Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study

Summary

Background

Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib.

Methods

This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846.

Findings

39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35–68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=−0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders.

Interpretation

Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done.

Funding

National Cancer Institute, supported in part by NCI CA15083 and CM62205.

Introduction

Despite progress in the treatment of cancers and a consequent decline in overall mortality in the USA, the incidence of thyroid cancer has doubled in the past decade, in association with an increase in mortality of more than 33%.1, 2, 3, 4 Of particular concern is the striking rise in the frequency of differentiated thyroid cancers among women in the USA;1, 4 with more than 37 000 new cases annually, this cancer has the seventh highest incidence and is the tenth most frequently diagnosed, ahead of ovarian, gastric, or oesophageal cancers.⁵ Moreover, the incidence of thyroid cancer among women is rising worldwide. Differentiated thyroid cancer is now the second most frequently diagnosed cancer among women in the Middle East, behind only breast cancer, and accounting for more than 10% of all cancers among women in Saudi Arabia.⁶

Fortunately, most patients with differentiated thyroid cancers have an excellent outlook with use of traditional therapies, including surgery, suppression of thyroid-stimulating hormone (TSH) secretion with levothyroxine, and therapeutic radioiodine, and sometimes also radiation therapy. Nevertheless, about 5% of patients with advanced thyroid cancer develop life-threatening progressive disease, which led to about 1600 deaths in 2009 in the USA alone.¹ Few therapeutic options are available for patients with aggressive and life-threatening, radioiodine-insensitive disease, with no clinically meaningful benefit yet demonstrated with traditional cytotoxic chemotherapy.⁷

Improved understanding of the molecular alterations in differentiated thyroid cancers, however, has led to the realisation that a variety of kinases, including the vascular endothelial growth factor (VEGF) receptor tyrosine kinases, are frequently activated in differentiated thyroid cancer lesions and surrounding stroma. This finding has provided a rationale for the development of targeted treatments for these cancers that can be tailored to the individual patient.7, 8 Consequently, we did a phase 2 therapeutic clinical trial to assess the efficacy and safety of pazopanib (Votrient, GlaxoSmithKline, Brentford, UK), a tyrosine-kinase inhibitor (TKI) targeting VEGF receptors, platelet-derived growth factor, and c-KIT, among other kinases,9, 10 in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers.