [1], [2], [3], [4], [5], [6], pazopanib was tested for its efficacy in a phase II study and subsequently, in a placebo-controlled phase III study in patients with pretreated, advanced,

Patients and measurements

Associations between pazopanib-induced HTN and antitumour efficacy were retrospectively assessed across two prospectively performed Soft Tissue and Bone Sarcoma Group (STBSG)-European Organisation for Research and Treatment of Cancer (EORTC) studies: EORTC 62043 [12], and EORTC 62072 [7] (see Table S1 in Supplementary Material). The EORTC 62043 trial was a single-arm, phase II study and assessed the activity of pazopanib in advanced STS patients who failed doxorubicin or ifosfamide-based

Baseline characteristics

Demographics and baseline characteristics of patients included in this analysis are presented in Table S2 (Supplementary Material). The median follow-up for the 62043 study was 3.2 years (IQR 2.8–3.7). The median follow-up for the phase III study was 2.2 years (IQR 1.8–2.5).

Controlled hypertension at baseline

Of the 337 patients in this study population, 73 patients (21.7%) had medically controlled hypertension at baseline. Table 1 summarises the BP readings (systolic and diastolic) at baseline grouped by the use of baseline

Discussion

This retrospective analysis revealed that pazopanib-induced HTN occurred in 39.9% of patients while on study treatment but that occurrence of HTN on pazopanib did not correlate with outcome in terms of PFS and OS in advanced STS patients. The occurrence of HTN therefore cannot serve as an early biomarker of pazopanib efficacy in this setting.

In previous studies it was suggested that VEGFR-TKI-induced HTN was associated with a better outcome in several tumour types. Despite its retrospective

Funding

This retrospective analysis was supported by the EORTC Charitable Trust.

Conflict of interest statement

SS: honoraria and research funding from GSK; ALC: honoraria from GSK, Novartis, Pfizer and Pharmamar; IJ: honoraria, research funding and participation to advisory board of GSK; PS: honoraria and research funding from GSK; consultant for GSK; SPC: consultant for GSK;RD: shares in GSK; JV: honoraria from GSK; WvdG: honoraria and research funding from GSK. All remaining authors have declared no conflict of interest.

Acknowledgements

The Phase II and III studies were collaborations between GSK and the EORTC STBSG. We thank all investigators, patients and their families for their contribution to this study.

References (27)

S.S. Yoon et al.
Circulating angiogenic factor levels correlate with extent of disease and risk of recurrence in patients with soft tissue sarcoma
Ann Oncol
(2004)
S.S. Yoon et al.
Angiogenic profile of soft tissue sarcomas based on analysis of circulating factors and microarray gene expression
J Surg Res
(2006)
W. van der Graaf et al.
Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial
Lancet
(2012)
G.D. Demetri et al.
Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial
Lancet
(2006)
O. Rixe et al.
Hypertension as a predictive factor of sunitinib activity
Ann Oncol
(2007)
S. George et al.
Hypertension as a potential biomarker of efficacy in patients with gastrointestinal stromal tumor treated with sunitinib
Ann Oncol
(2012)
C. Chao et al.
Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade
Ann Surg Oncol
(2001)
E.E. Pakos et al.
Expression of vascular endothelial growth factor and its receptor, KDR/Flk-1, in soft tissue sarcomas
Anticancer Res
(2005)
K. Yudoh et al.
Concentration of vascular endothelial growth factor in the tumor tissue as a prognostic factor of soft tissue sarcomas
Br J Cancer
(2001)
S. Sleijfer et al.
Angiogenesis inhibition in non-GIST soft tissue sarcomas
Oncologist
(2008)

H.X. Chen et al.

Adverse effects of anti-cancer agents that target the VEGF pathway

Nat Rev Clin Oncol

(2009)

R.J. Motzer et al.

Sunitinib in patients with metastatic renal cell carcinoma

JAMA

(2006)

R.C. Kane et al.

Sorafenib for the treatment of advanced renal cell carcinoma

Clin Cancer Res

(2006)

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Based solely on hypertension incidence as a surrogate marker in this and other studies, cediranib appears to be a potent VEGF receptor inhibitor. Comparative data on relative potency in vitro against different receptor tyrosine kinases do not seem helpful in predicting toxicity profiles, and hypertension is not a reliable efficacy biomarker.19 Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, the confirmation of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients.
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View full text

Hypertension (HTN) as a potential biomarker of efficacy in pazopanib-treated patients with advanced non-adipocytic soft tissue sarcoma. A retrospective study based on European Organisation for Research and Treatment of Cancer (EORTC) 62043 and 62072 trials

Highlights

Abstract

Background

Methods

Results

Conclusions

Section snippets

Background

Patients and measurements

Baseline characteristics

Controlled hypertension at baseline

Discussion

Funding

Conflict of interest statement

Acknowledgements

Ann Oncol

J Surg Res

Lancet

Lancet

Ann Oncol

Ann Oncol

Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade

Ann Surg Oncol

Expression of vascular endothelial growth factor and its receptor, KDR/Flk-1, in soft tissue sarcomas

Anticancer Res

Concentration of vascular endothelial growth factor in the tumor tissue as a prognostic factor of soft tissue sarcomas

Br J Cancer

Angiogenesis inhibition in non-GIST soft tissue sarcomas

Oncologist

Adverse effects of anti-cancer agents that target the VEGF pathway

Nat Rev Clin Oncol

Sunitinib in patients with metastatic renal cell carcinoma

JAMA

Sorafenib for the treatment of advanced renal cell carcinoma

Clin Cancer Res