Treatment of Hepatocellular Carcinoma With Lenvatinib.
Ontology highlight
ABSTRACT:
SUBMITTER: Han KH
PROVIDER: S-EPMC6284340 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
Publications
Treatment of Hepatocellular Carcinoma With Lenvatinib.
Gastroenterology & hepatology 20181101 11
Similar Datasets
Project description:During the last 10 years, the multikinase inhibitor sorafenib has emerged as the only systemic treatment for unresectable hepatocellular carcinoma (HCC). More recently, data from the Phase III REFLECT trial showed that another multikinase inhibitor, namely, lenvatinib, was non-inferior to sorafenib in terms of overall survival (OS). In contrast, with respect to OS, previous randomized Phase III trials have been negative, and several agents tested have failed to prove non-inferiority (or superiority) when compared with sorafenib in a first-line setting. Furthermore, the REFLECT trial demonstrated that lenvatinib, in comparison with sorafenib, significantly increased progression-free survival, time to progression, and objective response rate. Overall, the incidence of grade ?3 treatment-emergent adverse events (TEAEs) was similar in the two treatment arms of the trial, with a higher incidence of serious TEAEs in the lenvatinib arm. Encouraging efficacy signals had already been reported for immune checkpoint inhibitors in HCC, and different synergisms have been postulated in the frame of interplay between vascular endothelial growth factor receptor-2 inhibitors and immunotherapy. Given these premises, future approaches are being developed in Phase I trials testing lenvatinib in combination with pembrolizumab or nivolumab. As the treatment landscape of HCC is expanding with novel agents being approved for patients who are intolerant or are progressing on prior sorafenib, we will discuss current challenges pertaining to the optimal sequencing of active agents in first- and second-line setting.
| S-EPMC6362912 | biostudies-literature
Project description:Background/aimPost-progression treatment following tyrosine-kinase inhibitor (TKI) failure in patients with unresectable hepatocellular carcinoma (u-HCC) is important to prolong post-progression survival (PPS), which has a good correlation with overall survival (OS). This study aimed to elucidate the clinical features of progressive disease (PD) in patients treated with lenvatinib (LEN).Materials/methodsFrom March 2018 to June 2019, 156 u-HCC patients with Child-Pugh A were enrolled (median age: 71 years, Child-Pugh score 5:6 = 105:51, BCLC A:B:C = 8:56:92, modified albumin-bilirubin grade (mALBI) 1:2a:2b = 59:42:55, past history of sorafenib:regorafenib = 57:17). Clinical features were retrospectively evaluated.ResultsThe median observation period was 8.5 months. Median OS was not obtained, while median time to decline to Child-Pugh B (CPB) was 11.4 months, median time to progression (TTP) was 8.4 months, and the period of LEN administration was 7.3 months. When we compared predictive values for time to decline to CPB based on Child-Pugh score and mALBI, values for Akaike information criterion (AIC) score and c-index of mALBI were superior as compared to Child-Pugh score (AIC: 592.3 vs. 599.7) (c-index: 0.655 vs. 0.597). Of the 73 patients with PD, 32 (43.8%) showed no decline to CPB or death. After excluding 3 without alpha-fetoprotein data at PD determination, only 14 (20.0%) of 70 showed REACH-2 eligibility. Non-mALBI 1/2a at the start of LEN was a significant risk factor for decline to CPB during LEN treatment (HR 2.552, 95% CI: 1.577-4.129; p < 0.001).ConclusionIntroduction of TKI therapy including LEN for u-HCC patients with better hepatic function (mALBI 1/2a: ALBI score ≤-2.27), when possible, increases the chance of undergoing post-progression treatment, which can improve PPS.
