Dataset Information

Lenvatinib for the treatment of unresectable hepatocellular carcinoma: evidence to date.

ABSTRACT: 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.

SUBMITTER: Personeni N

PROVIDER: S-EPMC6362912 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Lenvatinib for the treatment of unresectable hepatocellular carcinoma: evidence to date.

Personeni Nicola N Pressiani Tiziana T Rimassa Lorenza L

Journal of hepatocellular carcinoma 20190131

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 superior ...[more]

PMID: 30775342

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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.

Project description:BACKGROUND:In a global, phase III, open-label, noninferiority trial (REFLECT), lenvatinib demonstrated noninferiority to sorafenib in overall survival and a statistically significant increase in progression-free survival in patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib became the first agent in more than 10?years to receive approval as first-line therapy for unresectable HCC, along with the previously approved sorafenib. The objective of this study was to determine the comparative cost-effectiveness of lenvatinib and sorafenib as a first-line therapy of unresectable HCC. MATERIALS AND METHODS:A state-transition model of unresectable HCC was developed in the form of a cost-utility analysis. The model time horizon was 5?years; the efficacy of the model was informed by the REFLECT trial, and costs and utilities were obtained from published literature. Probabilistic sensitivity analyses and subgroup analyses were performed to test the robustness of the model. RESULTS:Lenvatinib dominated sorafenib in the base case analysis. A probabilistic sensitivity analysis indicated that lenvatinib remains a cost-saving measure in 64.87% of the simulations. However, if the cost of sorafenib was reduced by 57%, lenvatinib would no longer be the dominant strategy. CONCLUSION:Lenvatinib offered a similar clinical effectiveness at a lower cost than sorafenib, suggesting that lenvatinib would be a cost-saving alternative in treating unresectable HCC. However, lenvatinib may fail to remain cost-saving if a significantly cheaper generic sorafenib becomes available. IMPLICATIONS FOR PRACTICE:This analysis suggests an actionable clinical policy that will achieve cost saving. This cost-utility analysis showed that lenvatinib had a similar clinical effectiveness at a lower cost than sorafenib, indicating that lenvatinib may be a cost-saving measure in patients with unresectable HCC, in which $23,719 could be saved per patient. The introduction of a new therapeutic option for the first time in 10?years in Canada provides an important opportunity for clinicians, researchers, and health care decision-makers to explore potential modifications in recommendations and practice guidelines.

Project description:PurposeThe immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti-PD-1 antibody) in unresectable HCC (uHCC).Patients and methodsIn this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase).ResultsA total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified.ConclusionLenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

Dataset Information

Lenvatinib for the treatment of unresectable hepatocellular carcinoma: evidence to date.

Publications

Lenvatinib for the treatment of unresectable hepatocellular carcinoma: evidence to date.

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