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BACKGROUND:Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed. METHODS: A total of 29 patients were randomized to a run-in of oral everolimus (30, 50, or 70 mg) or cetuximab (400 mg/m 2 loading, 250 mg/m 2 maintenance) weekly, followed by the combination in this dose-escalation study. Primary endpoints were phase 2 dose and toxicity characterization. [ 18 F]Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed as a pharmacodynamic marker of mTOR inhibition, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed as an indicator of tumor perfusion changes, at 3 time points. RESULTS: Everolimus and cetuximab were tolerable at full doses, with an expected toxicity profile. Dose-limiting toxicities in the everolimus 70 mg group included grade 3 skin toxicity in 2 patients, and mucositis in 1 patient. Of 16 patients evaluable for response, 5 had stable disease lasting 4 to 19 months. Mean change in maximum standardized uptake value (SUV max ) for those treated initially with everolimus was 224% (2% to 254%), and with cetuximab was 25% (223 to 36%). The K trans measured by DCE-MRI did not decrease, regardless of run-in drug. CONCLUSIONS: Everolimus and cetuximab can be safely administered at standard doses, and are associated with prolonged disease control. The recommended phase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. Imaging studies reveal that metabolic inhibition by everolimus alone and in combination with cetuximab predominates over changes in tumor perfusion in this patient population. Cancer 2014;120:77-85.

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6002 Background: We are conducting an open-label phase II study of sorafenib in patients with metastatic, iodine-refractory thyroid carcinoma. Methods: 55 Patients were administered sorafenib 400 mg orally BID. Responses were monitored by PET and CT. Primary endpoints were response rate (RR) and progression free survival (PFS) by RECIST criteria. BRAF and RAS mutation status is determined by DNA sequencing. Outcome data is evaluated using the Kaplan-Meier method and log-rank test. Biologic activity in tissue obtained during treatment at response and progression is being explored using immunohistochemistry (IHC) to pERK, pAKT and Ki-67 among others, in pretreatment blocks from virtually all patients, and a subset of 14 patients in whom on-treatment tissue is available. Results: We have completed accrual of the 55 patients planned for enrollment; median time on study is 34 weeks and 25 pts (45%) are male. Histological subtypes include papillary (PTC): 25 pts (47%); follicular/Hürthle Cell (FTC): 19 pts (36%); medullary: 4 pts (8%), and poorly differentiated/anaplastic: 5 pts (9%). 52/55 patients are evaluable for response at this time. Median PFS was 84 wks. Genotyping of BRAF is complete in 16 patients. For patients with PTC/FTC, the PFS for those with BRAFwt was 54 wks compared to 84+ wks for patients with BRAFV600E (p = 0.028). On-treatment tissue at progression demonstrates heterogeneity, with p-ERK and p-AKT suppressed in some areas, but highly expressed in others. Data at 6 months post accrual of the last patient will be presented along with patient thyroglobulin levels, PET and CT scans. IHC and additional genotyping will also be presented. Conclusions: Sorafenib has activity in patients with advanced thyroid cancer with an overall PFS of 84 wks. While most patients with PTC or FTC achieve durable responses, patients whose tumors harbor BRAFV600E have significantly longer PFS than those that are BRAFwt. [Table: see text]

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