Radioactive Iodine-refractory Differentiated Thyroid Cancer Research Articles

Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Real-World Treatment

Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Real-World Treatment

Efficacy and Safety of Multikinase Inhibitors for Patients With Refractory Thyroid Cancer: Systematic Review and Network Meta-Analysis.

Multikinase inhibitors (MKIs) improve the treatment of refractory thyroid cancer, including radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and advanced medullary thyroid carcinoma (aMTC). This study aims to compare the efficacy of MKIs in improving survival outcomes and safety. Comprehensive database searches of MEDLINE via PubMed, EMBASE, and Cochrane were performed from inception to December 2023. Three independent authors selected these studies. Randomized controlled trials that compared the use of a MKI to other MKIs or placebo were included. This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Risk of bias was analyzed using the Cochrane risk of bias 2 tool. Bayesian network meta-analysis was performed. Treatments were grouped into common nodes based on the type of MKI. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate, disease control rate, clinical benefit rate, and adverse events. Cabozantinib 60 mg/day (CAB60) was associated with the highest prolonged PFS in RAIR-DTC patients, followed by lentivatinib 18 or 24 mg/day (LEN18 or LEN24), and apatinib. PFS was also improved in aMTC patients who received CAB 140 mg/day (CAB140), CAB60, or anlotinib. A significantly greater improvement on the performance of OS was seen in CAB60, LEN24, anlotinib, and sorafenib in RAIR-DTC patients, but in aMTC patients there were lack of statistical differences. Compared with the low-dose MKIs, high-dose MKIs such as CAB, LEN, and vandetanib increased the incidence of adverse events. CAB60, LEN, and apatinib are promising topical MKIs with statistically significant primary outcomes in RAIR-DTC patients, while CAB and anlotinib are effective in prolonging PFS in aMTC patients.

Current Advances in Radioactive Iodine-Refractory Differentiated Thyroid Cancer.

Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, and certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine (RAI) therapy is a cornerstone in DTC management, but cancer cells can eventually develop resistance to RAI. Radioactive iodine-refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. The RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. 18F-FDG PET/CT has been widely used and has demonstrated prognostic value, but 18F-FDG DTC avidity may remain low. Fibroblast activation protein inhibitors (FA-Pi)s, prostatic-specific membrane antigen (PSMA), and somatostatin receptor (SSTR) tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in the diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse-event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed at re-inducing RAI accumulation in DTC cells. Results appear promising, but not excellent. RAIR-DTC remains a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation, with post-therapy whole-body scan (PT-WBS) the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents obliges physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice.

A Prospective Cohort Study Exploring the Effect of Lenvatinib Planned Drug Holidays in Treatment of Differentiated Thyroid Cancer.

Background: Although lenvatinib is the preferred treatment for unresectable radioactive iodine-refractory differentiated thyroid cancer (RR-DTC), this agent exerts considerable toxicities, which can lead to frequent dose interruptions and modifications. The adoption of planned drug holidays has been recently suggested as one means of minimizing or avoiding these severe adverse events. Our retrospective study demonstrated that planned drug holidays appear to be a promising strategy for continuing of lenvatinib. However, the benefits of planned drug holidays in a prospective study have yet to be clarified. Here, we investigated the impact of planned drug holidays on clinical outcomes in patients treated with lenvatinib in the COLLECT study. Methods: In COLLECT, a prospective observational study, patients with RR-DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities was permitted. Furthermore, planned drug holidays were allowed to avoid severe or intolerable toxicities. The present post hoc analysis focused on evaluating the impact of planned drug holidays on clinical outcomes, including overall survival (OS), time to treatment failure (TTF), time to failure strategy (TFS), and progression-free survival (PFS), in patients in the COLLECT study who were treated with lenvatinib. Results: In total, 262 patients were included. Of the 253 patients evaluable for efficacy, 73 undertook a planned drug holiday at the discretion of the attending physician. OS, TTF, TFS, and PFS were significantly longer in patients who used a planned drug holiday than in those who did not. The planned drug holiday group demonstrated notable clinical outcomes, with a 1-year OS of 95.8% and a 1-year PFS of 94.5%. Moreover, planned drug holidays demonstrated a clinically meaningful advantage in clinical outcomes. The planned drug holiday group had a significantly longer duration of administration at a dose of ≥10 mg. Conclusions: Planned drug holidays for lenvatinib were associated with significantly improved clinical outcomes compared to daily oral administration. Further investigation of the optimal treatment schedule for lenvatinib is warranted. Clinical Trial Registration: UMIN000022243.

