Elsevier

European Journal of Cancer

Volume 49, Issue 15, October 2013, Pages 3169-3175
European Journal of Cancer

Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with pazopanib after disease progression with other targeted therapies

https://doi.org/10.1016/j.ejca.2013.06.003Get rights and content

Abstract

Aim

The multi-tyrosine kinase inhibitor pazopanib prolongs progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory metastatic clear-cell renal cell carcinoma (ccRCC). Outcomes and safety data with pazopanib after targeted therapy (TT) are limited.

Methods

We retrospectively evaluated records of consecutive patients with metastatic ccRCC who had progressive disease (PD) after TT and received pazopanib from November 2009 through November 2011. Tumour response was assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumours (RECIST). PFS and overall survival (OS) were estimated by Kaplan–Meier methods.

Results

Ninety-three patients were identified. Median number of prior TTs was 2 (range, 1–5). There were 68 events (PD or death). Among 85 evaluable patients, 13 (15%) had a partial response. Median PFS was 6.5 months (95% CI: 4.5–9.7); median OS was 18.1 months (95% CI: 10.26–NA). Common adverse events (AEs) included fatigue (44%), elevated transaminases (35%), diarrhoea (30%), hypothyroidism (18%), nausea/vomiting (17%), anorexia (14%) and hypertension exacerbation (14%); 91% of AEs were grade 1/2. Eleven patients (12%) discontinued therapy due to AEs. There were no treatment-related deaths.

Concluding statement

Pazopanib demonstrated efficacy in patients with metastatic ccRCC after PD with other TTs. Toxicity overall was mild/moderate and manageable.

Introduction

Approximately 30% of patients with renal cell carcinoma (RCC) have advanced disease at their initial diagnosis, and 20–30% develop metastases after surgery for earlier-stage disease.1, 2 Although select patients with limited metastatic disease may be cured with metastasectomy, the vast majority with metastatic disease are incurable and require systemic therapy for palliation and prolonged survival.3 Until recently, cytokine therapy with interleukin-2 or interferon-alfa was the mainstay of systemic treatment in patients with metastatic RCC (mRCC). Recently, the anti-vascular endothelial growth factor (VEGF) agents and mammalian target of rapamycin (mTOR) inhibitors have supplanted cytokines as the mainstay therapy and have led to prolongation of progression-free survival (PFS) and, in some patients, overall survival (OS).4 Currently, there are four Food and Drug Administration-approved tyrosine-kinase inhibitors (TKIs) in the United States (US): sorafenib, sunitinib, pazopanib and axitinib. Several other novel agents are in preclinical development and clinical trials.5 Sorafenib, sunitinib and pazopanib have all gained marketing authorisation from the European Medicines Agency (EMA), and axitinib has been granted orphan drug status by the EMA.

Pazopanib is an oral angiogenesis inhibitor of VEGF receptors 1, 2 and 3, and platelet-derived growth factor receptors alpha and beta and c-Kit (CD117); it was approved for treatment of mRCC in the US in November 2009 and in Europe in June 2010. The safety and efficacy of pazopanib were evaluated in a randomised, double-blind, placebo-controlled phase III trial in both treatment-naive and cytokine-pretreated patients.6 Pazopanib demonstrated superior efficacy outcomes compared to placebo, with an improved median PFS of 9.2 months for all patients, 11 months for treatment-naive patients and 7.4 months for cytokine-pretreated patients, versus 4.2, 2.8 and 2.8 months, respectively, for patients treated with placebo. The overall response rate (ORR) with pazopanib was 30% versus 3% with placebo. Pazopanib is currently a National Comprehensive Cancer Network Class I treatment recommendation in the first-line setting and after cytokine therapy.

The efficacy and safety of pazopanib after treatment with other TTs are currently unknown. The goal of this retrospective study was to provide such data for pazopanib in patients with mRCC after treatment with other TTs.

Section snippets

Patients and methods

In this retrospective study, we included consecutive patients with mRCC who were treated from November 1, 2009, through November 1, 2011, in the Genitourinary Medical Oncology Clinic at The University of Texas, MD Anderson Cancer Center (MDACC) and who received pazopanib, after they experienced progressive disease (PD) with other TTs (sorafenib, sunitinib, bevacizumab, temsirolimus and/or everolimus). Inclusion criteria included mRCC, prior systemic therapy with at least one TT, and adequate

Patients’ characteristics

Ninety-three consecutive patients with metastatic clear-cell RCC previously treated with TT met the study’s inclusion criteria, and constitute the patient cohort in the analysis. Table 1 lists patients’ characteristics. Median age was 65 years, and 69% of patients were men. All patients had PD after treatment with at least one TT. The median number of prior TTs was 2 (range, 1–5). Including all prior TTs, cytokines, cytotoxics and experimental agents, 18 patients (20%) received pazopanib as

Discussion

Studies have established the efficacy of pazopanib by prolongation of PFS in treatment-naive and cytokine-pretreated patients with metastatic clear-cell RCC.7 Recently, results from a large randomised phase III trial in the first-line therapy of metastatic clear-cell RCC (the COMPARZ trial) showed that pazopanib was non-inferior in efficacy, compared to sunitinib.8 In the PISCES study, based on the primary end-point of patient preference related to drug tolerability, 70% of patients preferred

Funding

This work was supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant (5 P30 CA016672). Dr. Matrana is supported by NIH (T32CA009666-15).

Conflict of interest statement

Drs. Nizar M. Tannir and Eric Jonasch have research funding and have participated in Advisory Board Meetings with GlaxoSmithKline.

Acknowledgement

Special thanks to Karen Phillips, ELS(D), for reviewing and editing the manuscript.

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