Lenvatinib Treatment In Patients Research Articles

Surgical Intervention After Lenvatinib Treatment in Patients With Advanced Hepatocellular Carcinoma.

The survival and prognostic factors in patients with advanced hepatocellular carcinoma (HCC) who underwent surgical intervention after lenvatinib treatment is not well-understood. Seventy-six patients with advanced HCC who had lenvatinib treatment were retrospectively analyzed. Of 70 patients who were treated with lenvatinib, 14 patients underwent surgical intervention after lenvatinib treatment for 4-28 weeks. Progression-free survival (PFS) was significantly longer in patients who underwent surgical intervention than in patients with non-surgical treatment (median, 8.6 vs. 5.1 months, p=0.019). Non-significantly longer overall survival (OS) was also observed in patients with surgical intervention compared to patients with non-surgical treatment (median, unreached vs. 21.0 months, p=0.206). In patients who underwent surgical intervention, two patients had a partial response, and 12 had stable disease according to RECIST ver. 1.1 criteria. The serum alpha-fetoprotein (AFP) level was significantly lower after lenvatinib treatment than before lenvatinib treatment (median, 19.2 vs. 196.5 ng/ml, p=0.0081). Eleven patients underwent curative surgery with a 14% major postoperative complication (Clavien-Dindo ≥IIIa) rate. Patients who exhibited decreases in AFP levels or maintained AFP levels within the normal range during lenvatinib treatment had significantly longer PFS (median, 8.6 vs. 3.0 months, p=0.0009) and OS (median, unreached vs. 12.4 months, p=0.012) compared to those with persistently elevated AFP levels beyond the normal range. Surgical intervention after lenvatinib treatment for advanced HCC was associated with longer PFS. Patients exhibiting decreased AFP levels or maintaining AFP levels within the normal limit may be suitable candidates for surgical intervention after lenvatinib treatment for advanced HCC.

Population pharmacokinetic-pharmacodynamic modeling of serum biomarkers as predictors of tumor dynamics following lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC).

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptor-α (PDGFRα), KIT, and RET that have been implicated in pathogenic angiogenesis, tumor growth, and cancer. The primary objective of this work was to evaluate, by establishing quantitative relationships, whether lenvatinib exposure and longitudinal serum biomarker data (VEGF, Ang-2, Tie-2, and FGF-23) are predictors for change in longitudinal tumor size which was assessed based on data from 558 patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving either lenvatinib or placebo treatment. Lenvatinib PK was best described by a 3-compartment model with simultaneous first- and zero-order absorption and linear elimination from the central compartment with significant covariates (body weight, albumin <30 g/dL, ALP>ULN, RR-DTC, RCC, HCC subjects, and concomitant CYP3A inhibitors). Except for body weight, none of the covariates have any clinically meaningful effect on exposure to lenvatinib. Longitudinal biomarker measurements over time were reasonably well defined by a PK/PD model with common EC50, Emax, and a slope for disease progression for all biomarkers. Longitudinal tumor measurements over time were reasonably well defined by a tumor growth inhibition Emax model, which in addition to lenvatinib exposure, included model-predicted relative changes from baseline over time for Tie-2 and Ang-2 as having significant association with tumor response. The developed PK/PD models pave the way for dose optimization and potential prediction of clinical response.

Utility and optimal management of planned drug holidays during lenvatinib treatment in patients with unresectable differentiated thyroid cancer: a real-world multi-center study.

Lenvatinib achieves favorable therapeutic outcomes for patients with radioactive iodine therapy refractory differentiated thyroid cancer (DTC); however, its use is associated with a high incidence of adverse events. To avoid severe adverse events, planned drug holidays (PDH) have been proposed. This study aimed to evaluate treatment effects, identify prognostic factors, and investigate the usefulness of PDH in patients with unresectable DTC who received lenvatinib across the multi-institutions. Fifty-one patients with unresectable DTC treated with lenvatinib were evaluated retrospectively. Overall survival (OS) and progression-free survival (PFS) were calculated, and prognostic factors were assessed. OS, PFS, and time to treatment failure (TTF) were compared between patients with and without PDH. Lenvatinib administration schedule was evaluated in PDH. The 3-year OS and PFS rate were 53.5% and 42.1%, respectively. Multivariate analysis revealed that presence of maximum size of lung metastasis ≥10 mm was independent prognostic factor for poorer OS and PFS, and histology other than papillary thyroid carcinoma was the independent prognostic factor for poorer PFS. Twenty-five patients (49%) treated with PDH. There were significant differences in OS, PFS, and TTF between patients with and without PDH. Various schedules were used in PDH. Eight (32%) patients required switch to the different administration schedule. Our results suggest that PDHs may extend OS, PFS, and TTF. In patients with PDH, various schedules used for lenvatinib administration highlight the difficulty in determining a uniform administration schedule. Therefore, it is crucial to consider the optimal lenvatinib administration schedule on a case-by-case basis.

