Phase II study of everolimus and sorafenib for the treatment of metastatic thyroid cancer.

Abstract

6024 Background: Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR). Unpublished work from the Fagin lab shows that mTORC1 is also required for the growth promoting effects of the oncoproteins RET/PTC, RAS and BRAF in rat thyroid PCCL3 cells. Further work shows synergy of mTORC inhibitors with RET kinase inhibitors in medullary thyroid cancer cell lines. Sorafenib is an oral kinase inhibitor with in vitro activity against multiple targets, including RAF, RET, VEGFR1, and VEGFR2 that is compendium approved for the treatment of radioactive iodine-refractory (RAIR) and medullary (MTC) thyroid cancer. Methods: The study was a single institution, two-stage phase II design. Primary objective was response rate initiated on 9/21/2010. Eligible patients (pts) had progressive, RAIR/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-anaplastic, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 400 mg orally twice a day and Everolimus at 5 mg orally once daily. 41 patients were enrolled; 36 were eligible for the primary endpoint of response and 3 were evaluable for toxicity only at the data cutoff date of 1/10/13. Seventeen patients are still actively on study. Mutational analyses of tissue is ongoing. Results: Of the 41 eligible pts, demographics: female- 44% (18); median age-61 years (35-79). Grade 4-5 adverse events at least possibly related to drug: grade 4- Alanine Aminotransferase Increase (1 pt): grade 4- Hyperglycemia (1 pt): grade 4-Pancreatitis (1 pt). Histology and response data by partial response, confirmed and unconfirmed, (PR), stable disease (SD) and progression of disease (POD) are in the table below. The median time on treatment is 167 days (range 1 to 797 days) at the cutoff date of 1/10/2013. Conclusions: The combination of sorafenib and everolimus shows promising results, especially in the Hurthle cell and medullary subgroups where data from studies at Ohio State have suggested very poor response to sorafenib alone. Clinical trial information: NCT01141309. [Table: see text]

Sorafenib in radioactive iodine-refractory well-differentiated metastatic thyroid cancer

“…The systematic review uncovered four relevant sorafenib trials that evaluated its use in RAI-R DTC patients in combination with another targeted agent (see Table 3 ) such as tipifarnib (Hong et al, 14 Cabanillas et al 15 ), temsirolimus (Sherman et al 29 ), and everolimus (Sherman et al 30 ). Tipifarnib is a farnesyl transferase inhibitor, while temsirolimus is an intravenous inhibitor of mTOR and everolimus is an mTOR inhibitor given by mouth.…”

Autophagy in Thyroid Cancer: Present Knowledge and Future Perspectives

“…The combination of sorafenib and everolimus shows promising results: partial response rates were higher than those reported for sorafenib as a single agent, with a partial response of 56% for non-medullary TC. However, several grade-4 adverse events occurred possibly related to the drug ( 158 ).…”

Selective use of sorafenib in the treatment of thyroid cancer

“…More recently, the same authors evaluated 38 patients with thyroid cancer (ten MTC and 28 DTC) and showed that the combination of sorafenib and everolimus, another mTOR inhibitor, achieves better clinical responses than for sorafenib alone: PR 55% and SD 37%. 79 Brose et al 80 enrolled 35 patients with evidence of progression by RECIST criteria on sorafenib treatment and demonstrated an additional median PFS of 13.7 months, a SD ≥6 months of 54%, and a PR of 3% adding everolimus to sorafenib. 80 …”