Multiple Tyrosine Kinases Targeting in Thyroid Cancer – a Novel Treatment Strategy for an Increasing in Frequency Tumour

Michalis Karamouzis

Leboulleux S., et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised double-blind, phase II trial. Lancet Oncol 2012; 13: 897-905

Thyroid cancer is the most common endocrine neoplasm. Thyroid cancers can be classified on the basis of histology into differentiated thyroid cancers (DTCs), including papillary, follicular or Hürthle cell thyroid cancers, medullary thyroid cancers (MTCs) and anaplastic thyroid cancers. In patients with localised disease, the standard of care for DTCs is surgical resection, thyroid stimulating hormone suppression with levothyroxine and consideration for adjuvant radioiodine or external beam radiation therapy. Outcomes are generally favourable but up to 30% of patients will relapse after initial treatment. At disease recurrence, repeated radioiodine administration may be beneficial when the tumour takes up radioiodine. Patients who are refractory to radioiodine can achieve palliation of local symptoms with external beam radiotherapy with or without concurrent low-dose doxorubicin. The most frequently used chemotherapy agent in non-medullary thyroid cancer remains doxorubicin with single-agent response rates of about 17%. Other agents alone or in combination with doxorubicin offer no clear advantage over single-agent doxorubicin. Thus, there is an unmet need for effective systemic treatment for aggressive non-medullary thyroid cancers.

Targeted therapies, anticancer agents developed to inhibit specific molecular pathways that drive various human tumours, have caused a paradigm shift in the treatment of solid tumours. The study of thyroid carcinomas has revealed somatic mutations in several pathways such as B-type Raf kinase (B-Raf), K-Ras, and rearranged during transfection (RET) that are associated with development and progression of approximately 70% of these tumours. Therefore, lack of effective systemic therapies combined with a high incidence of driver mutations and over-expression of molecular pathways make refractory thyroid cancer an ideal candidate for treatment with novel targeted agents. Multikinase inhibitors have been shown to be the most promising targeted therapies against this disease by blocking pathway signalling like angiogenesis and, concomitantly, inhibiting mutated pathways. The results of the ZETA (Zactima Efficacy in Thyroid Cancer Assessment) trial led the United States Food and Drug Administration to approve vandetanib for the treatment of symptomatic or progressive MTC, constituting this the first targeted agent approved for thyroid cancer. Vandetanib is a once-daily (300mg) oral targeted agent that selectively targets RET, VEGF receptor, and EGFR tyrosine kinases.

In this European randomised phase II trial 145 previously-treated patients with locally advanced and/or metastatic differentiated thyroid carcinoma were randomised to receive vandetanib or placebo. A statistically significant improvement in progression-free survival (PFS) was noted in the patients that were treated with vandetanib compared to the patients in the placebo arm (11.1 months versus 5.9 months; HR=0.63, p=0.008). A predefined PFS subgroup analysis in 126 patients showed an improvement in PFS for patients with papillary thyroid cancer compared with other histological subtypes (16.2 months versus 7.7 months), although this difference was not statistically significant. No statistical significant result was reached regarding overall survival at the time of the analysis. However, a statistical significant difference was reached regarding disease control at 6 months for the patients in the vandetanib arm (56% versus 36% of patients taking placebo; p=0.017). Common adverse events (>10% of patients) in the vandetanib-treated patients were diarrhoea, hypertension, QT prolongation, skin toxicity and anorexia. The most common adverse events leading to vandetanib discontinuation were diarrhoea and QT prolongation, although no cardiac complications were reported.

Multi-targeted agents seem to be the next clinical practice changing step in the treatment of patients with locally advanced and/or metastatic differentiated thyroid cancers, although this notion should be verified in phase III trials.

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