Radioiodine-refractory Differentiated Thyroid Cancer Research Articles

Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer

.

Effectiveness and toxicity of lenvatinib in refractory thyroid cancer: Dutch real-life data.

The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial. From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies. A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade ≥3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0-15.5) and 18.3 (95% CI: 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04). PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life population and the SELECT study population regarding patient characteristics should be taken into account.

Efficacy and Limitations of Lenvatinib Therapy for Radioiodine-Refractory Differentiated Thyroid Cancer: Real-World Experiences.

Background: The ultimate clinical goal of advanced cancer treatment is improvement of survival. Tyrosine kinase inhibitors (TKIs) were recently approved for radioiodine-refractory differentiated thyroid carcinoma (RR-DTC) that is resistant to conventional therapies since they have significant potential to improve survival in patients who previously had no more treatment strategies available. However, eligible patients are limited in clinical practice, making it difficult to accurately determine the efficacy of TKIs. Patients and Methods: We retrospectively analyzed the efficacy of lenvatinib at a single institution, enrolling 42 RR-DTC patients. Results: The best overall response was partial remission in 26 (62%) patients, stable disease in 10 (24%) patients, and progressive disease (PD) in 6 (14%) patients. The results indicated three-year overall survival (OS) and progression-free survival rates of 51.0% and 32.4%, respectively. Twenty-three (55%) patients had backgrounds that did not match the inclusion criteria of the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. Furthermore, PD-experienced patients individually decided whether to continue lenvatinib, and 17 (41%) made the decision themselves; these patients had a three-year OS of 43.0% and postprogression survival (PPS) of 13.3 [95% confidence interval 6.1-not reached] months. Conclusions: Our real-world investigation revealed that patients have wide-ranging background characteristics, and the decision regarding continuation of therapy after PD is based on the patient's general condition. Our management protocol resulted in good PPS. Furthermore, our results indicated equivalent efficacy of lenvatinib as in the SELECT trial. In conclusion, lenvatinib proved effective for RR-DTC patients in a real-world setting.

Clinicopathological Features Predict Outcomes in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Treated with Sorafenib: A Real-World Study.

Because beneficial response and progression-free survival (PFS) were achieved by well-designed clinical trials with tyrosine kinase inhibitors (TKIs) in patients with progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC), the overall survival (OS) and improvement of therapeutic outcomes in the real world have been anticipated. This prospective, single-center, real-world study assessed the predictive significance of clinicopathological features on disease control rate (DCR), objective response rate (ORR), PFS, and OS in a cohort of 72 patients with progressive RR-DTC treated with sorafenib at an initial dose of 200 mg twice daily. Disease control, objective response, and biochemical effectiveness were achieved in 73.3%, 21.7%, and 77.9% of patients, respectively. The median PFS and OS were 17.6 and 28.9 months, respectively. Multivariate analyses showed that hand-foot syndrome (HFS) was an independent predictor for better DCR and ORR, and 131 I-avidity for higher ORR. In univariate analyses, longer PFS and OS were observed in patients with Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, pathologically well DTC, lung-only metastasis, absence of bone metastasis, biochemically nonineffective response, HFS, or radiological disease control. In multivariate analyses, only well DTC and ECOG PS ≤2 remained as independent prognostic factors for more favorable PFS and OS, respectively, whereas the absence of bone metastasis and biochemically nonineffective response independently predicted superior PFS and OS. This study demonstrated that clinicopathological features might play a vital role in predicting therapeutic outcomes in patients with progressive RR-DTC treated with sorafenib, warranting further optimization of candidates for TKIs. This prospective, single-center, real-world study was designed to investigate the significance of clinicopathological features in predicting response, progression-free survival, and overall survival in patients with progressive radioiodine-refractory differentiated thyroid cancer (DTC) treated with sorafenib. Multivariate analyses showed that hand-foot syndrome was an independent predictor for better response. Meanwhile, well DTC, Eastern Cooperative Oncology Group performance status ≤2, biochemically nonineffective response, and the absence of bone metastasis were independent prognostic factors for more favorable survival. This study demonstrated that clinicopathological features might play a vital role in predicting outcomes in sorafenib-treated patients with radioiodine-refractory DTC, warranting optimization of indications.

