Axitinib and sorafenib for thyroid cancer – pro

Medullary and papillary thyroid carcinoma (MTC and PTC) are two types of thyroid cancer that can originate from activating mutations or rearrangements in the RET gene. Axitinib has been studied for thyroid cancer. Two phase II studies were reported in the Journal of Clinical Oncology evaluating different axitinib and sorafenib therapies in patients with advanced thyroid cancer have special significance. The multicenter trial from Cohen et al used axitinib (AG-013736), an orally administered angiogenesis inhibitor. The study from Gupta-Abramson et al2 at the University of Pennsylvania used the oral agent sorafenib (Nexavar; Bayer Healthcare, West Haven, CT; Onyx Pharmaceuticals, Richmond, CA), which inhibits not only angiogenesis, but also RAF and RET kinases, which are important targets in thyroid cancers. Although these are different agents, the two studies had many similarities.

Eligible patients in both studies included a full spectrum of thyroid cancer histologic subtypes—from differentiated to anaplastic, with both medullary and nonmedullary cancers allowed—but papillary and follicular histologies predominated. All patients were judged by the involved investigators to be resistant or refractory to RAI. Although no complete responses were reported, a significant minority of patients had a major response to therapy by Response Evaluation Criteria in Solid Tumors (RECIST): 30% and 23%, respectively, for axitinib and sorafenib. Stable disease for no less than 3 months was also common, reported in 38% and 53%, respectively. The response waterfall plots indicated that most of these patients with stable disease had some objective disease regression, albeit of insufficient magnitude to fulfill RECIST criterion for a partial response, further suggesting that the reports of stable disease reflected at least in part therapeutic effect rather than simply slow growth of disease. Median progression-free survival rates were similar in both studies at approximately 18 months. The oral route of administration and noncytotoxic, targeted mechanism of action did not mean a lack of side effects. Grade 3 or 4 toxicities with both agents were not rare: 32% of patients treated with axitinib had at least one treatment-related adverse that was grade 3 or worse, and 47% of patients treated with sorafenib required dose reductions to control toxicities. Discontinuation of treatment occurred in 13% and 20% of patients treated with axitinib or sorafenib, respectively, because of toxicity.

Most recently, the DECISION trial, reproted in 2013 ASCO,  enrolled 417 patients with locally advanced or metastatic RAI-refractory DTC. Patients had progression within the past 14 months as defined by the Response Evaluation Criteria In Solid Tumors (RECIST). Those who had undergone previous treatment with targeted therapy or chemotherapy were excluded. Patients were randomly assigned 1:1 to 400 mg sorafenib orally twice daily or to placebo. Progression was assessed every 8 weeks, and if disease progressed patients on placebo were allowed to cross over to treatment.

The treatment and study arms were well balanced regarding sex, age, and Eastern Cooperative Oncology Group performance status (PS), with most patients in both arms having a PS of 0 or 1. Baseline disease characteristics including investigator-assessed histology, and lesion sites were well balanced between the study arms, as was median cumulative RAI exposure. The great majority of patients in both groups had distant metastases.

The study met its primary endpoint of PFS, with a statistically significant HR of 0.587. Dr. Brose noted that the curve in the placebo arm was short, at 5.8 months, reflecting the progressive nature of the disease in the patients enrolled in the study. Benefit of treatment was seen in all prespecified subgroups and across all regions (North America, Europe, and Asia) and age groups.

Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol. 2008 Oct 10;26(29):4708-13.

David G. Pfister andJames A. Fagin Refractory Thyroid Cancer: A Paradigm Shift in Treatment Is Not Far Off JCO October 10, 2008:4701-4704

Multicenter, Phase II Study of Axitinib, a Selective Second-Generation Inhibitor of Vascular Endothelial Growth Factor Receptors 1, 2, and 3, in Patients with Metastatic Melanoma Clin. Cancer Res. Dec 1, 2011:7462-7469

Hans H. G. Verbeek, Maria M. Alves, Jan-Willem B. de Groot, Jan Osinga, John T. M. Plukker, Thera P. Links and Robert M. W. Hofstra
The Effects of Four Different Tyrosine Kinase Inhibitors on Medullary and Papillary Thyroid Cancer Cells J. Clin. Endocrinol. Metab. Jun 1, 2011:E991-E995

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