In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.
Methods
This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice–web response system—with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors—to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266.
Findings
Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1–14·9) was non-inferior to sorafenib (12·3 months, 10·4–13·9; hazard ratio 0·92, 95% CI 0·79–1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib.
Interpretation
Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed.
Funding
Eisai Inc.
Introduction
Hepatocellular carcinoma is the most common type of liver cancer, which is the third leading cause of cancer deaths worldwide, causing nearly 745 000 deaths each year.1 The disease usually occurs in people with chronic liver disease, particularly cirrhosis, which limits the feasibility of surgical resection.2, 3 Sorafenib, an oral multikinase inhibitor, is the only systemic therapy proven to extend overall survival when used as a first-line treatment, showing a median improvement of 2·8 months compared with placebo (10·7 months vs 7·9 months; hazard ratio [HR] 0·69; p<0·001), despite a low response rate of 2%.4 In patients from the Asia-Pacific region taking sorafenib, the median improvement in overall survival compared with placebo was 2·3 months (6·5 months vs 4·2 months; HR 0·68; p=0·014).5
Drug development for hepatocellular carcinoma in the past 10 years has been marked by four failed global phase 3 trials (of sunitinib, brivanib, linifanib, and erlotinib plus sorafenib) that did not show non-inferiority6, 7, 8 or superiority9 to sorafenib in terms of overall survival in first-line treatment of hepatocellular carcinoma. No approved first-line systemic treatments are available for advanced unresectable hepatocellular carcinoma other than sorafenib. Only regorafenib and nivolumab are approved as second-line systemic treatments for patients who do not respond to sorafenib.10 Otherwise, best supportive care or participation in clinical trials is recommended in the second-line setting by treatment guidelines.11 Therefore, because of the paucity of systemic treatment options for patients with advanced hepatocellular carcinoma, a need exists to develop new drugs for effective management of this disease.
Lenvatinib is an oral multikinase inhibitor that targets VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT.12, 13, 14, 15 Lenvatinib monotherapy is approved for treatment of radioiodine-refractory differentiated thyroid cancer.16 Lenvatinib and everolimus are approved as a combined treatment for advanced renal cell carcinoma following one previous antiangiogenic therapy.17 In a phase 2 study of patients with advanced hepatocellular carcinoma, 12 mg lenvatinib once-daily showed clinical activity and had an acceptable safety profile.18 Based on dose adjustments depending on bodyweight and pharmacokinetic modelling data,19 a starting dose of lenvatinib was adopted (12 mg for patients ≥60 kg and 8 mg for patients <60 kg once-daily) for further clinical development in hepatocellular carcinoma. Given the efficacy signal observed in this phase 2 study,18 we did a phase 3 randomised, open-label, non-inferiority study to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.
Research in context
Evidence before this study
We searched PubMed from inception up to March 16, 2017 using the search terms “phase 3” [Title/Abstract] OR “phase III” [Title/Abstract] AND “hepatocellular carcinoma” [MeSH Terms]. The search was restricted to clinical trials in English language only and yielded 65 reports. Of these publications, 21 described the use of targeted drugs for treatment of hepatocellular carcinoma, 11 were studies of single-drug sorafenib treatment, and three were studies of sorafenib in combination with another drug. Five trials investigated targeted agents following treatment with sorafenib and four trials investigated first-line treatment of hepatocellular carcinoma with sorafenib as the comparator. None of these four trials met their primary endpoints of non-inferiority or superiority over sorafenib in terms of overall survival.
Added value of this study
To our knowledge, this is the first global phase 3 trial in 10 years to meet its primary endpoint of non-inferiority in terms of overall survival against sorafenib as a first-line treatment for hepatocellular carcinoma. Furthermore, lenvatinib showed statistically significant and clinically meaningful improvement in terms of all secondary endpoints (progression-free survival, time to progression, and objective response rate) with a reasonable safety profile.
Implications of all the available evidence
The results of this study support lenvatinib as a first-line treatment option for patients with unresectable hepatocellular carcinoma.
Section snippets
Study design and participants
This multicentre, phase 3, randomised, open-label, non-inferiority study was done at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions (China, Hong Kong, Japan, South Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand, Belgium, Canada, France, Germany, Israel, Italy, Poland, Russia, Spain, UK, and USA).
Eligible patients had unresectable hepatocellular carcinoma, with diagnoses confirmed histologically or cytologically, or confirmed clinically in
Results
Between March 1, 2013, and July 30, 2015, 1492 patients were recruited. 954 eligible patients from 20 countries were randomly assigned to receive lenvatinib (n=478) or sorafenib (n=476, figure 1).
