lenvatinib and Adenocarcinoma

Thyroid carcinoma is the most common endocrine neoplasm. Multimodal therapy including surgery, radioactive iodine (RAI) therapy, and indefinite suppression of thyroid-stimulating hormone has led to an 85% cure rate in differentiated thyroid tumors (DTT). Approximately 5-10% of patients will have recurrence or metastases that have the potential to become resistant to RAI treatment.. We are reporting a very rare case of late renal toxicity in a 68-year-old woman with a history of type 2 diabetes and metastatic RAI-resistant follicular thyroid carcinoma (Hurthle cell variant) who developed thrombotic microangiopathy 21 months after initiation of treatment.. It was determined that LEN should be held, due to worsening renal function secondary to TKI-induced kidney injury. Although the patient's renal function eventually improved and returned to her baseline after discontinuation of LEN, there was marked disease progression after drug cessation.. Renal toxicity is a rare adverse event (AE) that tends to occur typically within three weeks of initiation of treatment. The utilization of TKIs can lead to glomerulosclerosis, and careful considerations and precautions should be taken by clinicians who intend to initiate TKI therapy in patients with pre-existing diabetes to prevent renal toxicity.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Diabetes Mellitus, Type 2; Female; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Lenvatinib is a multitargeted tyrosine kinase inhibitor approved for treating patients with locally recurrent or metastatic progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC). In this review, we discuss recent developments in the optimization of RR-DTC treatment with lenvatinib.. Initiation of lenvatinib treatment before a worsening of Eastern Cooperative Oncology Group performance status and elevated neutrophil-to-lymphocyte ratio could benefit patients with progressive RR-DTC. The median duration of response with lenvatinib was inversely correlated with a smaller tumor burden, and prognosis was significantly worse in patients with a high tumor burden. An 18 mg/day starting dose of lenvatinib was not noninferior to 24 mg/day and had a comparable safety profile. Timely management of adverse events is crucial, as patients with shorter dose interruptions benefitted more from lenvatinib treatment. Caution should be exercised when initiating lenvatinib in patients who have tumor infiltration into the trachea or other organs, or certain histological subtypes of DTC, as these are risk factors for fistula formation or organ perforation. The Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT) eligibility criteria should be considered prior to initiating lenvatinib treatment.. Current evidence indicates that patients benefit most from lenvatinib treatment that is initiated earlier in advanced disease when the disease burden is low. A starting dose of lenvatinib 24 mg/day, with dose modifications as required, yields better outcomes as compared to 18 mg/day. Appropriate supportive care, including timely identification of adverse events, is essential to manage toxicities associated with lenvatinib, avoid longer dose interruptions, and maximize efficacy.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Patients with unresectable or metastatic differentiated thyroid carcinoma (DTC) are rare and require individualized therapy. This may require approaches not typically used in resectable disease. We report a patient treated with lenvatinib and external beam radiation therapy.. An 87-year-old woman presented with cT4N1aM1 papillary thyroid carcinoma with tracheal invasion. She was not a candidate for surgery, radioactive-iodine, or radiation, so a trial of lenvatinib was offered. Her tumor showed clinical, biochemical, and radiological response after 5 months of lenvatinib, and she subsequently received external beam radiation. She enjoys good quality of life without evidence of cancer progression off therapy 21 months post-initiation of treatment.. Lenvatinib may be effective in RAI-naïve advanced DTC patients as a component of individualized multimodal therapy when conventional options are not feasible.

Topics: Adenocarcinoma; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Iodine Radioisotopes; Phenylurea Compounds; Quality of Life; Quinolines; Thyroid Neoplasms

Bone is the second most common distant metastasis site in differentiated thyroid cancer (DTC) and is normally associated with the presence of other metastases, which are usually radioiodine-resistant. The presence of bone metastasis (BM) determines low survival and greater morbidity due to the frequency of skeletal-related events (SREs), which can be a serious complication of BM. There is evidence that antiresorptive therapy (AT) reduces SREs in other solid tumors, but not yet in DTC BM, for which data are scant. The same is true for systemic therapy with multikinase inhibitors (MKIs). In general, the results for MKI use are well known, although the effect on BM has rarely been evaluated. While MKIs are indicated in current clinical practice guidelines, studies evaluating the benefits and risks of concomitant treatment with MKIs and AT are lacking, and the available data come from small samples in retrospective studies. The objective of this article is to review the latest evidence for concomitant MKIs and AT.