Sorafenib and radioiodine-refractory differentiated thyroid cancer (RR-DTC): a systematic review and meta-analysis.

Except conventional treatments, research on medical approach for radioiodine-refractory differentiated thyroid cancer (RR-DTC) was considered particularly challenging. Sorafenib, a novel biological agent, has been widely studied in the treatment of RR-DTC for years. We performed a systematic review and meta-analysis to explore the efficiency and safety of treating RR-DTC patients with sorafenib. An electronic search on PubMed/Medline and Embase was carried out to search associated articles. Fixed-effects or random-effects models were chose according to the heterogeneity. A total of 15 eligible studies (636 patients) were included. As shown by the only randomised clinical trial-DECISION, sorafenib significantly improved progression-free survival (PFS) compared with placebo in patients with progressive RR-DTC. The pooled analysis indicated that there were 26% patients (95% CI: 0.19-0.34) achieved partial response (PR), and 44% patients (98% CI: 0.39-0.48) achieved stable disease (SD). The most frequent adverse effects (AEs) observed included hand-foot syndrome (HFS), diarrhoea, fatigue, alopecia, weight loss (WS) and rash, the incidence of all grades AEs for which were 71%, 60%, 59%, 55%, 51% and 50%, respectively. There were 68% patients (252/368), who had a dose reduction because of the drug toxicities and AEs. Sorafenib could improve PFS in patients with progressive RR-DTC, comparing with placebo. Due to the resistance to conventional treatments, sorafenib is considered as a promising treatment for RR-DTC by most physicians specialised in this field. However, the use of sorafenib should be cautious due to a high incidence of AEs caused by the agent. More effective agents with less toxicities are warranted.

Unmet Clinical Needs in the Treatment of Patients with Thyroid Cancer.

The increased incidence of thyroid cancer is a worldwide phenomenon; however, the issue of overdiagnosis has been most prominent in South Korea. The age-standardized mortality rate of thyroid cancer in Korea steeply increased from 1985 to 2004 (from 0.17 per 100,000 to 0.85 per 100,000), and then decreased until 2015 to 0.42 per 100,000, suggesting that early detection reduced mortality. However, early detection of thyroid cancer may be cost-ineffective, considering its very high prevalence and indolent course. Therefore, risk stratification and tailored management are vitally important, but many prognostic markers can only be evaluated postoperatively. Discovery of preoperative marker(s), especially for small cancers, is the most important unmet clinical need for thyroid cancer. Herein, we discuss some such factors that we recently discovered. Another unmet clinical need is better treatment of radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) and undifferentiated cancers. Although sorafenib and lenvatinib are available, better drugs are needed. We found that phosphoglycerate dehydrogenase, a critical enzyme for serine biosynthesis, could be a novel therapeutic target, and that the lymphocyte-to-monocyte ratio is a prognostic marker of survival in patients with anaplastic thyroid carcinoma or RAIR DTC. Deeper insights are needed into tumor-host interactions in thyroid cancer to improve treatment.

Ultrasound characteristics of cervical lesions in patients with radioiodine refractory differentiated thyroid cancer: A strobe-compliant article.

Radioiodine refractory (RAIR) is the major cause of thyroid cancer-related death. In order to avoid needless Radioiodine (RAI) therapy, recognizing the RAIR cases in time is important for the patients to obtain more time for the effective therapy.Evaluate the ultrasound features of cervical metastatic lymph node in patients with RAIR differentiated thyroid cancer (DTC).Seventeen adult patients with histologically confirmed locally advanced or metastatic RAIR-DTC were prospectively enrolled. The ultrasound (US) characteristics of cervical lesions in patients with the RAIR-DTC were compared with cervical lymph node metastasis from 59 non RAIR-DTC cases.Among the 17 patients, cervical lymph node metastasis was found in 15 patients (88.3%). The cervical lesions of RAIR-DTC (mean size, 2.0 cm) were larger than that in non RAIR-DTC group (mean size, 1.30 cm). More multiple lesions and more lesions with visible flow were found in the RAIR Group, while fewer hyperechogenic punctuations were found in RAIR group (P < .05). The distant metastasis rates showed that RAIR-DTC led to a poorer prognosis than those of patients in the non RAIR Group (P < .01).Ultrasound can help distinguish metastasized cervical lymph nodes of RAIR-DTC patients from non RAIR-DTC patients. For RAIR-DTC patients, a long-term US evaluation should be performed.

