Cost-Effectiveness of Sorafenib, Lenvatinib, and FOLFOX4 for Advanced Hepatocellular Carcinoma in China
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Objective: Liver cancer is the third leading cause of cancer mortality in China. This study assesses the cost-effectiveness of sorafenib, lenvatinib, and FOLFOX4 in the treatment of advanced hepatocellular carcinoma (HCC) to inform clinical decision-making.Material and Methods: We used a Markov model to simulate the progression of HCC and calculate Quality-Adjusted Life Years (QALYs) and Incremental Cost-Effectiveness Ratios (ICERs) under two scenarios. Costs were obtained from the Yaozhi Network, while transition probabilities and utilities were derived from the REFLECT, EACH, and CELESTIAL clinical trials. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to evaluate model robustness and parameter uncertainty.Results: In Scenario A, using market-listed prices, sorafenib, and lenvatinib were found to be more cost-effective than FOLFOX4, with ICERs of $11,635.28 and $1,499.93 per QALY, respectively, both below the cost-effectiveness threshold. In Scenario B, with centralized procurement prices, sorafenib had a negative ICER of -$7,351.26 per QALY, indicating cost savings with improved outcomes, while lenvatinib had an ICER of $2,685.99 per QALY. Sensitivity analysis revealed that drug costs, utilities of disease progression, and discount rates were key determinants of ICER values.Conclusion: Sorafenib and lenvatinib are significantly more cost-effective compared to FOLFOX4, particularly under centralized procurement pricing. These results support the inclusion of these treatments in public health policy to enhance healthcare outcomes and optimize resource allocation, thereby improving the economic and quality-of-life metrics for patients with HCC.Keywords:
Lenvatinib
A 70-year-old man was diagnosed with multiple lung metastases from hepatocellular carcinoma, and lenvatinib was initiated. Three months later, the response was progressive disease. Sorafenib therapy as a second-line drug was started. Three months later, the lung metastases had shrunk. After the sorafenib failure, the patient received regorafenib treatment for six months until failure. After the regorafenib failure, sorafenib rechallenge therapy as a fourth-line treatment was initiated. The sorafenib rechallenge, which continued for two months, induced a partial response. Sorafenib after lenvatinib failure and sorafenib rechallenge may be a good option, but further prospective studies are needed.
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There is a paucity of comparative data on the use of sorafenib and lenvatinib for unresectable hepatocellular carcinoma. We assessed the real-world treatment outcomes between using sorafenib and lenvatinib for unresectable hepatocellular carcinoma in the multiple molecular-targeted therapy era.We enrolled 386 patients treated with sorafenib or lenvatinib as the first-line therapy for unresectable hepatocellular carcinoma at multiple centers. Propensity score matching was performed to adjust for differences in baseline and tumor characteristics between the two groups. Propensity score matching identified 110 patients in each treatment group. The median overall survival was similar between lenvatinib and sorafenib (14.8 and 13.0 months, respectively; P = 0.352). The median progression-free survival was longer with lenvatinib than with sorafenib (7.6 and 3.9 months, respectively; P < 0.001). The overall response rate (P < 0.001) and disease control rate (P = 0.015), as defined by the modified Response Evaluation Criteria in Solid Tumors, were significantly better with lenvatinib than with sorafenib. The median overall survival was longer in patients who received subsequent treatment than in those who did not in the sorafenib group (23.1 and 5.7 months, respectively; P < 0.001), whereas the median overall survival with or without subsequent treatment did not differ significantly in the lenvatinib group (17.8 and 14.7 months, respectively; P = 0.439).Overall survival with sorafenib and lenvatinib was not significantly different. However, patients who received subsequent treatments had longer overall survival than those who received only first-line treatment with sorafenib, whereas lenvatinib did not show this effect.
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Abstract Background Although sorafenib was recommended as a first-line systemic therapy to prolong overall survival time in unresectable hepatocellular carcinoma (HCC), two randomized phase 3 noninferiority trials demonstrated that lenvatinib was noninferior to sorafenib in unresectable HCC. Methods This study included three trials containing 1462 patients identified by a database search using standard terms. We conducted the data analysis in Review Manager version 5.3 software. Results The outcomes showed that there were nonsignificant differences in OS of 6, 12, 18, 30 and 36 months, PFS of 18, 24, 30 and 36 months and AEs (grade < 3) between the lenvatinib group and the sorafenib group, and there were significant differences in OS of 24 months (p = 0.01), PFS of 6 (p < 0.00001) and 12 (p < 0.00001) months, ORR (p < 0.00001) and DCR (p < 0.00001) between the lenvatinib group and the sorafenib group. Conclusions Lenvatinib was not superior to sorafenib in terms of OS and AEs, and lenvatinib was superior to sorafenib in terms of secondary endpoints, including PFS, ORR and DCR, in unresectable HCC.
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Hepatocellular carcinoma (HCC) is a worldwide healthcare problem, with a rising incidence. In its advanced stage, the prognosis of untreated HCC is very poor. Only in 2007, after a long series of failed trials, the multi-tyrosine kinase inhibitor sorafenib demonstrated its superiority over placebo, becoming the first approved frontline therapy for advanced HCC. For a decade, all of the frontline trials using sorafenib as a comparator systematically failed, leaving this drug as the only available treatment in this setting. In 2018, lenvatinib mesylate (another multitarget tyrosine kinase inhibitor) demonstrated noninferiority compared to sorafenib in the phase III, randomized, controlled REFLECT trial. Currently, lenvatinib represents the only available alternative to sorafenib as a frontline systemic treatment of advanced HCC. In this monograph, we review the main preclinical and clinical evidence that emerged in the trials of lenvatinib, with particular attention to the features differentiating this drug from sorafenib.