Topics: Adenocarcinoma; Antineoplastic Agents; Bone Neoplasms; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Thyroid Neoplasms

Lenvatinib is one the most active drugs in radioiodine-refractory differentiated thyroid cancer (RR-DTC) such that it has become an important therapeutic tool in tumor control and survival. Renal and hepatic impairments are common comorbidities in cancer patients. Treating these patients is a challenge that requires careful consideration. As a first approach to patients with RR-DTC and renal or hepatic impairment, Summary of Product Characteristics recommendations for lenvatinib use and dose adjustments should be strictly followed. Close clinical and blood monitoring is the gold standard approach to optimizing lenvatinib's use during the whole course of treatment.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Antiangiogenic tyrosine kinase inhibitors are the treatment of choice in radioiodine refractory-differentiated thyroid cancer (RR-DTC). Nevertheless, these therapies present class toxicities that may impact their feasibility and patient's quality of life. Their mechanism of action explains the high prevalence of hypertension associated with their use, which reaches 68% with lenvatinib. Moreover, up to 85% of patients treated in the SELECT clinical trial were receiving baseline antihypertensive treatment. These data support the need for prevention, detection, and early management of hypertension. Prevention can be accomplished by controlling cardiovascular risk factors (hypertension, diabetes, obesity, and dyslipidemia) and those associated with lifestyle (smoking, harmful alcohol consumption, and physical inactivity) and electrolyte disorders. It is necessary to achieve stabilization of cardiovascular diseases. Detection involves baseline measurement and monitoring of blood pressure and cardiac function. Treatment requires optimization of baseline blood pressure and early initiation of antihypertensive agents.

Topics: Adenocarcinoma; Antihypertensive Agents; Antineoplastic Agents; Cardiovascular Diseases; Electrolytes; Heart Disease Risk Factors; Humans; Hypertension; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quality of Life; Quinolines; Risk Factors; Thyroid Neoplasms

Thyroid cancer is the most frequent endocrine tumor. However, in locally advanced or metastatic disease we have only two types of treatment at our disposal: radioactive iodine (RAI) when the disease is RAI-sensitive and multikinase inhibitors (MKIs), lenvatinib and sorafenib, when the disease becomes RAI-refractory (RR). This review revisits the published data on the potential combination of MKIs/lenvatinib with RAI in RR-differentiated thyroid cancer and evaluates some special situations where this combination may be of particular interest. The combination of MKIs/lenvatinib with RAI could, at least hypothetically, improve the efficacy seen in both treatments alone via a synergistic effect and with a lower rate of toxicity rates. Early preclinical data support this notion, while its generalized use awaits the results of ongoing clinical trials.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Sorafenib; Thyroid Neoplasms