Mitogen-Activated Protein Kinase Pathway Inhibition for Redifferentiation of Radioiodine Refractory Differentiated Thyroid Cancer: An Evolving Protocol.

Background: Some patients with metastatic differentiated thyroid cancer (DTC) lack iodine avidity and are therefore unsuitable for radioactive iodine (RAI) therapy. Limited experience suggests that single-agent selective mitogen-activated protein kinase (MAPK) pathway inhibitors can restore expression of the sodium-iodide symporter rendering RAI refractory (RAIR) DTC patients amenable to RAI therapy. The aim of this study was to assess the feasibility of mutation-guided MAPK-pathway blockade combined with thyroid hormone withdrawal (THW) for redifferentiation. Methods: This is a retrospective review of metastatic RAIR DTC and driver mutation in MAPK pathway, treated on a redifferentiation protocol. All patients had metastatic disease that had never been RAI-avid and/or imaging and biochemical progression despite treatment with RAI within the past 12 months. Patients with tumors harboring an NRAS mutation were treated with an MEK inhibitor (trametinib), and tumors with a BRAFV600E mutation with combined BRAF and MEK inhibition (dabrafenib and trametinib; or vemurafenib and cobimetinib) for four weeks. Thyrotropin stimulation was performed by THW for four weeks. Restoration of RAI uptake was determined by 124I positron emission tomography/computed tomography imaging. The response was assessed at least three months post-RAI. Results: From 2015 to 2017, six patients (age 45-70, four females) received redifferentiation therapy. Three patients had an NRAS mutation; two with follicular thyroid carcinoma (FTC) and one with a poorly differentiated thyroid carcinoma (PDTC); and three patients had a BRAFV600E mutation and papillary thyroid carcinoma (PTC). One NRAS and all BRAFV600E mutation cases demonstrated restoration of RAI uptake and proceeded to RAI therapy with a median follow-up of 16.6 months (range 13.5-42.3 months). The patient with an NRAS mutation and two of three patients with a BRAFV600E demonstrated partial imaging response beyond a three-month follow-up. Grade 3 adverse events (acneiform rash) were observed in two patients with NRAS mutations. Conclusions: Mutation-guided MAPK pathway inhibition with MEK inhibitor or a combination of BRAF inhibitor and MEK inhibitor under concurrent THW is a feasible and a promising strategy to redifferentiate RAIR DTC, thereby rendering them suitable for RAI therapy with satisfactory retention following treatment.

1862PD - Impact of lung metastasis on overall survival (OS) in the phase III SELECT study with lenvatinib (LEN) in patients (pts) with radioiodine refractory differentiated thyroid cancer (RR-DTC)