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In the past decade, sorafenib has been the only approved molecular-targeted agent for unresectable hepatocellular carcinoma (uHCC) without any authentic challenges. There has been an urging need for alternatives or superior options for a long while (1,2). At least 25 molecular-targeted drugs emerged in the past 15 years and had been tested for the efficacy and safety in treating uHCC, yet most of those trials have failed to show positive results ( Table 1 ).
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Aim Sequential administration of sorafenib followed by regorafenib or lenvatinib is effective against advanced hepatocellular carcinoma (HCC). In this study, we compared the safety profiles and anti‐tumor effects of sequential sorafenib and regorafenib or lenvatinib therapy in patients with HCC. Methods We investigated adverse events, treatment responses and dose intensities in patients with HCC who were consecutively treated with sorafenib followed by regorafenib or lenvatinib at the individual level. Results Each group included 20 patients. The safety profiles of regorafenib and sorafenib were similar. The severity of hypophosphatemia, palmar‐plantar erythrodysesthesia syndrome, and decreased neutrophil counts associated with regorafenib or sorafenib was similar in 12 patients. Conversely, the incidences and grades of adverse events differed between sorafenib and lenvatinib treatment. The anti‐tumor effects of regorafenib and lenvatinib compared with sorafenib were significantly different for each patient. The response to treatment and progression‐free survival were comparable for regorafenib and lenvatinib. The median relative dose intensities during the first 56 days of regorafenib and lenvatinib treatment were 83.6 and 80.0%, respectively. Conclusions Similar adverse events were experienced by patients during consecutive treatment with sorafenib and regorafenib, which was not observed during treatment with sorafenib and lenvatinib. The obtained safety profile of sorafenib provided meaningful insights for selecting sequential therapy for patients with advanced HCC.
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Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4.
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Aim : The aim of this retrospective multicenter study was to evaluate the differences in the timing for starting systemic therapies as the first-line treatment for hepatocellular carcinoma (HCC). Methods : A total of 375 patients with HCC treated with sorafenib from May 2009 to March 2018 and 56 patients treated with lenvatinib from March 2018 to November 2018 at our affiliated hospitals were included in this study. Results : The median ages of the sorafenib and lenvatinib groups were 71.0 (interquartile range [IQR] : 64.0-77.0) and 73.5 (IQR : 68.0 -80.0) years old, and 300 (80.0%) and 42 (75.0%) patients were men, respectively. The Barcelona Clinic Liver Cancer stage was early, intermediate and advanced in 39 patients (10.4%), 133 patients (35.5%) and 203 patients (54.1%) in the sorafenib group and 1 patient (1.8%), 17 patients (30.4%) and 38 patients (67.9%)in the lenvatinib group, respectively. In the analysis of intermediate HCC, patients who satisfied the criteria of TACE failure/refractoriness(P=0.017), those with ALBI grade 1 (P=0.040), and those with a serum AFP level <200 ng/ml (P=0.027)were found more frequently in the lenvatinib group than in the sorafenib group, with statistical significance. The objective response rate (ORR) of lenvatinib was 34.8% in the overall patients and 46.7%in the intermediate-stage HCC patients, which was significantly higher than sorafenib (P=0.001, P=0.017). Conclusions : The emergence of lenvatinib has encouraged physicians to start systemic chemotherapy earlier in intermediate-stage HCC patients.
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Objective The aim of this study was to assess the clinical impact of hand–foot syndrome (HFS) during treatment with two multikinase inhibitors, sorafenib and lenvatinib, in a large group of patients with advanced thyroid cancer. Moreover, we looked for possible associations between HFS occurrence and clinical and pathological features. Methods We retrospectively evaluated 239 patients with advanced thyroid cancer: 165 treated with lenvatinib and 74 with sorafenib. Statistical analyses were performed to verify which features could be correlated with HFS development. Results HFS was observed in 35/74 (47.4%) and in 43/165 (26.7%) patients treated with sorafenib or lenvatinib, respectively. The median latency from the drug beginning and HFS appearance was 27 days for sorafenib and 2.9 months for lenvatinib. G3/G4 toxicity was observed in 16/35 (45.7%) patients treated with sorafenib and only in 3/43 (7%) treated with lenvatinib. Drug dose reduction due to HFS was required in 19/74 (25.7%) and 3/165 (1.8%) patients treated with sorafenib and lenvatinib, respectively. HFS occurrence was significantly associated with a longer duration of therapy in both groups. Conclusion HFS was a frequent adverse event during both lenvatinib and sorafenib therapy, with a higher frequency and toxicity grade during sorafenib treatment. HFS was the most frequent reason for drug reduction or discontinuation in patient treated with sorafenib. Early diagnosis of HFS is important to allow early intervention, possibly in a multidisciplinary setting, and to avoid treatment discontinuation, which is highly relevant to obtain the maximum effectiveness of systemic therapy.
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