Significant clinical and biologic activity of RAF/VEGF-R kinase inhibitor BAY 43–9006 in patients with metastatic papillary thyroid carcinoma (PTC): Updated results of a phase II study

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Abstract
5534 Purpose: Oncogenic defects in the genes involving RAS-RAF-MAPK signaling pathway (RAS, BRAF, or RET/PTC) occur in ∼60% of PTC. VEGF also plays a critical role in thyroid cancer progression. Due to lack of effective treatment, systemic therapy for iodine-refractory PTC is desperately needed. Methods: The primary endpoint of this phase II trial was to assess the objective response rates of BAY 43–9006 in pts with metastatic PTC. Secondary endpoints included clinical response correlation with 1) serum thyroglobulin (Tg) levels; 2) functional imaging including FDG-PET, and DCE-MRI; and 3) tumor genotype and degree of signaling inhibition in tumor biopsies. Using a minimax 2-stage design, 16 or 25 chemo-naïve pts with iodine-refractory PTC were to be enrolled in Arm A (accessible tumor for biopsy). An exploratory Arm B was designed with a plan to halt accrual as soon as Arm A was fully accrued. Eligible pts for Arm B had other subtypes of thyroid cancer or prior chemo, and did not require tumor biopsies. Pts received BAY 43–9006 at the dose of 400 mg PO BID. Response was assessed every 8 wks using RECIST. Results: A total of 58 pts (Arm A = 20, Arm B = 38) were enrolled from October 2004 to August 2005. Median duration of follow-up is 36 weeks (range, 16–60). Of 56 pts assessable for toxicity, serious adverse events (AEs) included aspergillus infection (gr 5, n = 1), secondary AML (gr 5, n = 1) and diverticular rupture (gr 3, n = 1). Common Gr 3 AEs were hand-foot syndrome (n = 9) and musculoskeletal pain (n = 10). Two confirmed partial responses (PRs) and 6 minor responses (23–29% decrease in sum of the longest diameter) were observed in 16 evaluable pts on Arm A. In 10 Tg-response evaluable pts on Arm A, median decrease in Tg was 70% (range, 45–90). Significant decreases in tumor perfusion and SUVs were noted in such pts. In addition, one PR and one minor response (27% decrease in sum of longest diameter; 85% reduction in Tg) have been observed among 20 pts with PTC on Arm B. Data for functional imaging and tissue correlative studies will be presented. Conclusions: BAY 43–9006 is a well-tolerated targeted therapy that has significant clinical and biologic anti-tumor activity in pts with iodine-refractory metastatic PTC. No significant financial relationships to disclose.

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