Outcome of initial lenvatinib treatment in patients with unresectable anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is a very rare disease with a poor prognosis and with no established effective drug therapy. The present study aimed to report the outcomes of lenvatinib single-agent therapy as an initial drug treatment in ATC, and to investigate its safety and efficacy. This retrospective cohort study included 56 patients with unresectable primary ATC, of whom 36 were treated with lenvatinib and 12 with weekly paclitaxel, and 8 patients who refused any drug treatment who received palliative care. The average survival in the lenvatinib group was 5.8 months, which was significantly longer than 2.0 months in the paclitaxel group (P=0.005). The efficacy of lenvatinib in the 36 patients with ATC, whose primary tumors were unresectable, was evaluated. The response rate was 33% and the median overall survival time was 5.0 months. A safety review indicated that lenvatinib should be used under the careful observation of local findings. Two patients, who showed a reduction with lenvatinib, underwent conversion surgery, which prolonged the prognosis in terms of avoiding events, such as asphyxia, fistula and hemorrhage due to tumor growth; however, the surgical margins were positive, indicating that complete remission was impossible even if surgical resection was performed. Therefore, starting with lenvatinib treatment and identifying a therapeutic drug based on genomic analysis is an acceptable treatment strategy for ATC while halting the disease progression.

The Tyrosine Kinase Inhibitor Lenvatinib Inhibits Anaplastic Thyroid Carcinoma Growth by Targeting Pericytes in the Tumor Microenvironment.

Background: Anaplastic thyroid carcinoma (ATC) is a rapidly fatal cancer with a median survival of a few months. Enhanced therapeutic options for durable management of ATC will rely on an understanding of genetics and the role of the tumor microenvironment. The prognosis for patients with ATC has not improved despite more detailed scrutiny of underlying tumor genetics. Pericytes in the microenvironment play a key evasive role for thyroid carcinoma (TC) cells. Lenvatinib improves outcomes in patients with radioiodine-refractory well-differentiated TC. In addition to the unclear role of pericytes in ATC, the effect and mechanism of lenvatinib efficacy on ATC have not been sufficiently elucidated. Design: We assessed pericyte enrichment in ATC. We determined the effect of lenvatinib on ATC cell growth cocultured with pericytes and in a xenograft mouse model from human BRAFWT/V600E-ATC-derived cells coimplanted with pericytes. Results: ATC samples were significantly enriched in pericytes compared with normal thyroid samples. BRAFWT/V600E-ATC-derived cells were resistant to lenvatinib treatment shown by a lack of suppression of MAPK and Akt pathways. Moreover, lenvatinib increased CD47 protein (thrombospondin-1 [TSP-1] receptor) levels over time vs. vehicle. TSP-1 levels were downregulated upon lenvatinib at late vs. early time points. Critically, ATC cells, when cocultured with pericytes, showed increased sensitivity to this therapy and ultimately decreased number of cells. The coimplantation in vivo of ATC cells with pericytes increased ATC growth and did not downregulate TSP-1 in the microenvironment in vivo. Conclusions and Implications: Pericytes are enriched in ATC samples. Lenvatinib showed inhibitory effects on BRAFWT/V600E-ATC cells in the presence of pericytes. The presence of pericytes could be crucial for effective lenvatinib treatment in patients with ATC. Degree of pericyte abundance may be an attractive prognostic marker in assessing pharmacotherapeutic options. Effective durable management of ATC will rely on an understanding not only of genetics but also on the role of the tumor microenvironment.