Patient baseline characteristics were similar between treatment groups, except for baseline hepatitis C aetiology and α-fetoprotein concentrations (table 1). At the time of data cutoff (Nov 13, 2016, at 701 deaths), the median duration of follow-up was 27·7 months (IQR 23·3–32·8) in the lenvatinib
Discussion
To our knowledge, our study is the first global phase 3 trial in 10 years to show a treatment effect on overall survival, and the first ever positive trial against an active control. Our study showed lenvatinib to be non-inferior to sorafenib—the current standard of care in hepatocellular carcinoma—for overall survival. Lenvatinib showed statistically significant clinically meaningful improvement for all secondary efficacy endpoints (progression-free survival, time to progression, and objective
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2024, Clinics and Research in Hepatology and Gastroenterology
The optimal management of unresectable hepatocellular carcinoma (uHCC) remains an unresolved challenge. There is ongoing debate regarding the efficacy and safety of drug-eluting bead TACE (DEB-TACE) with tyrosine kinase inhibitors (TKIs).
We searched PubMed, Embase, Web of Science and the Cochrane Library for eligible studies. The main endpoints under investigation were survival outcomes, including overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Secondary outcomes encompassed tumor response rates and adverse events (AEs). Two researchers conducted the data extraction independently and assessed the quality of the studies. After pooling and analyzing the data, we assessed the heterogeneity and performed both subgroup analysis and sensitivity analysis. Additionally, we evaluated the potential for publication bias.
Eight studies with 1513 patients were finally retrieved. Compared to monotherapy, although bigeminal therapy exhibited improved survival benefits (OS: HR: 0.56, 95 % CI 0.41–0.76, p < 0.001; TTP: HR: 0.72, 95 % CI 0.59–0.87, p = 0.001) and tumor response (ORR: RR: 1.59; 95 % CI 1.19–2.13, p = 0.002; DCR: RR: 1.14; 95 % CI 1.03–1.26, p = 0.010), the reliability of results was affected by significant heterogeneity. In the subgroup analysis, compared to DEB-TACE alone, the bigeminal therapy failed to show any statistical differences. Compared to TKIs, it demonstrated significant advantages in both survival (OS: HR: 0.49, 95 % CI 0.40–0.61, p < 0.001; TTP: HR: 0.60, 95 % CI 0.48–0.75, p < 0.001) and tumor response (ORR: RR: 2.40, 95 % CI 1.86–3.09, p < 0.001; DCR: RR: 1.36, 95 % CI 1.20–1.54, p < 0.001) while low heterogeneity was observed. Concerning safety, DEB-TACE provides no more severe AEs while TKIs-related AEs require close monitoring.
Our findings suggest that DEB-TACE combined with TKIs may be a safe and effective treatment for uHCC, which is more suitable for patients in the advanced stage.
Hepatocellular carcinoma (HCC) has a poor prognosis, and the efficacy of current therapeutic strategies is extremely limited in advanced diseases. Our previous study reported that protein tyrosine phosphatase receptor epsilon (PTPRE) is a promoting factor in HCC progression. In this study, our objective was to evaluate the treatment effect of PTPRE inhibitors in different HCC preclinical models. Our results indicated that the PTPRE inhibitory compound 63 (Cpd-63) inhibited tumor cell proliferation, migration, and HCC organoid growth. Mechanism research revealed that Cpd-63 could inhibit the expression of MYC and MYC targets by inhibiting the activation of SRC. Additionally, we found that Cpd-63 could improve the response of sorafenib in HCC cells. In conclusion, we demonstrated that the PTPRE inhibitors represented a potential therapeutic agent for HCC management.
The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up.
COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child–Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03755791.
Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22·1 months (IQR 19·3–24·8). Median overall survival was 16·5 months (96% CI 14·5–18·7) for the combination treatment group and 15·5 months (12·2–20·0) for the sorafenib group (hazard ratio [HR] 0·98 [0·78–1·24]; stratified log-rank p=0·87). Median progression-free survival was 6·9 months (99% CI 5·7–8·2) for the combination treatment group, 4·3 months (2·9–6·1) for the sorafenib group, and 5·8 months (99% CI 5·4–8·2) for the single-agent cabozantinib group (HR 0·74 [0·56–0·97] for combination treatment vs sorafenib; HR 0·78 [99% CI 0·56–1·09], p=0·05, for single-agent cabozantinib vs sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] vs 18 [9%] vs 16 [9%]), aspartate aminotransferase increased (42 [10%] vs eight [4%] vs 17 [9%]), and alanine aminotransferase increased (40 [9%] vs six [3%] vs 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation).