Real-world practice patterns and outcomes for RAI-refractory differentiated thyroid cancer.

The optimal timing for initiating multi-kinase inhibitors (MKIs) in patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC) remains unclear. Thus, we evaluated the real-world practice patterns and outcomes in asymptomatic patients with progressive RAI-R DTC (≥1 lesion ≥1 cm in diameter) in the USA (US population) and outside the USA (non-US population). In this prospective, non-interventional, open-label study, eligible patients were chosen by treating physicians to receive MKI therapy (cohort 1) or undergo active surveillance (cohort 2) at study entry. Cohort 2 patients were allowed to transition to MKI therapy later. The primary endpoint was time to symptomatic progression (TTSP) from study entry. Data were compared descriptively. When endpoints were inestimable, 36-month rates were calculated. Of the 647 patients, 478 underwent active surveillance (cohort 2) and 169 received MKI treatment (cohort 1). Patients underwent surveillance at a higher rate in the US (92.6%) vs the non-US (66.9%) populations. Half of US and non-US patients who qualified for MKI treatment had initial American Thyroid Association (ATA) low-to-intermediate-risk disease. In cohort 2, the 36-month TTSP rates from study entry were 65.6% and 66.5% in the US and non-US populations, respectively. Cohort 2 patients treated later demonstrated 36-month TTSP rates of 30.8% and 55.8% in the US and non-US populations, respectively. Active surveillance is a viable option for asymptomatic patients with progressive RAI-R DTC. However, early intervention with MKI therapy may be more suitable for others. Further research is needed to identify patients who are optimal for active surveillance. NCT02303444.

Advances in the molecular mechanism and targeted therapy of radioactive-iodine refractory differentiated thyroid cancer.

Most patients with differentiated thyroid cancer have a good prognosis afterradioactive iodine-131 treatment, but there are still a small number of patients who are not sensitive to radioiodine treatment and may subsequently show disease progression. Therefore, radioactive-iodine refractory differentiated thyroid cancer treated with radioiodine usually shows reduced radioiodine uptake. Thus, when sodium iodine symporter expression, basolateral membrane localization and recycling degradation are abnormal, radioactive-iodine refractory differentiated thyroid cancer may occur. In recent years, with the deepening of research into the pathogenesis of this disease, an increasing number of molecules have become or are expected to become therapeutic targets. The application of corresponding inhibitors or combined treatment regimens for different molecular targets may be effective for patients with advanced radioactive-iodine refractory differentiated thyroid cancer. Currently, some targeted drugs that can improve the progression-free survival of patients with radioactive-iodine refractory differentiated thyroid cancer, such as sorafenib and lenvatinib, have been approved by the FDA for the treatment of radioactive-iodine refractory differentiated thyroid cancer. However, due to the adverse reactions and drug resistance caused by some targeted drugs, their application is limited. In response to targeted drug resistance and high rates of adverse reactions, research into new treatment combinations is being carried out; in addition to kinase inhibitor therapy, gene therapy and rutin-assisted iodine-131 therapy for radioactive-iodine refractory thyroid cancer have also made some progress. Thus, this article mainly focuses on sodium iodide symporter changes leading to the main molecular mechanisms in radioactive-iodine refractory differentiated thyroid cancer, some targeted drug resistance mechanisms and promising new treatments.

The efficacy and safety in radioactive iodine refractory thyroid cancer patients treated with sorafenib.

