Introduction
Thyroid cancer was diagnosed in approximately 212,000 individuals worldwide and resulted in about 35,000 deaths in 2008 [
1]. Its incidence has increased, on average, by 58 % in most populations [
2]. Despite its rising incidence, thyroid cancer mortality in the European Union has declined [
3]. Survival is stage-dependent, with a 5-year relative survival rate of 57.3 % for distant disease [
4].
Thyroid tumors have elevated levels of vascular endothelial growth factor (VEGF) compared with normal thyroid tissue [
5], suggesting the VEGF pathway as an appropriate therapeutic target. Several tyrosine kinase inhibitors (TKIs) targeting the VEGF pathway (e.g., sorafenib [
6‐
11], sunitinib [
12‐
14], axitinib [
15,
16], vandetanib [
17,
18], pazopanib [
19], motesanib [
20,
21], cabozantinib [
22‐
24], and lenvatinib [
25]) have been evaluated in patients with advanced thyroid cancer.
Axitinib, a potent and selective second-generation inhibitor of VEGF receptors (VEGFRs) [
26], is approved in the USA, European Union, and elsewhere for the treatment of advanced renal cell carcinoma (RCC) after failure of prior systemic therapy [
27]. The activity of axitinib was previously reported in a Phase II trial of patients with various histologic subtypes of advanced thyroid cancer in whom iodine-131 (
131I) failed to control the disease or
131I was not appropriate therapy [
16]. The final clinical results with long-term outcomes, including updated overall survival (OS), and pharmacokinetic/pharmacodynamic (PK/PD) analyses from this trial are reported here.
Discussion
A 38 % ORR and 21-month median duration of response for axitinib 5 mg twice daily is reported in patients with advanced thyroid cancer. Although the sample size was too small for definitive assessment, follicular histology appeared to be most responsive to axitinib (Table
1). Stable disease lasting ≥16 weeks, as defined by the protocol, occurred in an additional 18 (30 %) patients; however, 17 of those patients had stable disease lasting ≥30 weeks. These translated into 15-month median PFS and 35-month median OS. Results from another Phase II trial of axitinib in patients (
N = 52) with
131I-refractory advanced thyroid cancer demonstrated a comparable 35 % ORR, 16.1-month median PFS, and 27.2-month median OS [
15]. These two trials consistently demonstrated that axitinib has activity in the treatment of advanced thyroid cancer.
Since documented disease progression was not required prior to enrollment in this trial, PFS and OS data may be difficult to interpret in light of the natural history of metastatic thyroid cancer. Several randomized placebo-controlled Phase III trials evaluating VEGFR TKIs have now been conducted in patients with advanced thyroid cancer [
11,
17,
24]. Patients receiving placebo in those trials had median PFS of 4 months [
24] versus 19.3 months [
17] for medullary thyroid cancer (MTC) with versus without progressive disease at study entry. Likewise, patients with progressive differentiated thyroid cancer (DTC) who received placebo had median PFS of 5.8 months [
11]. In a randomized placebo-controlled Phase II trial, 16 (22 %) of 73 patients with DTC who received placebo had stable disease for a period of 12 months [
18]. Whereas median OS has not been reported from these placebo-controlled trials, the survival analyses may be confounded by crossover to active treatment. Several single-arm Phase II trials have evaluated VEGFR TKIs [
6‐
10,
12‐
14,
19‐
21,
25] for the treatment of advanced thyroid cancer (summarized in Online Resource 1). Only a few trials have reported median OS in patients treated with sorafenib: 23 and 38 months in non-progressive papillary thyroid cancer that was chemotherapy-naïve or previously treated with chemotherapy [
7], respectively, and 35 months in progressive DTC [
10].
The National Comprehensive Cancer Network 2013 Clinical Practice Guidelines [
34] suggest consideration of systemic therapy with small molecule kinase inhibitors for clinically progressive or symptomatic metastatic
131I-refractory DTC. Additionally, European Society for Medical Oncology 2012 Clinical Practice Guidelines [
35] recommend enrollment in clinical trials with TKIs for patients with metastatic DTC. Results from the current study suggest that axitinib may be a potential treatment option for
131I-refractory advanced DTC that is progressive or symptomatic. In long-term follow-up, the AE profile for axitinib was similar to previously reported results [
16], thus confirming axitinib is well tolerated, with manageable toxicities.
The results reported here suggest there is an increased likelihood of an objective response in patients with the greatest VEGF increases and sVEGFR2 decreases; however, due to the considerable overlap observed in proportions of responders and change in VEGF/sVEGFR2 quartiles, these may not be optimal biomarkers to predict response to axitinib. A previous study also suggested that changes in sVEGFR2 levels after initiation of motesanib might predict response in patients with metastatic DTC or MTC [
36]. In the current study, patients with higher axitinib AUC
ss-cycle1, a measure of inherent axitinib exposure, had greater reduction in tumor size, probability of PR, and greater median VEGF increases and sVEGFR decreases from baseline. In patients with metastatic RCC, greater axitinib exposure has also been associated with a higher ORR and longer PFS and OS [
37]. Other investigators have conducted PK/PD analyses in patients with thyroid cancer. For example, motesanib AUC
ss was a better predictor of response than dose [
38]. Also, maximum pazopanib plasma concentration during the first treatment cycle correlated with maximum change in tumor size and was significantly higher in patients who achieved responses [
19].
Limitations of the present trial included the number of patients with indeterminate or missing response assessments (n = 14), and the lack of control group and independent radiology review of response. Additionally, results for the 13 patients who continued axitinib for long periods of time in the extension study were based on data collected from this original trial. The extension study is ongoing and as of the cutoff date of June 1, 2012, duration of treatment ranged from 2.6 to 7.5 years in eight patients no longer receiving axitinib and from 6.2 to 7.4 years in five patients still receiving axitinib. Although AE data for long-term axitinib in the extension study were not yet available, five patients still on treatment were receiving total daily axitinib doses of 6–12 mg (data on file; Pfizer Inc, New York, NY, USA).
In conclusion, axitinib appears to be active in various histologic subtypes of advanced thyroid cancer, as evidenced by a high ORR and long median duration of response, PFS, and OS. A limited number of patients with anaplastic histology (n = 2) were enrolled, making definitive conclusions in this subtype impossible. Axitinib also demonstrated a generally favorable safety profile. Moreover, greater axitinib exposure was associated with favorable differences in biomarkers and reduction in tumor size. PK/PD analyses suggest that patients with higher axitinib exposure were more likely to achieve PR, thereby providing further rationale for dose increases in patients who tolerate the starting dose of 5 mg twice daily without elevated BP. Overall, these data suggest axitinib may be useful in the treatment of 131I-refractory advanced thyroid cancer, and individualized dose titration based on tolerability and BP assessment is warranted. Larger randomized trials are necessary to confirm the role of axitinib for the treatment of advanced thyroid cancer.
Acknowledgments
This study was supported by Pfizer Inc. Medical writing support was provided by Lilliam Poltorack, PharmD, and Joanna Bloom, PhD, at Engage Scientific Solutions and was funded by Pfizer Inc.