Sequential TKI treatments for iodine-refractory differentiated thyroid carcinomas.

Abstract

6092 Background: Tyrosine kinase inhibitors (TKI) are currently used to treat patients with advanced iodine-refractory differentiated thyroid cancers (DTC) but none has been approved by the FDA or the EMA until now. Sometimes, patients are treated with off-label TKI when a clinical trial is not available or in second- and third-line therapy. Methods: We hereby report the efficacy of “off-label” sorafenib and sunitinib treatments as first-, second- and third-line therapy in metastatic DTC patients from the French TUTHYREF (TUmeurs THYroïdiennes REFractaires) network. Primary endpoints were progression free survival (PFS) and tumor response according to sequential TKI treatment. Secondary endpoint was organ-specific metastatic site analysis. Results: 45 patients with advanced iodine-refractory DTC treated with off-label TKI were included in this study (26 men, mean age: 62 years). 22 had papillary, 10 had follicular and 13 had poorly DTC. 24/45 patients were treated with two and 3/45 with three lines of TKIs. Sorafenib was the most frequently used (57%) followed by sunitinib (21.5%) and vandetanib (21.5%). Partial response (PR) rate was of 29% in the 21 patients who received first-line sorafenib therapy whereas PR was observed in 57% of the 7 first-line sunitinib patients. There was no PR with second- (n=24) and third-line (n=3) treatments. However, median progression free survival (PFS) was similar in second- as compared to first-line sorafenib or sunitinib treatment (6.7 vs. 7.6 months, HR 0.85 (95CI 0.45-1.61) p=0.6). Liver metastases were the most responsive to treatment (n=7; mean of -30%), followed by lung (n=57; mean of -19%) and lymph node (n=43; mean of -13%) metastases. Bone (n=14) and pleural (n=9) lesions were the most refractory to treatment (mean of -1% and -5%, respectively). Conclusions: Due to the small number of patients, we could not recommend a specific treatment sequence (sorafenib then sunitinib) over another (sunitinib then sorafenib). But TKI therapy appears to be beneficial in refractory DTC patients even in second- and third-line therapy, with similar PFS and stable disease as best response. Bone and pleural metastases were the most refractory and liver lesions the most responsive to treatment.

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

“…Several correlative studies reported BRAF and other mutational statuses of participants (Kloos et al, 18 Brose et al 27 ). Other correlative studies noted areas of specific responsiveness (de la Fouchardiere et al, 16 Marotta et al, 25 Cabanillas et al 28 ) with most significant responses noted in lungs, lymph nodes, and liver lesions.…”

“…The Phase III Brose et al 1 study evaluated 57% papillary thyroid cancer, 25% FTC, and 10% PD (see Table 1 ). All of the studies used a sorafenib dose schedule of 400 mg twice daily, with the exception of the Adili et al 13 abstract, which did not include dose; the combination studies (Hong et al, 14 Cabanillas et al 15 [see Table 3 ]); and the observational studies by de la Fouchardiere et al, 16 which did not include dose, and Chen et al, 17 which used 200 mg twice daily (see Table 2 ). PR rates varied from 15% (Kloos et al 18 ) to 38% (Keefe et al 19 ), while SD rates varied from 34% (Hoftijzer et al 20 ) to 68% (Ahmed et al 21 , 22 ) in the Phase II setting.…”

“…The Brose et al Phase III randomized controlled trial met its primary endpoint with a median PFS (mPFS) of 10.8 months versus 5.8 months in the placebo group. 1 mPFS in Phase II trials and observational studies varied from 6.7 months (de la Fouchardiere et al 16 ) to 24 months (Keefe et al 19 ). The average mPFS was 15.2 months including Phase III, Phase II, and observational studies and excluding the Adili et al 13 2013 study of PD thyroid cancer.…”

“…Aside from including relevant combination trials that show promising synergistic effects between sorafenib and mTOR inhibitors, this systematic review included 18 trials (as opposed to five trials per the Anderson et al 33 and seven trials per the Shen et al 34 reviews). We included observational trials that were listed separately (see Table 2 ), the results of which were consistent with other prospective trials but may have included extra valuable information (de la Fouchardiere et al, 16 Chen et al, 17 Marotta et al, 25 Cabanillas et al 28 ). For example, these trials include observed anatomic areas of sorafenib responsiveness and measurements of thyroglobulin.…”

Clinical Efficacy of Targeted Biologic Agents as Second-Line Therapy of Advanced Thyroid Cancer

“…The diminished second-line efficacy in comparison to the front-line setting is expected and is consistent with the experience of other cancer types for which therapeutic efficacy declines with an increasing number of prior lines of therapy [22][23][24]. A recent study reported comparable efficacy of second-line and first-line multiple kinase inhibitor therapy for differentiated thyroid cancer patients with a trend in favor of front-line therapy (median PFS: 6.7 month vs. 7.6 months; hazard ratio: 0.85 [95% CI: 0.45-1.61]; p ϭ .6) [25]. Interestingly, we observed efficacy diminution with the vascular-targeting class of agents, whereas treatment with nonantiangiogenic agents achieved comparable efficacy in the front-line and second-line settings.…”