This review focuses on patients with differentiated thyroid carcinoma (DTC) associated with multiple primary malignant neoplasm (MPMN) treated by multikinase inhibitors (MKIs) as systemic treatment for advanced disease. Despite the increasing frequency of MPMNs (many at an advanced stage) and the usefulness of MKIs for multiple metastatic cancers, published data on the management of MPMN and MKI therapies in this scenario are scarce. There are infrequent descriptions of patients with advanced MPMN treated with MKIs, but only a few have described advanced DTC. The management of MPMNs, including DTC and its particular circumstances, is reviewed, focusing on the evidence for MKI therapies. Some considerations for MPMN patients with advanced DTC are discussed, with the intention of helping physicians make decisions in these challenging situations and improving treatment and patient outcomes.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Locoregional recurrence of differentiated thyroid cancer (DTC) occurs in 20% of thyroid cancer patients. Currently, there are many strategies for management of locoregional recurrence of DTC that lead to local control of the disease. The introduction of lenvatinib into the therapeutic armamentarium provides a new option for the treatment of radioiodine-refractory DTC (RR-DTC). However, results for simultaneous treatment with lenvatinib and locoregional therapies are unknown in patients with RR-DTC. This paper reviews the current status of this approach and gives recommendations on the management of lenvatinib during concomitant locoregional procedures.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Neoplasm Recurrence, Local; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Lenvatinib has been approved for the treatment of advanced differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) following the results of the SELECT trial which demonstrated a significant increase in progression-free survival and a high response rates. The data reported for lenvatinib in RAI-refractory DTC (RAI-R DTC) are the most significant to date in this patient population, with a RECIST objective response rate above 60% and almost 80% reduction in the risk of disease progression. Because the first indication in oncology for lenvatinib is specifically in RAI-R DTC, a period of familiarisation with its safety and efficacy profile is required. This review includes a series of specific recommendations for optimising the management of RAI-R DTC with lenvatinib, as well as specific guidelines for minimising the incidence and severity of adverse events (AEs), which enable dose intensity to be increased and this way maximise the benefits of the drug in the patient population treated. These recommendations were defined at a meeting of experts of different specialities, reviewing available scientific evidence on the drug, as well as their own direct personal experience in daily clinical practice. For toxicity to be properly managed, a multidisciplinary approach is required in which the different medical services, nursing staff and the patient and their careers are all involved. It is essential to assess the suitability of patients who are candidates for lenvatinib, as well as their clinical and physiological status prior to treatment. They must then be closely monitored to prevent and detect possible AEs. The main objective should be to maintain the dose that obtains the maximum therapeutic effect, discontinuing the treatment only if the toxicity becomes unmanageable or there is no clinical benefit.

Topics: Adenocarcinoma; Cell Differentiation; Humans; Iodine Radioisotopes; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Thyroid Neoplasms

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Doxorubicin; Humans; Indazoles; Japan; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Quinolines; Slovenia; Sorafenib; Sulfonamides; Thyroid Neoplasms; Treatment Outcome

In the phase 2 double-blind Study 211, a starting dose of lenvatinib 18 mg/day was compared with the approved starting dose of 24 mg/day in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). Predefined criteria for noninferiority for efficacy in the 18 mg arm were not met; safety was similar in both arms. Impact of lenvatinib treatment on health-related quality-of-life (HRQoL) was a secondary endpoint of Study 211.. Patients with RR-DTC were randomly assigned to a blinded starting dose of lenvatinib 18 mg/day or 24 mg/day. HRQoL was assessed at baseline, every 8 weeks until Week 24, then every 16 weeks, and at the off-treatment visit, using the EQ-5D-3L and FACT-G instruments. Completion and compliance rates, mean change from baseline, and times to first and definitive deterioration were evaluated.. Baseline EQ-5D and FACT-G scores, and overall changes from baseline, were comparable between patients in the lenvatinib 18 mg/day (n = 77) and 24 mg/day arms (n = 75). For the 18 mg versus 24 mg arms, least squares mean differences were -0.42 (95% CI -4.88, 4.03) for EQ-5D-VAS and 0.47 (95% CI -3.45, 4.39) for FACT-G total. Time to first deterioration did not significantly favor either arm; EQ-5D-VAS HR [18 mg/24 mg] 0.93 (95% CI 0.61-1.40), EQ-5D-HUI HR [18 mg/24 mg] 0.68 (95% CI 0.44-1.05), FACT-G total HR [18 mg/24 mg] 0.73 (95% CI 0.48-1.12). Time to definitive deterioration did not significantly favor either arm, though EQ-5D-VAS showed a trend in favor of the 24 mg arm (HR [18 mg/24 mg] 1.72; 95% CI 0.99-3.01); EQ-5D-HUI HR [18 mg/24 mg] was 0.96 (95% CI 0.57-1.63), FACT-G total HR [18 mg/24 mg] was 0.72 (95% CI 0.43-1.21).. In Study 211, HRQoL for patients in the lenvatinib 18 mg/day arm was not statistically different from that of patients in the 24 mg/day arm. These data further support the use of the approved lenvatinib starting dose of 24 mg/day in patients with RR-DTC.. NCT02702388.