| S-EPMC7024896 | biostudies-literature
Project description:On August 16, 2018, the U.S. Food and Drug Administration approved lenvatinib (Lenvima, Eisai Inc.) for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Approval was based on an international, multicenter, randomized, open-label, noninferiority trial (REFLECT; NCT01761266) conducted in 954 patients with previously untreated metastatic or unresectable HCC. Patients were randomized (1:1) to receive lenvatinib (12 mg orally once daily for patients with a baseline body weight ≥60 kg and 8 mg orally once daily for patients with a baseline body weight <60 kg) or sorafenib (400 mg orally twice daily) until radiological disease progression or unacceptable toxicity. REFLECT demonstrated that lenvatinib was noninferior but not statistically superior to sorafenib for overall survival (OS; hazard ratio, [HR] 0.92; 95% confidence intervals [CI], 0.79-1.06), with median OS of 13.6 and 12.3 months in the lenvatinib and sorafenib arms, respectively. REFLECT also demonstrated statistically significant improvements in investigator-assessed progression-free survival (PFS; HR, 0.66; 95% CI, 0.57-0.77]; p < 0.001), corresponding to median PFS of 7.4 and 3.7 months and overall response rate of 24.1% vs 9.2% per modified RECIST for HCC (mRECIST) in the lenvatinib and sorafenib arms, respectively. Consistent results were observed by an independent review facility per RECISTv1.1 and per mRECIST. The most common adverse reactions observed in the lenvatinib-treated patients (≥20%) in decreasing frequency were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea. IMPLICATIONS FOR PRACTICE: This article describes the U.S. Food and Drug Administration's review of data from a single trial, REFLECT, that supported the approval of lenvatinib, as a single agent, for the first-line treatment of unresectable hepatocellular carcinoma (HCC). REFLECT was an open-label, noninferiority trial that randomized 954 patients with HCC who were ineligible for liver-directed therapy with no prior systemic therapy for HCC to lenvatinib or sorafenib. REFLECT demonstrated that lenvatinib-treated patients had similar survival, more responses, and longer time to progression than those receiving sorafenib. Serious side effects were more common among lenvatinib-treated patients. Lenvatinib is an effective treatment for patients with previously untreated HCC.
| S-EPMC7930400 | biostudies-literature
Project description:BackgroundLenvatinib is a first-line agent for advanced hepatocellular carcinoma (HCC), but individual responses to treatment are highly heterogeneous. The aim of this study was to investigate the clinical parameters that influence the efficacy of Lenvatinib and to develop a prognostic model.MethodsWe retrospectively enrolled 333 Lenvatinib-treated patients with HCC with a median age of 57 years. Two hundred nd sixty-three of these patients had BCLC (2022) stage C. The median overall survival (mOS) time within the cohort was 12.1 months, and the median progression-free survival (mPFS) time was 4.7 months. Univariate Cox regression, best subset regression, and Lasso regression were used to screen primary variables for possible contribution to OS, multivariate Cox analysis was used to fit selected models, and the final model was selected using the maximum area under the curve (AUC) and minimum AIC. Receiver operating curves (ROC), calibration curves, and decision curve analysis were plotted to assess model performance, and 5-fold cross-validation was performed for internal validation. X-tile software was used to select the best cutoff points and to divide the study cohort into 3 different risk groups.ResultsSeven variables were included in the final model: BCLC stage, prior transarterial chemoembolization and immunotherapy history, tumor number, prognostic nutritional index, log (alpha-fetoprotein), and log (platelet-to-lymphocyte ratio). We named this final model the "multivariate prognostic model for Lenvatinib" (MPML), and a nomogram was constructed to predict the probability of survival at 6, 9, and 12 months. The MPML had good discrimination, calibration, and applicability. Cross-validation showed mean AUC values of 0.7779, 0.7738, and 0.7871 at 6, 9, and 12 months, respectively. According to nomogram points, mOS time was 21.57, 8.70, and 5.37 months in the low, medium, and high-risk groups, respectively (P < .001), and these differences were also observed in the PFS survival curve (P < .001).ConclusionsThe MPML stratified patients according to baseline clinical characteristics had a strong performance in predicting Lenvatinib efficacy and has the potential for use as an auxiliary clinical tool for individualized decision-making.
