Phase II trial of sorafenib in metastatic thyroid cancer

Abstract

Purpose: Based on the pivotal role of Ras-Raf-MAP-ERK signaling and vascular endothelial growth factor (VEGF) in papillary thyroid cancer (PTC), we conducted a phase II clinical trial of sorafenib targeting RAF and VEGF receptor kinases in PTC.

Patients and methods: The primary end point was the objective response rate. Secondary end points included response correlation with serum thyroglobulin (Tg); functional imaging; tumor genotype; and signaling inhibition in tumor biopsies. Using a Simon minimax two-stage design, 16 or 25 chemotherapy-naïve metastatic PTC patients were to be enrolled in arm A (accessible tumor for biopsy). Arm B patients had other subtypes of thyroid carcinoma or prior chemotherapy, and did not require tumor biopsies. Patients received 400 mg orally twice per day of sorafenib. Response was assessed every 2 months using RECIST (Response Evaluation Criteria in Solid Tumors).

Results: Of 41 PTC patients, six patients had a partial response (PR; 15%; 95% CI, 6 to 29) and 23 patients (56%; 95% CI, 40 to 72) had stable disease longer than 6 months. Median duration of PR was 7.5 months (range, 6 to 14). Median progression-free survival was 15 months (95% CI, 10 to 27.5). In 14 (78%) of 18 Tg-assessable PTC patients, Tg declined more than 25%. Common grade 3 adverse events included hand-foot skin reaction, musculoskeletal pain, and fatigue. BRAF mutation was detected in 17 (77%) of 22 PTCs analyzed. Four of 10 paired tumor biopsies from PTC patients showed a reduction in levels of vascular endothelial growth factor receptor phosphorylation, ERK phosphorylation, and in VEGF expression during sorafenib therapy. No PRs were noted among non-PTC patients.

Conclusion: Sorafenib is reasonably well-tolerated therapy with clinical and biologic antitumor activity in metastatic PTC.

Fig 1.

Study design. pts, patients; VEGF-R, vascular endothelial growth factor receptor; MRI, magnetic resonance imaging; RECIST, Response Evaluation Criteria in Solid Tumors.

Fig 2.

(A) Maximum percentage of tumor reduction for target lesions for by Response Evaluation Criteria in Solid Tumors in all papillary thyroid cancer (PTC) patients who had stable disease (SD) or partial response (PR). With intent to treat analysis, six PRs (15%), 25 SDs (61%), and five PDs (12%) were noted in total of 41 patients with PTCs (33 chemotherapy naïve, eight with prior chemotherapy). Each bar represents an individual patient. Chemotherapy naïve (blue) or prior chemotherapy (gold) status is noted by different color of the bar. (B) Kaplan-Meier analysis of progression-free survival (PFS) among all PTC patients (n = 41) who received at least one dose of sorafenib. For PTC chemotherapy-naïve patients (n = 33), median PFS is 16 months with 95% CI of 8 to 27.5. For PTC patients with prior chemotherapy (n = 8), median PFS is 10 months with 95% CI of 4 to 28. Using log-rank test to compare the curves for PFS, no statistically significant difference (P = .8627) was found in PFS between PTC groups. (C) Kaplan-Meier analysis of overall survival (OS). OS among all PTC patients (n = 41) who received at least one dose of sorafenib. For PTC chemotherapy-naïve patients (n = 33), median OS is 23 months with 95% CI of 18 to 34). For PTC patients with prior chemotherapy, median OS is 37.5 months with 95% CI of 4 to 42.5. Using log-rank test to compare the curves for OS, no statistically significant difference (P = .4787) was found in OS between PTC groups.

Fig A1.

Illustration of development of hypoattenuation in tumor lesion on computed tomography scan in response to sorafenib in a patient with papillary thyroid cancer. Tg, thyroglobulin.

Fig A2.

(A) Serum thyroglobulin (Tg) levels with therapy in patients with papillary thyroid cancer (PTC) on arm A (n = 9). (B) Serum thyroglobulin levels with therapy in patients with PTC on arm B (n = 9). Patients 023, 048, 013, 029, 044 were cytotoxic chemotherapy-naïve PTC patients while 006, 021, 052, 034 had prior cytotoxic chemotherapy. 005-PR, patient No. 005 who has partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST); 006-PR, patient No. 006 in arm B who has partial response (PR) by RECIST; SD, stable disease; PD, progressive disease.

Fig A3.

Typical severe hand-foot syndrome affecting palms with erythema, skin peeling, and cracking attributed to sorafenib.

Fig A4.

Fine needle aspiration samples were obtained from two patients (cases A and B) before initiation of sorafenib (0) and 8 weeks after treatment was initiated (8 weeks). Both of these patients had a BRAF V600E mutation. In case A, high levels of immunoactive phosphorylated vascular endothelial growth factor receptor (pVEGFR), VEGF, and phosphorylated ERK (pERK) and phosphorylated AKT (pAKT) were detected before treatment and the levels were reduced on therapy. Diff-Quik (Dade Behring, Newark, DE) staining confirms the presence of thyroid cancer cells. Case B demonstrated no evidence of immunactive pVEGFR, VEGF, or pERK before therapy. pAKT was detected but was not changed during treatment with sorafenib.