Topics: Adenocarcinoma; Double-Blind Method; Humans; Iodine Radioisotopes; Quality of Life; Thyroid Neoplasms

Neoadjuvant chemoradiation with fluoropyrimidine followed by surgery and adjuvant chemotherapy has been the standard treatment of locally advanced stages II and III rectal cancer for many years. There is a high risk for disease recurrence; therefore, optimizing chemoradiation strategies remains an unmet need. Based on a few studies, there is evidence of the synergistic effect of VEGF/PDGFR blockade with radiation.. In this phase I, dose-escalation and dose-expansion study, we studied 3 different dose levels of lenvatinib in combination with capecitabine-based chemoradiation for locally advanced rectal cancer.. A total of 20 patients were enrolled, and 19 were eligible for assessment of efficacy. The combination was well tolerated, with an MTD of 24 mg lenvatinib. The downstaging rate for the cohort and the pCR was 84.2% and 37.8%, respectively. Blood-based protein biomarkers TSP-2, VEGF-R3, and VEGF correlated with NAR score and were also differentially expressed between response categories. The NAR, or neoadjuvant rectal score, encompasses cT clinical tumor stage, pT pathological tumor stage, and pN pathological nodal stage and provides a continuous variable for evaluating clinical trial outcomes.. The combination of lenvatinib with capecitabine and radiation in locally advanced rectal cancer was found to be safe and tolerable, and potential blood-based biomarkers were identified.. NCT02935309.

Topics: Adenocarcinoma; Capecitabine; Chemoradiotherapy; Fluorouracil; Humans; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Phenylurea Compounds; Quinolines; Rectal Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor A

Radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) is an aggressive form of thyroid cancer. Lenvatinib is a multikinase inhibitor approved for treatment of RAI-R DTC. The impact of tumor response and tumor burden on overall survival (OS) after lenvatinib treatment in patients with RAI-R DTC was assessed.. Data from patients treated with lenvatinib (N = 261) in SELECT were retrospectively analyzed. Patients were divided into lenvatinib responder or nonresponder subgroups and into low (≤40 mm) or high (>40 mm) tumor burden subgroups based on baseline sums of diameters of target lesions using Response Evaluation Criteria in Solid Tumors, version 1.1 (cutoff values were determined by receiver-operating characteristic analyses). Associations of tumor response and tumor burden with OS were assessed.. Median OS was prolonged in lenvatinib responders versus nonresponders (52.2 vs 19.0 months; hazard ratio [HR], 0.32; 95% CI, 0.23-0.46). Patients with a lower tumor burden who received lenvatinib had prolonged OS versus those with a higher tumor burden (median OS, not reached vs 29.1 months, respectively; HR, 0.42; 95% CI, 0.28-0.63). Baseline tumor burden was associated with OS by multivariate analysis (HR, 0.56; 95% CI, 0.35-0.89; P = .0138).. Patients with a lower tumor burden receiving lenvatinib had prolonged OS compared with those with a higher tumor burden receiving lenvatinib. Baseline tumor burden may be a prognostic factor for OS in patients with RAI-R DTC treated with lenvatinib.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Thyroid Neoplasms; Tumor Burden

Topics: Adenocarcinoma; Antineoplastic Agents; Cohort Studies; Humans; Iodine Radioisotopes; Phenylurea Compounds; Prospective Studies; Protein Kinase Inhibitors; Quinolines; Sorafenib; Thyroid Neoplasms