First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals.
Nivolumab was the first immune checkpoint inhibitor approved for hepatocellular carcinoma (HCC). External beam radiation therapy (EBRT) is locally effective and may enhance the effectiveness of immunotherapy. This study investigated the efficacy and safety of concurrent nivolumab and EBRT in HCC with macrovascular invasion.
In this phase II multicenter trial, patients with HCC and macrovascular invasion were concurrently treated with intravenous nivolumab (3 mg/kg every 2 weeks) and EBRT, followed by maintenance nivolumab until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) and safety, and secondary endpoints were overall survival, time-to-progression, objective response rate, and disease control rate.
Between January 2020 and June 2021, 50 patients (male 84%, median age 62.5) were enrolled; 47 (94.0%) and 13 (26.0%) with portal (Vp1/2, n = 21; Vp3, n = 23; Vp4, n = 3) and hepatic vein invasion, respectively. Patients received EBRT (median dose: 50 [IQR 43–50] Gy) after the first nivolumab dose. The median number of nivolumab doses was 8.5. Median PFS was 5.6 (90% CI 3.6–9.9) months. Median overall survival and time-to-progression were 15.2 (90% CI 10.8–19.6) and 5.6 (90% CI 3.6–9.9) months, respectively. The objective response rate and disease control rate were 36.0% and 74.0%, respectively. The median duration of response was 9.9 months. Of 35 patients with follow-up data, 23 received subsequent systemic treatment, including atezolizumab-bevacizumab, sorafenib, lenvatinib, and regorafenib. Treatment-related any grade adverse events (AEs) and grade 3/4 AEs occurred in 40 (80.0%) and 6 (12.0%) patients, respectively. Common treatment-related AEs included pruritus (38.0%) and rash (16.0%), with no treatment-related deaths.
Concurrent nivolumab therapy and EBRT showed encouraging PFS with acceptable safety in patients with advanced HCC and macrovascular invasion.
Immune checkpoint inhibitors, the standard care for advanced hepatocellular carcinoma (HCC), show relatively poor therapeutic effects in patients with advanced HCC and macrovascular invasion. In this investigator-initiated phase II study, we, for the first time, show that concurrent external beam radiation therapy with nivolumab, an immune checkpoint inhibitor, led to encouraging progression-free survival in patients with HCC and macrovascular invasion. The concurrent treatment was tolerable without significant safety concerns. Further randomized studies investigating the combination of immunotherapy and external beam radiation therapy are required.
The high mutation rate of CTNNB1 (37 %) and Wnt-β-catenin signal-associated genes (54 %) has been notified in hepatocellular carcinoma (HCC). The activation of Wnt-β-catenin signal pathway was reported to be associated with an immune “desert” phenotype, but the underlying mechanism remains unclear. Here we mainly employed orthotopic HCC models to explore on it. Mass cytometry depicted the immune contexture of orthotopic HCC syngeneic grafts, unveiling that the exogenous expression of β-catenin significantly increased the percentage of myeloid-derived suppressor cells (MDSCs) and decreased the percentage of CD8+ T-cells. Flow cytometry and immunohistochemistry further confirmed the findings. The protein microarray analysis, Western blot and PCR identified PF4 as its downstream regulating cytokine. Intratumorally injection of cytokine PF4 enhanced the accumulation of MDSCs. Knockout of PF4 abolished the effect of β-catenin on recruiting MDSCs. Chromatin immunoprecipitation and luciferase reporter assay demonstrated that β-catenin increases the mRNA level of PF4 via binding to PF4's promoter region. In vitro chemotaxis assay and in vivo administration of specific inhibitors identified CXCR3 on MDSCs as receptor for recruiting PF4. Lastly, the significant correlations across β-catenin, PF4 and MDSCs and CD8+ T-cells infiltration were verified in HCC clinical samples. Our results unveiled HCC tumor cell intrinsic hyperactivation of β-catenin can recruit MDSC through PF4-CXCR3, which contributes to the formation of immune “desert” phenotype. Our study provided new insights into the development of immunotherapeutic strategy of HCC with CTNNB1 mutation.
This study identifies PF4-CXCR3-MDSCs as a downstream mechanism underlying CTNNB1 mutation associated immune “desert” phenotype.