Sorafenib included in Chinese medical insurance is the earliest targeted drug for radioactive iodine refractory differentiated thyroid cancer (RR-DTC). This study is to further demonstrate the clinical efficacy and safety of sorafenib used in Zhujiang Hospital of Southern Medical University. RR-DTC patients treated at our Department of Nuclear Medicine in Zhujiang Hospital of Southern Medical University (October 2017-May 2020) were retrospectively analyzed. Treatment effects, progression-free survival (PFS), and adverse effects (AEs) during medication were evaluated. Of the 31 patients included, 26 patients were evaluated for efficacy with a median follow-up time of 17.5 months (4.0-51.0 months). The disease control rate (DCR) was 57.7% (n = 15) and the objective response rate (ORR) was 26.9% (n= 7). Most patients with disease control had thyroglobulin decreases of more than 60% (p = 0.004), ORRs were favorable in patients with lung metastasis and lung-only metastasis (p = 0.010 and 0.001, respectively). The PFS of the 26 patients analyzed was 16.5 months (95%CI: 14.41 -23.90 months). In the subgroup analysis, female, patients with lung-only metastasis, hand-foot skin syndrome (HFS), and thyroglobulin response ≥ 60% observed longer PFS (p = 0.038, 0.045, 0.035, and 0.000, respectively), while patients with bone metastasis had lower PFS (p = 0.035). The most common toxicity profile was HFS (93.5%), followed by diarrhea (83.9%), alopecia (74.2%). All the side effects were mainly grade 1-2. Grade 3-4 adverse reactions were more common in diarrhea and HFS. Sorafenib has promising efficacy in RR-DTC, especially in patients with lung metastasis and lung-only metastasis. The AEs of sorafenib were generally mild, and the main AE was HFS.

Molecular basis and targeted therapy in thyroid cancer: Progress and opportunities.

Thyroid cancer (TC) is the most prevalent endocrine malignant tumor. Surgery, chemotherapy, radiotherapy, and radioactive iodine (RAI) therapy are the standard TC treatment modalities. However, recurrence or tumor metastasis remains the main challenge in the management of anaplastic thyroid cancer (ATC) and radioiodine (RAI) radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). Several multi-tyrosine kinase inhibitors (MKIs), or immune checkpoint inhibitors in combination with MKIs, have emerged as novel therapies for controlling the progression of DTC, medullary thyroid cancer (MTC), and ATC. Here, we discuss and summarize the molecular basis of TC, review molecularly targeted therapeutic drugs in clinical research, and explore potentially novel molecular therapeutic targets. We focused on the evaluation of current and recently emerging tyrosine kinase inhibitors approved for systemic therapy for TC, including lenvatinib, sorafenib and cabozantinib in DTC, vandetanib, cabozantinib, and RET-specific inhibitor (selpercatinib and pralsetinib) in MTC, combination dabrafenib with trametinib in ATC. In addition, we also discuss promising treatments that are in clinical trials and may be incorporated into clinical practice in the future, briefly describe the resistance mechanisms of targeted therapies, emphasizing that personalized medicine is critical to the design of second-line therapies.

A multicenter, single-arm phase 2 study of surufatinib plus toripalimab for patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer.