Progressive erythrocytosis under lenvatinib treatment in patients with advanced hepatocellular carcinoma

PurposeThis manuscript reports on the occurrence of early and frequent erythrocytosis in advanced hepatocellular carcinoma (HCC) patients treated with lenvatinib.MethodsA cohort of 23 patients with advanced HCC, treated with this antiangiogenic drug for at least one month, was retrospectively analyzed.ResultsThese patients (82.7% men, median age 58.3, cirrhosis in 60.8%) were treated between October 2019 and September 2020 with lenvatinib, as first-line systemic therapy for 82.6% of them. For 20 patients (87%), an early and significant increase in hemoglobin (Hb) level, up to 1.41 g/dL (p < 0.001) was reported and remained elevated. Ten patients (43.5%), all men, reached erythrocytosis (Hb > 16.5 g/dL), 7 were treated with low-dose aspirin for primary thromboprophylaxis and 2 needed phlebotomy. None underwent thromboembolic complications. A significant Hb decrease was observed after treatment discontinuation (p < 0.05). Erythropoietin (EPO) serum levels also increased, which was attributed to HCC after immunostaining for EPO in liver biopsies. The Naranjo adverse drug reaction probability scale documented the relationship between erythrocytosis and lenvatinib and regression at treatment discontinuation. Erythrocytosis was hypothesized to be a class effect of anti-VEGF therapies, the magnitude of which might depend on the IC50 value of each molecule.ConclusionThis report documents the frequent occurrence of erythrocytosis during lenvatinib treatment for advanced HCC, likely secondary to EPO secretion by tumor cells through the antiangiogenic activity levatinib. An early and close monitoring of hematologic parameters is, thus, recommended, together with thromboprophylaxis by low-dose aspirin and phlebotomy in case of symptomatic erythrocytosis.

Analysis of adverse events leading to dose reduction/interruption of lenvatinib treatment in patients with Child-Pugh B unresectable hepatocellular carcinoma.

We aimed to compare the safety of lenvatinib as first-line treatment for unresectable hepatocellular carcinoma (HCC) in patients with Child-Pugh A (CP-A) and Child-Pugh B (CP-B) and to determine the adverse events (AEs) that cause dose reduction/interruption of treatment in patients with CP-B. Sixty-six patients with lenvatinib as a first-line treatment for HCC at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and January 2022 were retrospectively evaluated. We analyzed the treatment duration, AEs, and reasons for dose reduction/interruption associated with lenvatinib treatment in patients with CP-A and CP-B HCC. The CP-B group had significantly more cases of grade ≥ 2 fatigue and anorexia than the CP-A group (p = 0.045 and p = 0.042, respectively). Regarding AEs that caused dose reduction/interruption of treatment, the CP-A group had significantly more cases of proteinuria than the CP-B group (p = 0.015), whereas the CP-B group had significantly more cases of hand-foot syndrome (HFS) than the CP-A group (p = 0.013). Patients with CP-B have greater difficulty than patients with CP-A in continuing treatment with repeated dose reductions/interruption of treatment due to intolerable grade ≥ 2 AEs (fatigue and anorexia). HFS is more likely to cause dose reduction/interruption of treatment in CP-B than in CP-A unresectable HCC.

The beneficial impact of metabolic dysfunction-associated fatty liver disease on lenvatinib treatment in patients with non-viral hepatocellular carcinoma.

Lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Metabolic dysfunction-associated fatty liver disease (MAFLD) is becoming a major etiology of HCC. We aimed to evaluate the impact of MAFLD on the efficacy of lenvatinib. We enrolled 320 patients with HCC who were treated with lenvatinib. All patients were classified into the MAFLD (n=155) and non-MAFLD (n=165) groups. Independent factors for overall survival (OS) were analyzed. In the stratification analysis, HCC was categorized as non-viral (n=115) or viral HCC (n=205). The OS rate was significantly higher in the MAFLD group than in the non-MAFLD group (median 21.1 vs. 15.1months, p=0.002). Multivariate analysis demonstrated that, in addition to albumin-bilirubin grade and Barcelona Clinic Liver Cancer stage, MAFLD was identified as an independent factor for OS (HR 0.722, 95% CI 0.539-0.966, p=0.028). In the stratification analysis, the OS rate was significantly higher in the MAFLD group than in the non-MAFLD group among patients with non-viral HCC (median 21.1 vs. 15.1months, p=0.002), but not in patients with viral HCC. Furthermore, MAFLD was an independent negative risk factor for OS in patients with non-viral HCC (HR 0.506, 95% CI 0.297-0.864, P<0.01). However, MAFLD was not an independent factor for OS in patients with viral HCC. MAFLD was a beneficial factor for survival in patients with HCC treated with lenvatinib. Moreover, the better OS of the MAFLD group was more pronounced in patients with non-viral HCC. Lenvatinib may be a suitable agent for patients with non-viral HCC and MAFLD.