BackgroundIn the randomized phase III SELECT study, LEN demonstrated a significant prolongation of progression-free survival compared with placebo (PBO) in pts with RR-DTC. There was no significant difference in overall survival (OS) between LEN and PBO arms which was likely due to>80% of pts on the PBO arm crossing over to open-label LEN treatment. This exploratory post hoc analysis investigated the impact of measurable lung metastasis on OS from the SELECT study. MethodsThe hazard ratio (HR) for OS (data cutoff, September 1, 2016) and the 95% CIs were estimated using the Cox proportional hazards model. The influence of various baseline characteristics on OS was analyzed using a multivariate analysis based on a Cox proportional hazards model. Subgroup analysis of OS was conducted based on maximum size of measurable lung metastasis (≥ 1cm per RECIST 1.1) at baseline. ResultsIn the overall population (392 pts), median OS of LEN (261 pts) and PBO (131 pts, with 115 pts crossed over to LEN) arms, were 40.3 months (M) and 34.5 M, respectively (hazard ratio [HR] 0.87, 95% CI 0.66 –1.15, P=0.3170). In 306 pts with lung metastasis of≥1.0cm, significant prolongation of OS was observed with LEN (199 pts) compared with PBO (107 pts, with 95 pts crossed over to LEN) (HR 0.63, 95% CI 0.47–0.85, P=0.0025). This was maintained after adjustment for baseline characteristics in the multivariate model. Similar trends of OS prolongation by LEN were observed in pts with lung metastasis of≥1.5cm, ≥ 2.0cm, and 1.0–2.0cm (Table). ConclusionsIn pts with lung metastasis of≥1.0cm, LEN significantly prolonged OS compared to pts treated by PBO including those crossed over to LEN. This post-hoc analysis suggests that RR-DTC pts with lung metastasis could be candidates for targeted therapy. Table1862PD Overall survival by size of measurable lung metastasis at baselineTableLung LesionNumber of PtsMedian OS (M)HR95% CIP ValueLENPBOLENPBO≥1.0cm19910744.733.10.630.47 – 0.850.0025≥1.5cm1508444.122.30.630.45 – 0.890.0082≥2.0cm945834.719.30.650.44 – 0.980.03831.0–2.0cm1054949.238.60.630.40 – 0.990.0438*≥ 1cm per RECIST 1.1 Clinical trial identificationNCT01321554; Release date: December 30, 2016. Editorial acknowledgementOxford PharmaGenesis, Newtown, PA, USA; Funded by Eisai Inc. Legal entity responsible for the studyEisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. FundingEisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. DisclosureM. Tahara: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self): Merck Serono; Honoraria (self): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Boehringer-Ingelheim; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Novartis. N. Kiyota: Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Merck Serono; Honoraria (self), Research grant / Funding (institution): Astra-Zeneca; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Chugai Pharmaceutical. A..O. Hoff: Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Astra-Zeneca; Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Genzyme. T.K. Owonikoko: Advisory / Consultancy, Research grant / Funding (institution): Novartis, Celgene, Bayer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune, Abbvie; Advisory / Consultancy, Research grant / Funding (institution): G1 Therapeutics, Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Amgen, Loxo/Lilly; Research grant / Funding (institution): Astellas, Stemcentrx, Regeneron, Corvus Pharmaceuticals; Research grant / Funding (institution): United Therapeutics, Fujifilm, Pfizer; Research grant / Funding (institution): Aeglea Biotherapeutics, Incyte, Merck; Advisory / Consultancy: Sandoz, Eisai, Takeda, Seattle Genetics; Advisory / Consultancy: BerGenBio, PharmaMar, Boehringer Ingelheim; Advisory / Consultancy: EMD Serono, Xcovery; Advisory / Consultancy: Heron Pharmaceuticals, Armo BioSciences; Shareholder / Stockholder / Stock options: Cambium Oncology. C.E. Dutcus: Full / Part-time employment: Eisai Inc.. T. Suzuki: Full / Part-time employment: Eisai Co., Ltd. M. Ren: Full / Part-time employment: Eisai Inc.. S. Misir: Full / Part-time employment: Eisai Inc. L.J. Wirth: Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merck. All other authors have declared no conflicts of interest.

Short Call Abstracts

Short Call Abstracts

Evaluation of the Qtc Interval During Lenvatinib Treatment in Radioiodine-Refractory Differentiated Thyroid Cancer: Reports from the Real-Life Clinical Practice

As for other tyrosine kinase inhibitors, a prolongation of ECG-recorded QTc intervals may be observed during lenvatinib treatment; a warning on this phenomenon has been stated. However, methods and frequency of ECG recordings have seldom been reported in this context. We present two cases of patients treated with lenvatinib for radioiodine-refractory differentiated thyroid cancer in whom the QTc interval was long monitored through a weekly 12-lead ECG registration. Overall, the maximum QTc increase above baseline was 3 and 31ms in the first and second patient, respectively. QTc interval did not reach the toxicity value for drug withdrawal in either of the patients. These data may provide further information on cardiac safety profile of lenvatinib in a real-life practice.