6089 Background: For patients (pts) with radioactive iodine–refractory differentiated thyroid cancer (RAIR-DTC), there presents a considerable therapeutic challenge with poor long-term outcomes. The open-label, multi-cohort, single-arm phase 2 study was performed to evaluate surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) in combination with toripalimab (an anti-PD-1 antibody) in pts with RAIR-DTC. Methods: Eligible pts were with locally advanced or metastatic RAIR-DTC who were not amenable for surgery or external beam radiotherapy, with a radiologically confirmed disease progression within 12 months before treatment, and with ≥6 months since last radioiodine treatment. Enrolled pts received surufatinib 250 mg orally, QD, plus toripalimab 240 mg IV, Q3W, until disease progression or reaching the maximum treatment duration with toripalimab of 24 months, or other protocol-specified criteria. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From March 2020 to November 2021, 15 pts were enrolled and received a median duration of 11.1 months of the combination treatment, with a median age of 61 years (range: 37-74). 9 (60%) pts were male, and 12 (80%) had papillary thyroid cancer. Of the 13 pts with PD-L1 immunochemical results, 6 pts had PD-L1 CPS ≥1%. As of 28 Dec 2022, the median follow-up duration was 22.11 months. Of the 15 pts with at least one post-baseline tumor assessment, the confirmed ORR was 33.3% (5 PRs) and DCR was 93.3%. mDoR was 8.34 months. mPFS (95%CI) was 10.91 months (4.01, NA). mOS was not reached, and 12-month OS rate was 100%. 14 (93.3%) pts had treatment-emergent adverse events (TEAEs), and 10 (66.7%) pts reported grade ≥3 TEAEs, most commonly (≥10% pts) with hypocalcemia (20%), diarrhea (20%) and hypertension (13%). There was no death due to TEAE in the study. Conclusions: Surufatinib plus toripalimab showed encouraging antitumor activity and tolerable safety profile in pts with locally advanced or metastatic RAIR-DTC. Clinical trial information: NCT04169672 .

Prognostic value of serum stimulating thyroglobulin in metastatic radioactive iodine refractory differentiated thyroid cancer

Purpose: To investigate the prognostic value of serum-stimulated thyroglobulin (ps-Tg) before the first 131I therapy in patients with metastatic radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). Methods: From August 2017 to August 2020, the clinical data for 160 patients with thyroid papillary carcinoma (PTC) who received thyroidectomy and 131I treatment were analyzed retrospectively. Differences in clinical data and related thyroid indices were compared. Univariate and multivariate logistic regression analyses were used to analyze the related factors affecting the occurrence of RR-DTC. Receiver-operator characteristic (ROC) curves were used to determine the discriminative power of ps-Tg in predicting RR-DTC, while the Kaplan-Meier survival curve of ps-Tg for RR-DTC was drawn. Results: A total of 160 patients with thyroid cancer were enrolled, including 47 males, and 113 females (70.62 %). Overall mean age was 39 ± 13 years old. The follow-up results showed that 68 patients with thyroid cancer were refractory to radioactive iodine. The ps-Tg of the iodine-refractory group was higher than that of the iodine-receptive group (p < 0.001). Multivariate logistic regression showed that ps-Tg was an independent risk factor for RR-DTC (OR = 1.086, p = 0.000). The optimal cut-off value of ps-Tg for predicting progression to RR-DTC was 19.21 μg/L. Kaplan-Meier survival curve showed that the risk of iodine refractory in patients with thyroid cancer (≥ 19.21 μg/L) was higher than that of patients with thyroid cancer < 19.21 μg/L (p < 0.001). Conclusion: The ps-Tg before the first 131I therapy independently predicts the occurrence of metastatic RR-DTC when ps-Tg is greater than the risk of RR-DTC increase. This finding will be helpful in predicting the occurrence of RR-DTC, in order to determine the best time to start treatment and make individualized treatment decisions.

Clinical Utility of Cabozantinib in the Treatment of Locally Advanced or Metastatic Differentiated Thyroid Carcinoma: Patient Selection and Reported Outcomes.

Treatment of differentiated thyroid cancer (DTC) is multidisciplinary and begins with surgical intervention. Often, radioactive iodine is used as the prototype targeted therapy to ablate any residual thyroid tissue or metastatic deposits. While these initial therapeutic modalities are often curative with no need for further treatment, many patients develop radioactive-iodine refractory (RAIR) disease. When patients present with progressive RAIR disease, they often require systemic therapy. Several multikinase inhibitors have been approved for treatment of DTC, with sorafenib and lenvatinib employed in frontline treatment settings since approvals in 2013 and 2015, respectively. While patients have benefited from such treatment, progression is inevitable, and until recently, there were no established second-line options. Cabozantinib was recently approved for treatment of patients with DTC who have progressed on either frontline sorafenib or lenvatinib. Molecular testing for driver mutations or gene fusions, such as BRAF V600E or RET or NTRK fusions, has become standard recommendations for RAIR DTC patients due to excellent treatment options with highly selective targeted therapies, most RAIR DTC patients do not harbor such aberrations or have so-called "undruggable" mutations, making rendering cabozantinib an attractive and feasible treatment option for many patients.