Sorafenib versus nivolumab after lenvatinib treatment failure in patients with advanced hepatocellular carcinoma.

An optimal sequential anti-hepatocellular carcinoma (HCC) agent that can be used after failed lenvatinib treatment has not been established. Here, we compared the outcomes of sorafenib and nivolumab as second-line agents after failed lenvatinib treatment in patients with advanced HCC. Patients with advanced HCC who had received sorafenib or nivolumab as second-line agents after failed lenvatinib treatment were recruited from two Korean tertiary institutions between November 2018 and June 2020. The median age of the 60 participants (52 treated with sorafenib and eight treated with nivolumab) at baseline was 56.8 years. The demographic, laboratory and tumor variables, as well as lenvatinib treatment duration, were similar between the two groups. The median durations of sorafenib and nivolumab treatment were 1.2 and 2.6 months, respectively ( P = 0.164). Twenty-four (40.0%) patients died during the follow-up period (median, 15.8 months). The median overall survival (OS) of the study population was 5.8 months. The median OS of patients treated with sorafenib was significantly longer than the median OS of patients treated with nivolumab (8.7 vs. 3.0 months; P = 0.046). Sorafenib treatment (vs. nivolumab) was independently associated with a lower risk of mortality (hazard ratio = 0.194; 95% confidence interval, 0.053-0.708; P = 0.013). Worse Eastern Cooperative Oncology Group performance status, larger maximal tumor size, lymph node metastases and higher total bilirubin levels were independently associated with increased mortality risk (all P < 0.05). Lenvatinib-sorafenib sequential treatment resulted in significantly better survival did than lenvatinib-nivolumab sequential treatment in patients with advanced HCC. Larger studies are needed to validate our results.

Changes in Body Composition Predict the Time to Treatment Failure of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma: A Pilot Retrospective Study

ABSTRACT: Aim Changes in body composition parameters are important prognostic factors in hepatocellular carcinoma (HCC) treatment. This study aimed to assess the clinical impact of early changes in body composition during lenvatinib (LEN) treatment on its time to treatment failure (TTF) for patients with advanced HCC. Methods In this retrospective study, we enrolled 65 patients who were administered LEN as the first-line treatment for unresectable HCC and evaluated the body composition change using computed tomography. We focused on the body composition change after 2 weeks of LEN treatment and assessed its impact on TTF and prognosis. Results Significant changes in body composition were observed during 14 weeks of LEN treatment. Among these changes, mean-skeletal muscle attenuation (SMA) decreased significantly within 2 weeks (P = 0.004) without symptoms or changes in the other parameters. In multivariate analysis, this early change in mean-SMA after LEN treatment was a significant predictor of time to treatment failure (HR: 2.67, 95%CI: 1.338–5.081, P = 0.005) in patients with HCC. Conclusions This study revealed that LEN treatment induces a change in the skeletal muscle asymptomatically for a short period, and evaluation of this change may help to predict the TTF of LEN treatment in patients with HCC. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2022.2049322 .

Risk Factors of Proteinuria in Patients with Hepatocellular Carcinoma Receiving Lenvatinib.