| S-EPMC10546830 | biostudies-literature
Project description:BackgroundThe aims of this study were to evaluate the efficacy of additional treatment, especially lenvatinib-transarterial chemoembolization (TACE) sequential therapy, for unresectable hepatocellular carcinoma (HCC).MethodsConsecutive 56 patients who underwent lenvatinib treatment were reviewed. Oncological aggressiveness of tumor was estimated using a dynamic CT enhancement pattern classification, and clinical impact of subsequent treatment was investigated through analysis of progression-free survival (PFS), post-progression survival (PPS), and multivariate analysis of potential confounders for survival after progression during lenvatinib therapy.ResultsHeterogeneous enhancement patterns (Type-3 and -4), which are reportedly associated with higher oncological aggressiveness of HCC, were associated with better objective response to lenvatinib compared to homogeneous enhancement pattern (Type-2) (86 and 85% vs. 53% in modified Response Evaluation Criteria in Solid Tumors), resulting in similar PFS (p = 0.313). Because of significantly worse PPS, overall survival of Type-4 tumor was poor compared to Type-2 or -3 tumors (p = 0.009). However, subgroup of patients who achieved subsequent treatment showed significantly better PPS, regardless of CT enhancement pattern. Multivariate analysis confirmed that use of lenvatinib-TACE sequential treatment after progression during lenvatinib therapy was associated with better PPS (hazard ratio [HR], 0.08; 95% CI, 0.01-0.71; p = 0.023), while Type-4 enhancement pattern was correlated with worse PPS (HR, 2.92; 95% CI, 1.06-8.05; p = 0.039).ConclusionOncological aggressiveness of HCC estimated by CT enhancement pattern was predictive of PPS after progression during lenvatinib. Successful subsequent treatment with lenvatinib-TACE sequential therapy may offer survival benefit regardless of CT enhancement pattern of HCC.
| S-EPMC7768146 | biostudies-literature
Project description:Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic Liver Cancer (BCLC) intermediate stage were the key factors in achieving therapeutic efficacy. The management of adverse events plays an important role in continuing lenvatinib treatment. While sequential therapies contributed to prolonging overall survival, effective molecular targeted agents for the administration after lenvatinib have not been established. Repeated transcatheter arterial chemoembolization (TACE) was associated with a decline in the liver function and poor therapeutic response in BCLC intermediate patients. Recently, the Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement proposed the criteria for TACE unsuitability. Upfront systemic therapy may be better for the BCLC intermediate stage HCC patients with a high tumor burden, while selective TACE will be recommended for obtaining a curative response in patients with a low tumor burden. This article reviews the therapeutic response, management of adverse events, post-progression treatment after Lenvatinib, and treatment strategy for BCLC intermediate stage HCC.
| S-EPMC7825021 | biostudies-literature
Project description:There are limited reports regarding early predictors of objective response (OR) in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. This retrospective study including 70 patients aimed to investigate the efficacy of hepatic biochemical markers. Changes in tumor marker (alpha-fetoprotein (AFP)/des-gamma-carboxy prothrombin (DCP)) levels and albumin-bilirubin (ALBI) score between the baseline value and that estimated one month after treatment were evaluated. We identified several predictors of OR, including changes in tumor marker levels. The OR rate calculated using modified Response Evaluation Criteria in Solid Tumor (mRECIST) was 41.4%. Response was defined as a reduction in AFP and DCP levels of ≥40% from baseline. OR was significantly associated with AFP response, but not with DCP. Predictors of OR were evaluated in two groups (high-AFP group: baseline AFP ≥ 10 ng/mL; low-AFP group: remaining patients). A multivariate analysis identified AFP response (odds ratio, 51.389; p = 0.001) and ALBI score (odds ratio, 6.866; p = 0.039) as independent predictors of OR in the high-AFP and low-AFP groups, respectively. Changes in the ALBI score indicated deterioration in both responders and non-responders, with a significant difference in non-responders (p = 0.003). AFP response, baseline ALBI score, and change in the ALBI score were early predictors of OR in patients with HCC undergoing lenvatinib treatment.