Pembrolizumab, an anti-PD-1 antibody, results in tumour response in around 15% of patients with advanced gastric cancer who have a PD-L1 combined positive score of at least 1. Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased tumour-associated macrophages and increased infiltration of CD8 T cells, resulting in enhanced anti-tumour activity of PD-1 inhibitors in an in-vivo model. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced gastric cancer in a phase 2 study.. This study was an open-label, single-arm, phase 2 trial undertaken at the National Cancer Center Hospital East (Chiba, Japan). Eligible patients were aged 20 years or older and had metastatic or recurrent adenocarcinoma of the stomach or gastro-oesophageal junction, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), irrespective of the number of previous lines of treatment. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks until disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate according to RECIST, analysed in all patients who were eligible and received protocol treatment at least once. The safety analysis included all those who received protocol treatment at least once, regardless of eligibility. This study is registered at ClinicalTrials.gov, NCT03609359, and enrolment is complete.. Between Oct 15, 2018, and March 25, 2019, 29 patients were enrolled in the first-line or second-line settings. At data cutoff (March 20, 2020), the median follow-up was 12·6 months (IQR 10·5-14·3). 20 (69%, 95% CI 49-85) of 29 patients had an objective response. The most common grade 3 treatment-related adverse events were hypertension (in 11 [38%] patients), proteinuria (five [17%]), and platelet count decrease (two [7%]). No grade 4 treatment-related adverse events, serious treatment-related adverse events, or treatment-related deaths occurred.. Lenvatinib plus pembrolizumab showed promising anti-tumour activity with an acceptable safety profile in patients with advanced gastric cancer. On the basis of these results, a confirmatory trial will be planned in the future.. Merck Sharp & Dohme.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Quinolines; Stomach Neoplasms

Lenvatinib showed promising results in a subgroup of patients with poorly differentiated thyroid carcinoma (PDTC) in the SELECT trial. Our aim was to report the effectiveness and tolerability of lenvatinib in our series of PDTC patients.. Medical records of eight consecutive patients with PDTC treated with lenvatinib in a single center between January 2019 and October 2022 were retrospectively reviewed. Inclusion criteria were PDTC diagnosis based on Turin criteria and evidence of disease progression in the previous 6 months.. Eight PDTC patients received an average dose of lenvatinib of 18.1 mg for a median duration of treatment of 10.3 months. The baseline Eastern Cooperative Oncology Group performance status was ≥2 in 50% of patients. Two patients had unresectable primary tumor. Seven patients showed extrathyroidal disease, particularly mediastinal lymph nodes (85.7%), lung (71.4%), and bone (71.4%). The disease control rate was 100%, with partial response and stable disease in 12.5 and 87.5%, respectively. The median time to best overall response was 3 months, and the median duration of response was 7.5 months. Median progression-free survival was 12 months and median overall survival was not reached. At 6, 12, and 18 months, overall survival was 87.5, 71.4, and 57.1%, respectively. All patients experienced drug-related adverse effects (AEs). Four (50%) had dose reductions and two (25%) had temporary treatment interruptions. Lenvatinib was stopped in two patients due to grade ≥3 AEs.. Lenvatinib is an effective treatment for real-world PDTC patients. Adequate management of comorbidities and AEs increases treatment tolerability and minimizes dose reductions.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Retrospective Studies; Thyroid Neoplasms

Recently, selpercatinib, a highly selective inhibitor of

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Republic of Korea; Thyroid Neoplasms

Topics: Adenocarcinoma; Humans; Oxyphil Cells; Phenylurea Compounds; Thyroid Neoplasms

Most thyroid cancers of follicular origin have a favorable outcome. Only a small percentage of patients will develop metastatic disease, some of which will become radioiodine refractory (RAI-R). Important challenges to ensure the best therapeutic outcomes include proper, timely, and appropriate diagnosis; decisions on local, systemic treatments; management of side effects of therapies; and a good relationship between the specialist, patients, and caregivers.. With the aim of providing suggestions that can be useful in everyday practice, a multidisciplinary group of experts organized the following document, based on their shared clinical experience with patients with RAI-R differentiated thyroid cancer (DTC) undergoing treatment with lenvatinib. The main areas covered are patient selection, initiation of therapy, follow-up, and management of adverse events.. It is essential to provide guidance for the management of RAI-R DTC patients with systemic therapies, and especially lenvatinib, since compliance and adherence to treatment are fundamental to achieve the best outcomes. While the therapeutic landscape in RAI-R DTC is evolving, with new targeted therapies, immunotherapy, etc., lenvatinib is expected to remain a first-line treatment and mainstay of therapy for several years in the vast majority of patients and settings. The guidance herein covers baseline work-up and initiation of systemic therapy, relevance of symptoms, multidisciplinary assessment, and patient education. Practical information based on expert experience is also given for the starting dose of lenvatinib, follow-up and monitoring, as well as the management of adverse events and discontinuation and reinitiating of therapy. The importance of patient engagement is also stressed.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Thyroid Neoplasms