Neutrophil-to-lymphocyte ratio as an independent factor for worse prognosis in radioiodine refractory thyroid cancer patients.

This study aimed to evaluate neutrophil to lymphocyte ratio (NLR) as a laboratory biomarker in radioactive iodine-refractory (RAIR) locally advanced and/or metastatic differentiated thyroid cancer (DTC) and determine its correlation with overall survival (OS). We retrospectively included 172 patients with locally advanced and/or metastatic RAIR DTC admitted between 1993 and 2021 at INCA. Age at diagnosis, histology, presence of distant metastasis (DM), DM site, neutrophil-to- lymphocyte ratio (NLR), imaging studies such as PET/CT results, progression free survival (PFS) and overall survival (OS) data were analyzed. NLR was calculated at the time of locally advanced and/or metastatic disease diagnosis and the cutoff value was 3. Survival curves were established using the Kaplan-Meier method. The confidence interval is 95%, and a p-value of less than 0.05 was considered statistically significant RESULTS: Out of 172 patients, 106 were locally advanced, and 150 presented DM at some point during follow-up. Regarding NLR data, 35 had NLR over 3 and 137 had NLR under 3. Higher NLR at was associated with shorter OS (6 vs. 10; p = 0.05) and with highest SUV on FDG PET-CT (15.9 vs. 7.7, p = 0.013). We found no association between higher NLR and age at diagnosis, DM or final status. NLR higher than 3 at the time of locally advanced and/or metastatic disease diagnosis is an independent fator for shorter OS in RAIR DTC patients. Noteworthy higher NLR was also associated with highest SUV on FDG PET-CT in this population.

Kinase inhibitors in thyroid cancers.

The treatment landscape for thyroid cancers has changed rapidly with the availability of kinase inhibitors against VEGFR, BRAF, MEK, NTRK, and RET. We provide an up-to-date review of the role of kinase inhibitors in thyroid cancer and discuss upcoming trials. A comprehensive review of the available literature describing kinase inhibitors in thyroid cancer was performed. Kinase inhibitors have become the standard of care for patients with metastatic radioactive iodine-refractory thyroid cancer. Short-term treatment can re-sensitize differentiated thyroid cancer to radioactive iodine, thereby potentially improving outcomes and sparing toxicities associated with the long-term use of kinase inhibitors. The approval of cabozantinib as salvage therapy for progressive radioactive iodine-refractory differentiated thyroid cancer following failure with sorafenib or lenvatinib adds to the available armamentarium of active agents. Vandetanib and cabozantinib have become mainstay treatments for metastatic medullary thyroid cancer regardless of RET mutation status. Selpercatinib and pralsetinib, potent and selective receptor kinase inhibitors with activity against RET, have revolutionized the treatment paradigm for medullary thyroid cancers and other cancers with driver mutations in RET. Dabrafenib plus trametinib for BRAF mutated anaplastic thyroid cancer provides an effective treatment option for this aggressive cancer with a dismal prognosis. In order to design the next generation of agents for thyroid cancer, future efforts will need to focus on developing a better understanding of the mechanisms of resistance to kinase inhibition including bypass signaling and escape mutations.

1644O Donafenib in locally advanced/metastatic, radioactive iodine-refractory, differentiated thyroid cancer: A randomized, double-blind, placebo-controlled, multi-center phase III clinical trial (DIRECTION)

Donafenib, an oral multi-kinase inhibitor that targets Raf/MEK/ERK, VEGFR, PDGFR, has shown potent efficacy and well-tolerated safety profile in patients with progressive locally advanced/metastatic radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) in a phase II study. The DIRECTION study aims to evaluate the efficacy and safety of donafenib and initiated when there was no available TKI for Chinese RAIR-DTC patients.