| S-EPMC7225985 | biostudies-literature
Project description:Background and aimWe evaluated the efficacy of rechallenge transcatheter arterial chemoembolization (TACE) after lenvatinib (LEN) treatment in patients with previous TACE failure/refractoriness.MethodsWe enrolled 63 consecutive patients with a history of TACE failure/refractoriness prior to LEN treatment as a first-line systemic therapy. We reviewed the clinical backgrounds and courses of the patients.ResultsIn total, 25 patients underwent rechallenge TACE after LEN due to LEN-refractoriness (17 cases) or intolerance (8 cases). A complete or partial response was obtained for 13 (65.0%) of the 20 patients whose therapeutic effects were determined. The survival rate of patients who underwent rechallenge TACE was significantly higher than that of patients who did not undergo rechallenge TACE (median survival time, not reached vs 403 days, P = 0.015). Rechallenge TACE significantly reduced the risk of death in univariate (hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.08-0.69, P = 0.008) and multivariate analyses (HR 0.26, 95% CI 0.08-0.80, P = 0.019). If complete or partial response was obtained by rechallenge TACE, the median survival time of these patients was significantly longer than those of the progressive disease (PD) group (P = 0.05), and the median survival time of the PD group after rechallenge TACE was not different from that of the group who did not undergo rechallenge TACE (P = 0.36). We did not observe a decrease in the ALBI score after TACE.ConclusionRechallenge TACE after LEN is an effective treatment that may result in a favorable prognosis.
| S-EPMC9667401 | biostudies-literature
Project description:BackgroundCombining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC).AimsTo explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC.MethodsThis multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety.ResultsBy March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events.ConclusionFirst-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC.
| S-EPMC8907842 | biostudies-literature
Project description:BACKGROUND:Fatigue is a common adverse event during lenvatinib treatment in patients with hepatocellular carcinoma. One mechanism contributing to development of fatigue might involve abnormal adenosine triphosphate synthesis that is caused by carnitine deficiency. To address this possibility, we examined the relationship between carnitine levels and fatigue during lenvatinib treatment. METHODS:This prospective study evaluated 20 patients with hepatocellular carcinoma who underwent lenvatinib treatment. Both blood and urine samples were collected from the patients before starting lenvatinib therapy (day 0), and on days 3, 7, 14, and 28 thereafter. Plasma and urine concentrations of free and acyl carnitine (AC) were assessed at each time point. The changes in daily fatigue were evaluated using the Brief Fatigue Inventory (BFI). RESULTS:Plasma levels of free carnitine (FC) at days 3 and 7 were significantly higher compared with baseline (p = 0.005, p = 0.005, respectively). The urine FC level at day 3 was significantly higher compared with baseline (p = 0.030) and that of day 7 tended to be higher compared with baseline (p = 0.057). The plasma AC concentration at days 14 and 28 was significantly higher compared with that of baseline (p = 0.002, p = 0.005, respectively). The plasma AC-to-FC (AC/FC) ratio on days 14 and 28 was significantly higher compared with baseline (p = 0.001, p = 0.003, respectively). There were significant correlations between the plasma AC/FC ratio and the change in the BFI score at days 14 and 28 (r = 0.461, p = 0.041; r = 0.770, p = 0.002, respectively). CONCLUSIONS:Longitudinal assessments of carnitine and fatigue in patients with hepatocellular carcinoma suggest that lenvatinib affects the carnitine system in patients undergoing lenvatinib therapy and that carnitine insufficiency increases fatigue. The occurrence of carnitine insufficiency may be a common cause of fatigue during the treatment.
| S-EPMC7053710 | biostudies-literature