Ataxia telangiectasia and Rad3-related protein (ATR) is a critical component of the DNA damage response and a potential target in the treatment of cancers. An ATR inhibitor, BAY 1895344, was evaluated for its use in differentiated thyroid cancer (DTC) therapy. BAY 1895344 inhibited cell viability in four DTC cell lines (TPC1, K1, FTC-133, and FTC-238) in a dose-dependent manner. BAY 1895344 treatment arrested DTC cells in the G2/M phase, increased caspase-3 activity, and caused apoptosis. BAY 1895344 in combination with either sorafenib or lenvatinib showed mainly synergistic effects in four DTC cell lines. The combination of BAY 1895344 with dabrafenib plus trametinib revealed synergistic effects in K1 cells that harbor BRAFV600E. BAY 1895344 monotherapy retarded the growth of K1 and FTC-133 tumors in xenograft models. The combinations of BAY 1895344 plus lenvatinib and BAY 1895344 with dabrafenib plus trametinib were more effective than any single therapy in a K1 xenograft model. No appreciable toxicity appeared in animals treated with either a single therapy or a combination treatment. Our findings provide the rationale for the development of clinical trials of BAY 1895344 in the treatment of DTC.

Topics: Adenocarcinoma; Animals; Ataxia Telangiectasia Mutated Proteins; Humans; Phenylurea Compounds; Sorafenib; Thyroid Neoplasms

The optimal timing for starting lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) has long been controversial because of the relatively slow-growing nature of differentiated thyroid cancer. The aim of this study was to establish a scoring system using known clinical factors to simplify decision-making in when to start lenvatinib in RR-DTC patients.. We retrospectively analyzed RR-DTC patients treated with lenvatinib. We developed the clinical indication scoring algorithm on the basis of age, tumor-related symptoms, histology, metastatic sites, neutrophil-to-lymphocyte ratio, size of lung metastases, baseline sum of tumor diameters, and tumor-volume doubling time that was used to categorize patients into low-, intermediate-, and high-risk groups.. A total of 59 patients were analyzed; 13 low-risk, 36 intermediate-risk, and 10 high-risk. The respective median progression-free survival from the initiation of lenvatinib was 93.7 months in the low-risk group, 20.3 months in the intermediate-risk group, and 6.2 months in the high-risk group (p < 0.02). Patients in the high-risk group had significantly worse overall survival compared with those in the low-risk (hazard ratio [HR] 6.59, 95% confidence interval [CI] 1.25-34.90, p < 0.03) or intermediate-risk (HR 2.99, 95% CI 1.03-8.63, p < 0.05) group. Using our proposed algorithm, patients in the intermediate-risk group showed treatment outcomes similar to that were observed in the pivotal trial of lenvatinib, and were the optimal patients to start lenvatinib.. Our proposed scoring system can separate treatment outcomes and prognosis of RR-DTC patients treated with lenvatinib. This simple algorithm can be helpful for oncologists in deciding whether to start lenvatinib treatment in patients with RR-DTC.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Thyroid Neoplasms

Tyrosine kinase inhibitors (TKIs) have provided excellent clinical benefits to patients with advanced differentiated thyroid cancer (DTC): however, the tumor status for which maximum efficacy can be obtained remains controversial. We conducted this study to identify effective clinical predictors, focusing on disease progression.. Using the data of 42 DTC patients treated with lenvatinib, we investigated the clinical factors related to overall survival (OS) and progression-free survival (PFS), and conducted analyses by the scoring of the factors.. The 3 year OS and median PFS were 51% and 13.8 months, respectively. Univariate analysis identified performance status (PS), tumor-related symptoms, and tumor diameter as the only factors affecting both these outcomes. Giving 1-point for each of these three factors, a higher score was significantly related to shorter OS and PFS. Patients with two or fewer points (n = 34) had better median OS (NR vs 3.9 months, p < 0.001) and PFS (15.7 vs 2.1 months, p < 0.001) than patients with three points (n = 8). Patients with all three factors had a significantly worse prognosis than patients with two or fewer factors.. DTC patients with all three indicators are unlikely to have longer survival. Therefore, it is important to commence TKIs before disease progression.