Proteinuria is one of the most frequently reported adverse events leading to the discontinuation of lenvatinib treatment in patients with advanced hepatocellular carcinoma (HCC). However, there are no reports regarding the risk factors of proteinuria in patients with HCC or patients receiving lenvatinib. We retrospectively reviewed the medical records of patients with HCC receiving lenvatinib at the Kobe City Medical Center General Hospital between April 2018 and December 2020. The severity of proteinuria was graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A multivariate Cox proportional hazards model was employed to identify the risk factors of developing grade ≥2 proteinuria. Among the 37 patients included, 3 patients had grade-1 proteinuria at baseline and 10 patients had estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at baseline. Grades 1, 2, and 3 proteinuria were observed in 15 (40.5%), 10 (27.0%), and 2 (5.4%) patients, respectively, during lenvatinib treatment. The median value of eGFR was significantly lower in patients who developed grade ≥2 proteinuria than those with grade ≤1 proteinuria (59.6 vs. 78.1 mL/min/1.73 m2, p = 0.045). Multivariate analysis revealed that pre-existing proteinuria at baseline (hazard ratio (HR), 9.72; 95% confidence interval (CI), 1.29-52.21; p = 0.030), and eGFR <60 mL/min/1.73 m2 at baseline (HR, 4.49; 95% CI, 1.32-16.07; p = 0.017) were significantly associated with developing grade ≥2 proteinuria. These patients should be monitored carefully, and our preliminary data should be confirmed by further studies.

Early Alpha-Fetoprotein Response Is Associated With Survival in Patients With HBV-Related Hepatocellular Carcinoma Receiving Lenvatinib.

Background/PurposeLenvatinib is a first-line treatment for unresectable hepatocellular carcinoma (uHCC). We assessed the value of early alpha-fetoprotein (AFP) response for predicting clinical outcomes with lenvatinib treatment in patients with HBV-related uHCC and elevated AFP levels.MethodsThis retrospective analysis included patients with HBV-related uHCC and baseline AFP levels ≥20 ng/ml who received lenvatinib for >1 month between November 2018 and May 2021. Early AFP response was defined as a >20% decrease in AFP serum level from baseline after 4 weeks of lenvatinib treatment. Radiological response (Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival, and overall survival were assessed in AFP responders and non-responders.ResultsOf the 46 patients analyzed, 30 (65.2%) were early AFP responders and 16 (34.8%) were non-responders. Compared to the non-responders, early AFP responders had a significantly higher objective response rate (34.5% vs 6.3%, p=0.0349), disease control rate (82.8% vs 50.0%; p=0.0203) and longer median progression-free survival (13.0 vs 7.0 months; HR, 0.464; 95% CI, 0.222-0.967; p=0.028). A subsequent multivariate analysis confirmed that early AFP response (HR, 0.387; 95% CI, 0.183-0.992; p=0.0154), Eastern Cooperative Oncology Group Performance Status of 0 (HR, 0.890; 95% CI, 0.811-0.976; p=0.0132) and Albumin-Bilirubin grade 1 (HR, 0.457; 95% CI, 0.269-0.963; p=0.0327) were independent prognostic factors for longer progression-free survival.ConclusionAFP is an important prognostic factor and a predictive biomarker for survival benefit with lenvatinib treatment in patients with HBV-related uHCC.

Association of early alpha-fetoprotein response with survival in patients with HBV-related hepatocellular carcinoma receiving lenvatinib.

448 Background: Lenvatinib is a standard first-line treatment for unresectable hepatocellular carcinoma (uHCC). We assessed the value of early alpha-fetoprotein (AFP) response for predicting clinical outcomes to lenvatinib treatment in patients with HBV-related uHCC and elevated AFP levels. Methods: This was a retrospective analysis of the medical records of consecutive patients with HBV-related uHCC and baseline AFP levels ≥20 ng/ml who received lenvatinib for &gt; 1 month at The First Hospital of Jilin University between November 2018 and May 2021. Early AFP response was defined as a &gt; 20% decrease in AFP serum level from baseline after 4 weeks of lenvatinib treatment. We evaluated radiological response using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as well as progression-free survival (PFS), and overall survival (OS) in AFP responders and non-responders. Potential prognostic factors for PFS and OS were assessed using univariate and multivariate Cox proportional hazards models. Intergroup differences were compared using a Mann–Whitney U test for continuous variables, a Fisher’s exact test for categorical variables and a log–rank test for survival data. Results: Medical records from 79 patients were screened and a total of 46 patients were included in the analysis; 84.4% had received lenvatinib in first-line, 63% were Child-Pugh class A, 56.4% had extrahepatic metastases, 35.6% had portal vein thrombosis and 10.3% and 87.2% had BCLC stage B and C disease, respectively. Of the 46 patients, 65.2% (n = 30) were early AFP responders and 34.8% (n = 16) were AFP non-responders. Baseline characteristics were balanced between early AFP responders and non-responders, except for age (≥60 years: 43.3% vs. 12.5%; p = 0.0366) and presence of portal vein thrombosis (46.7% vs. 13.3%; p = 0.0277). The median follow-up time was 18.0 (IQR, 3-29) months. Early AFP responders versus non-responders had a significantly higher objective response rate (34.5% vs 6.3%, p = 0.0349), disease control rate (82.8% vs 50.0%; p = 0.0203) and a longer median PFS (13.0 vs 7.0 months; HR, 0.464; 95% CI, 0.222-0.967; p = 0.028). Multivariate analysis confirmed that early AFP response (HR, 0.366; 95% CI, 0.169-0.795; p = 0.0110), ECOG PS of 0 (HR, 0.497; 95% CI, 0.323-0.877; p = 0.0326) and ALBI grade 1 (HR, 0.411; 95% CI, 0.277-0.863; p = 0.0283) were independent prognostic factors for longer PFS. Conclusions: AFP is an important prognostic factor and a predictive biomarker of survival benefit for patients with HBV-related uHCC receiving treatment with lenvatinib.

Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation: A retrospective analysis.

410 Background: Lenvatinib is approved for use in patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, its clinical outcomes in patients experiencing HCC recurrence after liver transplantation (LT), remain unclear. Further, despite of immunotherapeutic advances (atezolizumab plus bevacizumab, pembrolizumab, and nivolumab) in the management of advanced HCC, patients with prior LT are not benefited because of the risk of allograft rejection, and they are also excluded in the most prospective clinical trials for novel agents. Thus, we investigated the efficacy and safety of lenvatinib treatment in patients with recurrent HCC after LT. Methods: This single center, retrospective study included 22 patients with recurrent HCC after LT who received lenvatinib at the Asan Medical Center, South Korea, between November 2019 and March 2021. Lenvatinib was given 12mg/day for bodyweight ≥ 60 kg or 8 mg/day for bodyweight &lt; 60 kg. Response and adverse events (AEs) were graded according to RECIST v1.1 and NCI CTCAE v5.0. Results: The median age was 58 years (range, 20-69) and 95.5% (n = 21) were male. Most common etiology of HCC was hepatitis B (n = 18, 81.8%). The median time to recurrence after LT was 6.6 months (95% CI, 4.2-9.1 months). Prior to systemic therapy, transarterial embolization (TACE) (n = 12, 54.5%) was the most commonly used therapy for recurred HCC after LT. At the time of lenvatinib initiation, 95.5% (n = 21) of the patients were Child-Pugh A with 15 (68.2%) and 7 (31.8%) patients classified as ALBI grades 1 and 2, respectively. All patients were at BCLC stage C and lenvatinib was administered as first-line (n = 19) and second-line (n = 3) therapy. The objective response rate (ORR) was 13.6%. With a median follow-up duration of 5.2 months (range, 1.7-14.5 months), the median progression-free survival (PFS) was 6.6 months (95% CI: 3.6-9.5 months) and overall survival (OS) was 14.5 months (95% CI: not assessable). The 6-month PFS and OS rates were 59.8% and 88.8%, respectively. Patients with ALBI grade 2 showed significantly poorer OS [11.1 months (95% CI: not assessable)] compared to patients with ALBI grade 1 [14.5 months (95% CI: not assessable)] ( p= 0.011). AEs were hypertension (n = 8, 36.4%), thrombocytopenia (n = 7, 31.8%), and fatigue (n = 6, 27.3%). Conclusions: Lenvatinib was effective and showed manageable toxicities in patients with recurrent HCC after LT. These outcomes are comparable to those from the pivotal REFLECT trial where patients with LT were excluded. Better baseline liver function (ALBI grade 1) at lenvatinib initiation correlated with better survival outcomes.

A proposed clinical scoring system for initiation of lenvatinib treatment in radioiodine-refractory thyroid cancer patients.

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.

Adaptation of lenvatinib treatment in patients with hepatocellular carcinoma and portal vein tumor thrombosis.