FDG PET/CT for the early prediction of RAI therapy response in patients with metastatic differentiated thyroid carcinoma.

BackgroundIn some patients with metastatic differentiated thyroid cancer, even if they had substantial of radioactive iodine (RAI) uptake, the RAI therapy response was poor. We investigated the usefulness of FDG PET/CT for the early prediction of RAI therapy response in the patients with metastatic differentiated thyroid cancer (DTC).MethodsThe 54 metastatic DTC patients who underwent both RAI therapy scan and FDG PET/CT at the same period were enrolled in the study. Clinical information and several parameters from RAI therapy scan and FDG PET/CT were investigated. Therapeutic response of RAI was assessed as two categories: response rate (RR) and disease control rate (DCR).ResultsTwenty-two patients (41%) had therapeutic response to RAI therapy, whereas 32 (59%) patients did not. There were no significant differences in age, sex, stage, histology, metastasis site, stimulated Tg or Tg-Ab, therapeutic doses, and even RAI uptake pattern among two groups. However, there was a significant negative correlation between FDG avidity of metastatic lesions and RR (OR = 0.233; p = 0.016). Although the patient group with only RAI uptake showed a significant correlation with RR (OR = 5.833; p = 0.01), the patient group with both RAI and FDG uptake did not show any significant correlation with RR. In the subgroup analysis, uptake grades of RAI or FDG was well correlated with DCR.ConclusionsThe patient group with FDG uptake in metastatic DTC showed poor response to RAI therapy regardless of the degree of RAI uptake. Therefore, FDG PET/CT may help us identify the patients with radioiodine refractory DTC and establish an appropriate treatment strategy in the early period.

Influence of tumor size and Eastern Cooperative Oncology Group performance status (ECOG PS) at baseline on patient (pt) outcomes in lenvatinib-treated radioiodine-refractory differentiated thyroid cancer (RR-DTC).

6081 Background: In SELECT, lenvatinib significantly improved progression-free survival (PFS) of pts with RR-DTC versus placebo (18.3 v 3.6 months; hazard ratio [HR]: 0.21 [99% CI: 0.14, 0.31]; P&lt;0.001). Here we examine the treatment of RR-DTC with lenvatinib in relation to tumor size (sum of all targeted lesions) and ECOG PS. Methods: In this post hoc analysis of SELECT with pts randomized to receive lenvatinib, Kaplan-Meier estimates of time to ECOG PS ≥2 were calculated for subgroups of pts according to baseline ECOG PS or tumor size. Objective response rate (ORR) and Kaplan-Meier estimates of overall survival (OS) and PFS according to ECOG PS (0 or 1) at baseline were calculated. Correlations between ECOG PS at baseline (0 or 1) and maximum tumor shrinkage were calculated using one-way analysis of variance. Results: Pts with ECOG PS 0 or 1 at baseline had similar demographic and disease characteristics. ORR was 78.5% and 51.0% for pts with ECOG PS 0 and 1 at baseline, respectively (odds ratio [95% CI]: 3.508 [2.018, 6.097]). Mean maximum percent decrease in tumor size was significantly greater in pts with baseline ECOG PS 0 (-46.13%) versus pts with ECOG PS 1 (-37.16%; P=0.0017). For pts with ECOG PS 1 at baseline, time to ECOG PS ≥2 was numerically shorter with tumor size &gt;60 mm versus tumor size ≤60 mm (HR [95% CI]: 1.450 [0.708, 2.967]). Additional results are summarized in the table. Conclusions: Among pts with RR-DTC, PFS, OS, ORR, and time to ECOG ≥2 were generally better for patients with lower ECOG PS or smaller tumor size at baseline. These results may indicate that it is beneficial to start lenvatinib in pts with RR-DTC early, before ECOG PS worsens and tumor size increases. Clinical trial information: NCT01321554. [Table: see text]

A phase 3 (COSMIC-311), randomized, double-blind, placebo-controlled study of cabozantinib in patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy.