Vascular Endothelial Growth Factor Receptor Inhibitors in Chinese Patients With Advanced Radioactive Iodine-Refractory Differentiated Thyroid Cancer: A Network Meta-Analysis and Cost-Effectiveness Analysis.

IntroductionTwo targeted drugs (apatinib and lenvatinib) show clinical efficacy in first-line treatment of Chinese patients with radioactive advanced iodine-refractory differentiated thyroid cancer (RAIR-DTC) and are recommended by the Chinese Society of Clinical Oncology guidelines. Considering the high clinical cost of long-term vascular endothelial growth factor receptor inhibitor administration and to determine which of the two targeted drugs is preferable, we opted to conduct a cost-effectiveness analysis (CEA) and network meta-analysis (NMA).Material and MethodsThe results of NMA and CEA included in the two phase III randomized clinical trials REALITY (NCT03048877) and Study-308 (NCT02966093), in which Bayesian NMA and CEA were performed on 243 and 149 Chinese patients, respectively, were retrieved. Overall survival and progression-free survival (PFS) for apatinib versus lenvatinib were determined by NMA. CEA involved the development of a 20-year Markov model to obtain the total cost and quality-adjusted life-years (QALYs), and this was followed by sensitivity and subgroup analyses.ResultsCompared with lenvatinib, apatinib therapy provided a 0.837 improvement in QALY and $6,975 reduction in costs. The hazard ratio of apatinib versus lenvatinib and the cost of the targeted drugs had a significant impact on the model. According to the sensitivity analysis, apatinib was more cost-effective and had no correlation with willingness-to-pay in China. Subgroup analysis showed that apatinib maintained PFS more economically.ConclusionNMA and CEA demonstrated that apatinib was more cost-effective compared to lenvatinib in the first-line treatment of Chinese RAIR-DTC patients.

Cost-Effectiveness of Apatinib and Cabozantinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid Cancer.

Background: The effectiveness of apatinib and cabozantinib for the treatment of radioactive iodine–refractory differentiated thyroid cancer (RAIR-DTC) has been demonstrated recently. We aimed to evaluate the cost-effectiveness of these treatments from the Chinese healthcare system perspective. Methods: Two partitioned survival models over a 10-year horizon were built to compare the cost and effectiveness of apatinib vs. placebo and cabozantinib vs. placebo based on the clinical data from the phase 3 randomized REALITY and COSMIC-311 trials. Costs and utility data were obtained from the literature and institutional database. The incremental cost-effectiveness ratio (ICER) was calculated. One-way and probabilistic sensitivity analysis was performed to test the robustness of the conclusion. Results: Apatinib yielded an additional quality-adjusted life-year (QALY) of 0.74 at an additional cost of Chinese Renminbi ¥44,077. The ICER was ¥93,460 (US dollar $13545)/QALY and it was below the current willingness-to-pay (WTP) threshold of ¥217341/QALY. Cabozantinib was associated with an additional QALY of 0.79 at an extra cost of ¥3,55,614 when compared with placebo, and the ICER was ¥4,52,325 ($65,554)/QALY, which was above the WTP threshold. The conclusion were robust under one-way and probabilistic sensitivity analysis. The price of cabozantinib has to drop to ¥5.87/mg (39% of the current price) for it has a 50% likelihood of being cost-effective. Conclusion: Apatinib is cost-effective for RAIR-DTC when compared with placebo from the perspective of Chinese healthcare system. However, based on the current evidence, cabozantinib might not be cost-effective and a reduction of price is warranted.