The aim of this study was to clarify the adaptation of lenvatinib treatment in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). Fifty-three patients with HCC were treated with lenvatinib. Before and after treatment blood sampling, patients were examined by computed tomography and ultrasonography. In patients with portal trunk invasion (Vp4), the analysis focused on the degree of occlusion due to the tumor in the portal trunk. In patients without major PVTT {ie, invasion of the primary branch of the portal vein [Vp3] or Vp4}, portal blood flow volume was measured by Doppler analysis; however, Doppler analysis is difficult to perform in patients with major PVTT, so the time from administration of the contrast agent to when it reached the primary branch of the portal vein (portal vein arrival time) was evaluated with the contrast agent Sonazoid. Patients with Vp4 had a significantly worse prognosis than patients with Vp3 and a significant increase in Child-Pugh score at 2months. Patients with major PVTT had a poor prognosis if the degree of occlusion of the portal trunk was 70% or more. In patients without major PVTT, portal blood flow was significantly decreased after administration of lenvatinib; and in patients with major PVTT, the hepatic artery and portal vein arrival times were significantly increased. Lenvatinib treatment should be avoided in patients with Vp4 with a high degree of portal trunk occlusion because of concerns about decreased portal blood flow.

Influence of NOS3 rs2070744 genotypes on hepatocellular carcinoma patients treated with lenvatinib

We investigated whether or not nitric oxide synthase 3 (NOS3) rs2070744 genotypes can affect the response for lenvatinib treatment in patients with hepatocellular carcinoma (HCC). We evaluated the relation of the NOS3 rs2070744 genotypes to the tumor response, progression-free survival (PFS), and overall survival (OS) as the response for lenvatinib. We also examined the association between fibroblast growth factor receptor (FGFR) gene polymorphisms, a potential feature of lenvatinib, and the response. There were no significant differences between the studies for either PFS or OS, even though patients with the TT genotype had a longer mean PFS (hazard ratio [HR] 0.60; p = 0.069) and mean OS (HR 0.46; p = 0.075) than those with the TC/CC genotypes. However, patients with a single-nucleotide polymorphism (SNP) combination pattern of the NOS3 rs2070744 TC/CC and FGFR4 rs351855 CT/TT genotypes had a significantly shorter mean PFS (HR 2.56; p = 0.006) and mean OS (HR 3.36; p = 0.013) than those with the other genotypes. The NOS3 rs2070744 genotypes did not influence the clinical response. However, the SNP combination pattern of the NOS3 rs2070744 and FGFR4 rs351855 genotypes may be helpful as treatment effect predictors and prognostic factors for HCC patients treated with lenvatinib.

Relationship between outcomes and relative dose intensity of lenvatinib treatment in patients with advanced hepatocellular carcinoma

Background and aimsLenvatinib (LEN) is a newly developed tyrosine kinase inhibitor, and is approved as a first-line treatment for advanced hepatocellular carcinoma (HCC) in Japan. This retrospective multi-center study investigated the effect of the relative dose intensity (RDI) of LEN on response rate, progression-free survival (PFS), and overall survival (OS). MethodsThis retrospective study enrolled 123 patients with advanced HCC who were treated with LEN at six hospitals in Japan between March 2018 and December 2019. These patients were divided into two groups: RDI ≥70% (RDI 70 group, N = 70) or RDI < 70% (control group, N = 53) in the first 30 days. The following data were compared between groups: patient backgrounds, adverse events, treatment outcomes, PFS, and OS. PFS and OS were analyzed using the Kaplan-Meier method, followed by the log-rank test. To identify significant factors that contributed to response, PFS, and OS, multivariate analysis was performed using factors for which P-values were <0.10 in univariate analysis. ResultsThe proportion of patients with Child-Pugh class 5A was significantly greater in the RDI 70 group than that in the control group (64.3% vs. 28.3%, P < 0.01). Dose interruption due to adverse events was significantly more common in the control group. The response rate was significantly higher in the RDI 70 group than that in the control group (35.7% vs. 11.3%, P < 0.01). Median PFS was significantly longer in the RDI 70 group (9.4 vs. 4.7 months, P < 0.01). Multivariate analysis showed that RDI ≥70% (hazard ratio (HR) = 0.55, P = 0.025), hypertension grade ≥ 2 (HR = 0.47, P = 0.019), and response (HR = 0.52, P = 0.033) were independently associated with improved PFS. Median OS was also significantly longer in the RDI 70 group (20.0 vs. 13.3 months, P = 0.045). Multivariate analysis showed that female sex (HR = 0.33, P = 0.034) and disease control (HR = 0.31, P < 0.01) were independently associated with improved OS. RDI ≥70% was not statistically significant in multivariate analysis. ConclusionsOur study revealed the importance of achieving RDI ≥70% in the first 30 days of treatment to maximize the effects of LEN.