TPS6097 Background: Treatment options are limited for patients with RAI-refractory DTC that is resistant to VEGFR-targeted therapy. Cabozantinib inhibits receptor tyrosine kinases including VEGFR2, MET, AXL, and RET, which are implicated in the development of DTC, and has shown clinical activity in early-phase studies of patients with RAI-refractory DTC. This study evaluates the efficacy and safety of cabozantinib in patients with RAI-refractory DTC who have progressed during or after prior VEGFR-targeted therapy. Methods: This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial (NCT03690388). The co-primary endpoints are progression-free survival and objective response rate evaluated by blinded independent radiology committee (BIRC) per RECIST v 1.1. Additional endpoints include safety, overall survival, quality of life, and changes in relevant biomarker levels (eg, thyroglobulin). Approximately 300 patients will be randomized in a 2:1 ratio to receive either cabozantinib (60 mg QD orally) or placebo. Randomization is stratified by prior treatment with lenvatinib and age (≤ 65 yrs vs &gt; 65 yrs). Eligible patients must have a pathologic diagnosis of DTC and must have been previously treated with or deemed ineligible for treatment with iodine-131 for DTC. Patients must have received lenvatinib or sorafenib for DTC and progressed during or following treatment with a VEGFR inhibitor. Up to 2 prior VEGFR-targeting TKI agents are allowed. Patients randomized to placebo may be eligible for real time on-study crossover to cabozantinib based on BIRC confirmation of disease progression. Unblinded patients randomized to cabozantinib may continue on study treatment if there is clinical benefit per investigator. Key words: Radioiodine-refractory differentiated thyroid cancer, cabozantinib, VEGFR-targeted therapy, trial-in-progress. Clinical trial information: NCT03690388.

Exploratory analysis of prognostic factors for lenvatinib in radioiodine-refractory differentiated thyroid cancer.

Multitarget kinase inhibitors (m-TKI), including lenvatinib, are now available as treatment options for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, the optimal timing of treatment initiation with m-TKI in these patients remains to be defined. We retrospectively reviewed the clinical records of 30 consecutive patients with RR-DTC. The relationship between clinical characteristics was evaluated, including tumor growth parameters at pretreatment/post-treatment and efficacy of lenvatinib. A total of 26 patients with RR-DTC treated with lenvatinib were evaluable for response and eligible for analysis. From the results of multivariate analysis, baseline tumor size and tumor-related symptoms were independent negative prognostic factors for overall survival (OS) and progression-free survival (PFS). Pretreatment tumor growth parameters were not prognostic for either PFS or OS. Patients with RR-DTC with a high tumor burden and tumor-related symptoms had significantly worse prognosis. Greater tumor reduction after starting lenvatinib may lead to better prognosis, irrespective of pretreatment high tumor growth rate.

Is It Time to Update the Classification for Radioiodine-Refractory Differentiated Thyroid Cancer?

Is It Time to Update the Classification for Radioiodine-Refractory Differentiated Thyroid Cancer?

Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine-refractory differentiated thyroid cancer

BackgroundIn the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly improved efficacy outcomes versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). Lenvatinib-treated patients had more adverse events (AEs), which were generally managed with dose modifications, including dose interruption. This exploratory post hoc analysis investigated the impact of dose interruption on lenvatinib efficacy. MethodsDose modifications were required for grade 3 or intolerable grade 2 AEs in SELECT. Lenvatinib-treated patients were dichotomised based on the duration of dose interruption relative to total treatment duration: shorter dose interruption (<10% of total treatment duration) and longer dose interruption (≥10%). ResultsAt the time of primary data cut-off (November 15, 2013; median follow-up, 17.1 months), the median progression-free survival (PFS) for the shorter dose-interruption group had not yet been reached, whereas median PFS for the longer dose-interruption group was 12.8 months (95% confidence interval [CI], 9.3–16.5). Compared with placebo, the hazard ratios for PFS in the shorter and longer dose-interruption groups were 0.14 (95% CI, 0.09–0.20) and 0.31 (95% CI, 0.22–0.43), respectively. In a multivariate model, dose interruption was significantly associated with lenvatinib efficacy, even after adjustment for patient characteristics. ConclusionsLenvatinib improved efficacy outcomes versus placebo in patients with RR-DTC, regardless of the duration of dose interruption; however, those with shorter dose interruptions had a greater magnitude of benefit versus those with longer interruptions. This analysis highlights the importance of timely management of lenvatinib toxicities to minimise dose interruptions and maximise lenvatinib efficacy in patients with RR-DTC. ClinicalTrials.gov numberNCT01321554