Anlotinib in radioactive iodine-refractory differentiated thyroid cancer and the usefulness of SUVmax as an prognostic indicator.

e18077 Background: Radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) is characterized by poor therapeutic effect on radioactive iodine with poor prognosis. Therefore, a variety of molecularly targeted drugs are used in the treatment of RAIR-DTC. However, sorafenib and lenvatinib are not “broad-spectrum” anti-cancer drugs for RAIR-DTC. The efficacy and safety of Anlotinib in the treatment of RAIR-DTC need to be studied. Methods: From September 2020 to September 2021, 9 patients with RAIR-DTC were included. Follow-up continued until disease progression or intolerable adverse events occurred. Efficacy was evaluated by serum triglycerides (Tg) and imaging (RECIST1.1). Adverse events were also recorded. Gender, age, maximum standard unit value (SUVmax), tumor metabolic volume (MTV), total glycolysis (TLG), pathological type and tumor stage were included in the univariate analysis. Results: 8 patients reached the standard of “partial biochemical remission”. The average Tg level of these 8 patients decreased by 74.8% after Anlotinib treatment. 15 target lesions (TLs) were found in 6 patients. The average reduction ratio of TLs in these 6 patients was 28.7%. Furthermore, we observed three (50%) PR, three (50%) SD, with an ORR of 50% and a DCR of 100% in these 6 patients. The severity of AEs in all 9 patients did not exceed Grade 2. The most common AEs were hand-foot skin reactions, diarrhea, and hypertension, which accounted for 5/9, 3/9, and 3/9, respectively. Serious drug-related AEs did not occur. The average decrease in Tg after 3 courses was significantly greater in the high metabolism group (TL SUVmax 27.9) compared with the average decrease in the low metabolism group (TL SUVmax < 7.9), with 83.25% and 16.11% respectively (p = 0.027). There was no correlation between age, gender, pathological type, staging, other metabolic indexes of PET/CT and the ratio of patients' Tg reduction. Conclusions: Anlotinib can be used for the treatment of RAIR-DTC. This study confirmed the efficacy of Anlotinib with a high disease control rate. SUVmax can be used as an indicator to predict the therapeutic effect of Anlotinib in RAIR-DTC patients.

Apatinib versus placebo in patients with locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer: Post hoc analyses from the REALITY randomized clinical trial.

6095 Background: In the multicenter, double-blind, randomized, phase 3 REALITY study, apatinib significantly improved clinical benefits in terms of progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared to placebo with a tolerable safety profile in patients with progressive locally advanced or metastatic radioactive iodine-refractory, differentiated thyroid cancer (RAIR-DTC). Here, we investigate the association between baseline characteristics and survival endpoints. Methods: Post-hoc analyses of PFS and OS were done in patients treated with apatinib according to the following subgroups: ECOG performance status (PS) (0 vs 1-2), thyroglobulin (Tg) ( < 223 vs ≥ 223 ng/mL), and tumor target lesions diameter ( < 33.2 vs ≥ 33.2 cm). Results: Among 92 patients with RAIR-DTC included in the study, 46 patients received apatinib. As of December 3, 2021, median PFS was 25.77 (95% CI 11.14-not reached [NR]) vs 11.08 months (95% CI 7.17-NR) for ECOG PS 0 / 1-2, though no statistical significance (HR 0.454, 95% CI 0.161-1.285, p = 0.1373). The median OS was significant prolonged in patients with ECOG PS of 0 compared with those ECOG 1-2 (not reached vs 29.42 months, 95% CI 18.87-NR; HR 0.199, 95% CI 0.054-0.733, p = 0.0152). In subgroups by Tg, median PFS was 25.77 (95% CI 9.11-NR) vs 11.08 (95% CI 5.65-NR) months for Tg < 223 / ≥ 223 ng/mL. A trend towards improved PFS was observed (HR 0.444, 95% CI 0.145-1.361, p = 0.1556). The median OS was significantly improved in patients with Tg < 223 in contrast to those Tg ≥ 223 ng/mL (NR vs 25.87 months, 95% CI 13.58-NR; HR 0.151, 95% CI 0.033-0.689, p = 0. 0147). The median PFS for tumor target lesions diameter < 33.2 cm was significantly improved relative to those ≥33.2 cm (25.77, 95% CI 11.14-NR vs 9.11 months, 95% CI 5.65-NR) with a significant difference (HR 0.289, 95% CI 0.097- 0.859, p = 0.0255); OS data in two subgroups were not mature (NR, 95% CI 29.42-NR vs NR, 95% CI 17.95-NR; HR 0.364, 95% CI 0.112-1.184, p = 0.0932). Conclusions: Post-hoc analysis indicated that among patients receiving apatinib, longer OS benefits were associated with better ECOG PS, lower Tg levels; longer PFS benefits were associated with smaller tumor diameter. These results suggest a better prognosis for early initiation of apatinib treatment in patients with RAIR-DTC. Clinical trial information: NCT03048877.

