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Abstract
The emergence of serine-threonine small molecule, multi-targeted kinase inhibitors over the past decade is greatly impacting the therapeutic armamentarium for numerous malignancies, especially thyroid carcinoma. Chief among them are a class of agents referred to as vascular endothelial growth factor signal pathway inhibitors. Sorafenib is a lead compound that has been recently approved by the US FDA for radioactive iodine-refractory differentiated thyroid cancer (DTC). Sorafenib clearly is altering the natural history of DTC. In the largest randomized Phase III study ever conducted in DTC, sorafenib significantly improved progression-free survival compared to placebo (10.8 vs 5.8 months) and had an acceptable and manageable safety profile, though commonly attributed side effects of hand-foot skin reaction, diarrhea and hypertension were more frequent than in other settings. This agent represents a new treatment option for patients with progressive radioactive iodine-refractory DTC.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
Regarding BRAF biomarker status, not all tumors express BRAF and in the DECISION trial (on the order of 46% of tumors analyzed) BRAF mutation status was less than that reported in other thyroid cancer studies.
Sorafenib also inhibits kinase targets beyond BRAF, especially those that are part of the VEGF signaling pathway and the antitumor effects of this compound are likely mediated through these other kinase targets.
Raf inhibitors, including sorafenib, have been found to induce paradoxical activation of the MAPK pathway. BRAF inhibition leads to an upstream activation via an alternative MAPK pathway Citation[57]. This causes increasing signaling cascade through the CRAF pathway and leads to MAPK activation and hence the emergence of secondary treatment-related cutaneous neoplasms (e.g., squamous cell carcinoma) Citation[57].
While the DECISION trial is the largest randomized study ever conducted in this disease, it still constitutes a relatively small patient sample size. As clinical experience is gained with this agent, we will have a better understanding of optimal starting dose and dose modification; better appreciation of biomarker guidance to both select and monitor patients while on therapy and a greater appreciation of the spectrum of clinical toxicity, appropriate management of toxicities and effective strategies to minimize these toxicities.