Reduction in Tumor Stain at 2 Weeks after Treatment Initiation Is a Predictor of the Efficacy of Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma

Background and Aims: Lenvatinib is an oral anticancer drug for patients with unresectable advanced hepatocellular carcinoma (HCC). We evaluated whether a reduction in tumor stain at 2 weeks after lenvatinib treatment in patients with unresectable HCC is a predictor of early treatment efficacy at 12 weeks. Patients and Methods: Of the 23 patients who initiated lenvatinib treatment between April 2018 and January 2019, treatment efficacy was measured in 15 patients for more than 12 weeks after treatment. Changes in tumor stain, tumor size on contrast-enhanced computed tomography (CT), and serum levels of tumor markers were evaluated 2 weeks after lenvatinib treatment. Therapeutic efficacy was assessed by tumor stain and tumor size by contrast-enhanced CT within the first 12 weeks, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines. Results: At 12 weeks, efficacy evaluation of 15 patients revealed that 11 of them experienced partial responses, for a response rate of 73.3%. In the first 2 weeks, 13 patients (86.7%) experienced a decreased tumor stain, including 10 responders (90.9%) and 3 non-responders (75.0%). All patients in the non-responder group had required a lenvatinib dose reduction due to adverse events within 12 weeks. On contrast-enhanced CT, the change rate of tumor stain to HCC at 2 weeks after treatment was <0.8 among 10 responders (90.9%) and 1 non-responder (25.0%; p = 0.033). No significant differences between responders and non-responders were observed with regard to most characteristics at baseline and at 2 weeks after treatment initiation. However, significant differences were observed between groups in the presence or absence of a dose suspension period, the presence or absence of lenvatinib dose reduction from the maximum value during the first 2 weeks, and decreased tumor stain at 2 weeks after treatment initiation. Conclusion: Reduction in tumor stain at 2 weeks after lenvatinib treatment may be an early biomarker of efficacy at 12 weeks in patients with unresectable HCC.

Lenvatinib prolongs the progression‑free survival time of patients with intermediate‑stage hepatocellular carcinoma refractory to transarterial chemoembolization: A multicenter cohort study using data mining analysis

Tyrosine kinase inhibitors are considered for use in patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). The aim of the present retrospective study was to identify factors associated with progression-free survival (PFS) and to evaluate the indications for lenvatinib treatment in patients with intermediate-stage HCC refractory to TACE using a data-mining analysis. A total of 171 patients with intermediate-stage HCC refractory to TACE were included. All patients were classified into three groups according to their HCC treatment: Lenvatinib (n=45), sorafenib (n=53) and TACE (n=73) groups. PFS time was calculated using the Kaplan-Meier method and analyzed using a log-rank test. Factors associated with PFS time were evaluated using multivariate and decision-tree analyses. The median PFS time was 5.8, 3.2 and 2.4 months in the lenvatinib, sorafenib and TACE groups, respectively (P<0.001). In the Cox regression analysis, lenvatinib treatment and being within the up-to-seven criteria were identified as independent factors for PFS (lenvatinib, P<0.0001; within up-to-seven, P=0.001). The decision-tree analysis revealed that patients beyond the up-to-seven criteria, treated with lenvatinib and with albumin-bilirubin (ALBI) grade 1 had a longer PFS time (245.2±107.9 days) than patients beyond the up-to-seven criteria, treated with lenvatinib and with ALBI grade 2 (147.1±78.6 days). Additionally, lenvatinib was independently associated with longer PFS time in patients with intermediate-stage HCC refractory to TACE. Therefore, lenvatinib may be recommended for patients who have intermediate-stage HCC refractory to TACE, ALBI grade 1 and who are within the up-to-seven criteria.