Topics: Adenocarcinoma; Antineoplastic Agents; Disease Progression; Humans; Iodine Radioisotopes; Protein Kinase Inhibitors; Thyroid Neoplasms

Lenvatinib is started at a standard dose, continuing with dose reduction and interruption, balancing between efficacy and adverse events (AEs). Because few drugs are available for thyroid cancer, efforts for continuing treatment with one agent, such as "dose escalation (DE)", are made. The dose is increased, aiming to regain the anti-tumor effect after dose reduction. The effects of lenvatinib DE in differentiated thyroid carcinoma (DTC) patients are reported.. The efficacy of lenvatinib DE in DTC patients using the serum thyroglobulin (Tg) level and management of AEs was investigated.. A total of 70 DE episodes in 33 patients were investigated. The median increased dose was 2.0 (1.0-14.0) mg, increased from 8.6 (2-16) mg to 10.1 (6-24) mg. The serum Tg level decreased in 53 DE episodes. Though the serum Tg level in 17 DE episodes was not decreased, the Tg rate of increase was decreased in 7 of these DE episodes using the Tg-doubling rate. Overall, clinical benefit was seen in 60 (86%) DE episodes. AEs that could not be controlled after DEs were seen in only 16% of cases. No intolerable AEs were observed in patients who received more drug holidays at the time of DEs compared to two times before the DEs.. DE may become one of the standard treatment strategies after disease progression if AEs are well managed. Drug holidays may be a key for successfully controlling AEs with DE. DE can be useful for controlling progressive disease with increasing Tg levels.

Topics: Adenocarcinoma; Antineoplastic Agents; Disease Progression; Dose-Response Relationship, Drug; Humans; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

Hepatoid adenocarcinoma (HAC) is an adenocarcinoma with components similar to those of hepatocellular carcinoma. Primary HAC of the gallbladder is extremely rare; to our knowledge, there is no consensus on the treatment after diagnosis. We reported an 82-year-old Japanese female of primary HAC of the gallbladder with postoperative recurrence that responded to lenvatinib. A total of 9 months has passed since the start of chemotherapy with lenvatinib, and the patient is in good general condition. To establish an effective treatment for primary HAC of the gallbladder, further accumulation and investigation of cases are recommended.

Topics: Adenocarcinoma; Aged, 80 and over; Carcinoma, Hepatocellular; Contrast Media; Female; Gallbladder; Humans; Liver Neoplasms; Magnetic Resonance Imaging

This study aimed to analyze the clinical course of patients with differentiated thyroid cancer (DTC) who were treated by lenvatinib and investigate the specific criteria for the initiation of lenvatinib in lung metastasis.. A total of 111 patients with DTC treated by lenvatinib were included in the study. Patients were divided into two groups based on the target lesion for the initiation of lenvatinib: lung metastasis group and other metastases group.. In the univariate analysis, the tumor size for the lung metastasis (p = 0.002) and the factor of lung metastasis group (p < 0.001) were significantly associated with overall survival (OS). Multivariate analysis revealed that the factor of lung metastasis group [hazard ratio, 0.408; 95% confidence interval (CI), 0.206-0.810; p = 0.010] was the only independent prognostic factor of OS. Of the 53 patients in the lung metastasis group, 12 (23%) had lung metastasis-related finding such as pleural effusion (n = 12), hemoptysis (n = 2), and dyspnea (n = 1) at the initiation of lenvatinib treatment. The median OS in patients with or without lung metastasis-related findings were 41.0 [95% CI, 10.4-not available (NA)] months and 62.9 (95% CI, 53.0-NA) months, respectively (p = 0.022).. Patients with lung metastasis-related finding at the initiation of lenvatinib treatment had a poorer prognosis among the lung metastasis group. It is important to consider not only the tumor size but also the presence of lung metastasis-related findings when initiating lenvatinib treatment for DTC patients with lung metastasis.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Lung Neoplasms; Phenylurea Compounds; Prognosis; Quinolines; Thyroid Neoplasms