Prolonged duration of response in lenvatinib responders with thyroid cancer (Russian translation)

We present an updated analysis of lenvatinib in radioiodine-refractory differentiated thyroid cancer (RR-DTC) with new duration of response (DOR) data unavailable for the primary analysis. In this randomized, double-blind, multicenter, placebo-controlled phase 3 study, patients ≥18 years old with measurable, pathologically confirmed RR-DTC with independent radiologic confirmation of disease progression within the previous 13 months were randomized 2:1 to oral lenvatinib 24 mg/day or placebo. The main outcome measures for this analysis are DOR and progression-free survival (PFS). The median DOR for all lenvatinib responders (patients with complete or partial responses; objective response rate: 60.2 %; 95 % confidence interval (CI) 54.2–66.1) was 30.0 months (95 % CI 18.4–36.7) and was generally similar across subgroups. DOR was shorter in patients with greater disease burden and with brain and liver metastases. Updated median PFS was longer in the overall lenvatinib group vs placebo (19.4 vs 3.7 months; hazard ratio (HR) 0.24; 99 % CI 0.17–0.35; nominal P &lt;0.0001). In lenvatinib responders, median PFS was 33.1 months (95 % CI 27.8–44.6) vs 7.9 months (95 % CI 5.8–10.7) in nonresponders. The median DOR of 30.0 months seen with patients who achieved complete or partial responses with lenvatinib (60.2 %) demonstrates that lenvatinib responders can have prolonged, durable and clinically meaningful responses. Prolonged PFS (33.1 months) was also observed in these lenvatinib responders.

New aspects in thyroid cancer treatment : Highlights of the ASCO Annual Meeting 2018

Whereas surgical treatment of thyroid carcinoma plays an important role especially in the early stages, amultimodal approach is pursued in the palliative setting, which, in addition to classical chemotherapy primarily involves treatment with tyrosine kinase inhibitors. An analysis of clinical trials and studies presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2018 is presented. In particular, studies on the treatment of radioiodine-refractory differentiated thyroid cancer, anaplastic thyroid cancer and immunotherapy were selected and analyzed. Clinically and preclinically relevant studies are presented and critically interpreted in this review.

Identification of novel sodium iodide symporter (NIS) interactors which modulate radioiodine uptake

Patients termed to have radioiodine-refractory differentiated thyroid cancer (RR-DTC) cannot accumulate sufficient radioiodine for a therapeutic response due to sodium iodide symporter (NIS) dysregulation via diminished expression and/or altered plasma membrane localisation. Previous studies identified novel therapeutics to increase NIS expression, but these are associated with poor tolerance and resistance. Meanwhile, regulation of NIS plasma membrane localisation remains poorly defined and, despite protein-protein interactions being well-described to modulate trafficking events, the NIS interactome is limited. Here, two novel functional NIS interactors – ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP) – were identified by mass spectrometry, which positively and negatively modulated radioiodine uptake respectively. In papillary thyroid cancer (PTC), ARF4 is downregulated, and VCP overexpressed, which may provide a putative explanation for repressed NIS function. Subsequent investigations identified co-localisation between ARF4 and NIS at the Golgi as well as co-incident trafficking at the plasma membrane, which led to the hypothesis that ARF4 promotes NIS trafficking to the plasma membrane. In contrast, VCP decreased NIS protein expression, which was suggestive of a role for VCP in NIS processing and degradation. Pharmacological inhibitors Eeyarestatin-1 and NMS-873 overcame VCP inhibition of NIS function, which may highlight a novel therapeutic strategy for RR-DTC.