Recent Improvements in the Treatment of High-Risk Thyroid Cancer

Thyroid cancer is one of the slow-growing tumors with excellent oncological outcomes. However, a small set of patients with unexpectedly severe outcomes are usually ignored. Anaplastic thyroid cancer (ATC) remains one of the most aggressive and lethal solid tumors. Recently, dabrafenib and trametinib combination therapy or neoadjuvant BRAF induction therapy has shown promising results. In addition, a combination of targeted drugs, immunotherapy, surgery, and radiation therapy can improve overall survival in ATC patients. Another disease for which there is no breakthrough treatment is radioactive iodine-refractory differentiated thyroid cancer (DTC). To date, multikinase inhibitors (sorafenib, lenvatinib) targeting the growth factor signaling pathway have been developed and approved as anticancer agents for patients with advanced DTC. This review includes results from multikinase inhibitors to the emergence of new target molecules, including rearrangements during transformation (RET) and tropomyosin receptor kinase (TRK).

Apatinib vs Placebo in Patients With Locally Advanced or Metastatic, Radioactive Iodine–Refractory Differentiated Thyroid Cancer

Patients with radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) have a poor prognosis and limited treatment options. To assess the efficacy and safety of apatinib, a highly selective vascular endothelial growth factor (VEGFR-2) inhibitor, in patients with progressive locally advanced or metastatic RAIR-DTC. This randomized, double-blind, placebo-controlled, phase 3 trial (Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer [REALITY]) was conducted in 92 patients with progressive locally advanced or metastatic RAIR-DTC between February 17, 2017, and March 2, 2020, at 21 sites within China, and the data cutoff date for this analysis was March 25, 2020. Patients were randomly assigned (1:1) to apatinib, 500 mg/d, or placebo. Patients who developed progression while receiving placebo were allowed to cross over to apatinib. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival, objective response rate (ORR), disease control rate (DCR), duration of response, time to objective response, and safety. Intention-to-treat analyses were performed to evaluate efficacy. Of the 92 patients included in the trial, 56 were women (60.9%); mean (SD) age at baseline was 55.7 (10.6) years. Patients were randomized to the apatinib (n = 46) or placebo (n = 46) group. The median follow-up duration was 18.1 (IQR, 12.7-22.2) months. The median PFS was 22.2 (95% CI, 10.91-not reached) months for apatinib vs 4.5 (95% CI, 1.94-9.17) months for placebo (hazard ratio, 0.26; 95% CI, 0.14-0.47; P < .001). The confirmed ORR was 54.3% (95% CI, 39.0%-69.1%) and the DCR was 95.7% (95% CI, 85.2%-99.5%) in the apatinib group vs an ORR of 2.2% (95% CI, 0.1%-11.5%) and DCR of 58.7% (95% CI, 43.2%-73.0%) in the placebo group. The median overall survival was not reached for apatinib (95% CI, 26.25-not reached) and was 29.9 months (95% CI, 18.96-not reached) for placebo (hazard ratio, 0.42; 95% CI, 0.18-0.97; P = .04). The most common grade 3 or higher-level treatment-related adverse events in the apatinib group were hypertension (16 [34.8%]), hand-foot syndrome (8 [17.4%]), proteinuria (7 [15.2%]), and diarrhea (7 [15.2%])-none of which occurred in the placebo group. The REALITY trial met its primary end point of PFS at the prespecified interim analysis. Apatinib showed significant clinical benefits in both prolonged PFS and overall survival with a manageable safety profile in patients with progressive locally advanced or metastatic RAIR-DTC. ClinicalTrials.gov Identifier: NCT03048877.