Lenvatinib is a standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, because of the high incidence of adverse events resulting from this treatment, it is not easy to maintain the dose intensity of lenvatinib, especially in Japanese patients. Although the prognostic impact of lenvatinib dose interruption has been reported, the target dose intensity of lenvatinib to optimize survival benefits remains unknown. We therefore propose a target dose intensity of lenvatinib during the first 8 weeks of treatment. We retrospectively analyzed 42 RR-DTC patients who were treated with lenvatinib for more than 8 weeks. We performed receiver operating characteristic curve analysis to determine the cut-off value of 8 weeks' relative dose intensity (8w-RDI) to predict treatment response, and identified that the optimal cut-off value of 8w-RDI was 60% (sensitivity: 81.8%; specificity: 80.6%). Median progression-free survival (PFS) (not reached [NR] vs. 11.0 months; hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.11-0.72; p < 0.01) and overall survival (NR vs. 27.6 months; HR 0.44; 95% CI 0.11-0.91; p = 0.03) were longer in the higher 8w-RDI (≥60%) patients than in the lower 8w-RDI (<60%) patients. Multivariate analysis revealed that 8w-RDI at ≥60% was an independent prognostic factor for PFS (HR 0.29; 95% CI 0.09-0.96; p = 0.04). Targeting for ≥60% of the relative dose intensity during the first 8 weeks of lenvatinib treatment can be sufficient to achieve significant tumor shrinkage and prolong PFS in RR-DTC patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Prognosis; Quinolines; Thyroid Neoplasms; Young Adult

Lenvatinib has become the most commonly prescribed first-line (1L) agent for the treatment of radioactive iodine-refractory differentiated thyroid cancer (RAI-r DTC) since its approval in 2015. With no real-world studies describing clinical outcomes of 1L lenvatinib and subsequent therapy, the current study aimed to assess treatment sequencing and related clinical outcomes in patients treated with 1L lenvatinib in the USA METHODS: We conducted a multisite, retrospective chart review of US patients with a diagnosis of RAI-r DTC who had initiated 1L therapy with lenvatinib from January 1, 2016 through May 31, 2017 with follow-up through October 17, 2018. Physicians completed electronic case report forms for two patient cohorts: patients still receiving 1L lenvatinib (cohort 1) and those who had initiated second-line (2L) therapy prior to data cutoff (cohort 2). Real-world objective response rate (ORR) was assessed for both cohorts. Progression-free survival (PFS) and overall survival (OS) were assessed for cohort 2.. A total of 252 patients met the study criteria with 71 in cohort 1 and 181 in cohort 2. Patients were predominantly female, had papillary DTC, and had lung metastases. The ORR was 64.8% for cohort 1 and 53.6% for cohort 2. In cohort 2, median PFS from 1L lenvatinib initiation was 14.0 months (95% CI 12.7-15.0). Second-line treatments included sorafenib (49.7%), cabozantinib (19.3%), and other targeted/chemotherapy/immuno-oncology agents. The ORR in 2L therapy was 15.5%. For cohort 2, the 12-, 18-, and 24-month OS from initiation of 1L lenvatinib was 92.8%, 81.5%, and 66.9%, respectively.. In this first real-world examination of clinical effectiveness of 1L lenvatinib and subsequent therapy among patients in the US, the results demonstrated that treatment with 1L lenvatinib followed by another 2L therapy may deliver a clinical benefit, thus allowing a number of potential 2L options following 1L lenvatinib for patients with RAI-r DTC.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cohort Studies; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Quinolines; Retrospective Studies; Thyroid Neoplasms; Treatment Outcome; United States