Lenvatinib Research Articles

Atezolizumab/bevacizumab and lenvatinib for hepatocellular carcinoma: A comparative analysis in a European real-world cohort.

Immunotherapy-based combinations are currently the standard of care in the systemic treatment of patients with HCC. Recent studies have reported unexpectedly long survival with lenvatinib (LEN), supporting its use in first-line treatment for HCC. This study aims to compare the real-world effectiveness of LEN to atezolizumab/bevacizumab (AZ/BV). A retrospective analysis was conducted to evaluate the effectiveness and safety of frontline AZ/BV or LEN therapy in patients with advanced HCC across 18 university hospitals in Europe. The study included 412 patients (AZ/BV: n=207; LEN: n=205). Baseline characteristics were comparable between the 2 treatment groups. However, patients treated with AZ/BV had a significantly longer median progression-free survival compared to those receiving LEN. The risk of hepatic decompensation was significantly higher in patients with impaired baseline liver function (albumin-bilirubin [ALBI] grade 2) treated with AZ/BV compared to those with preserved liver function. Patients with alcohol-associated liver disease had poorer baseline liver function compared to other etiologies and exhibited a worse outcome under AZ/BV. In this real-world cohort, survival rates were similar between patients treated with LEN and those treated with AZ/BV, confirming that both are viable first-line options for HCC. The increased risk of hepatic decompensation in patients treated with AZ/BV who have impaired baseline liver function underscores the need for careful monitoring. Future trials should aim to distinguish more clearly between metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease.

Poor Tolerability of Lenvatinib in Elderly Patients with Advanced Hepatocellular Carcinoma after Disease Progression following First-Line Atezolizumab Plus Bevacizumab: A Multicenter Study

Introduction: We investigated the effectiveness of lenvatinib (LEN) after disease progression following first-line treatment with atezolizumab plus bevacizumab (Atez/Bev) in patients with unresectable hepatocellular carcinoma (HCC). Methods: One hundred and ten HCC patients treated with Atez/Bev as first-line systemic chemotherapy were enrolled and underwent dynamic computerized tomography/magnetic resonance imaging to determine the treatment response. We evaluated the treatment efficacy and prognosis after second-line LEN treatment, especially in elderly patients. Results: Of the 110 study patients, 88 patients (80%) were determined to have progressive disease (PD) during the observation periods, and 40 patients received second-line LEN therapy. The 40 patients included 13 patients who were unable to continue LEN until the initial evaluation due to adverse events (AE). The 27 patients who were able to continue LEN therapy (Group A) were significantly younger at initiation of Atez/Bev than those who could not continue (71 vs. 77 years old, p = 0.013). Comparing the OS and PFS between Group A and 44 patients that included 13 patients who were unable to continue LEN and 31 patients did not receive the second-line treatment (Group B), the former had significantly better OS than Group B (31.1 vs. 17.8 months, p = 0.035). Conclusions: The tolerability of second-line LEN therapy was lower in elderly patients, and the OS from the start of Atez/Bev therapy was different depending on the tolerability of second-line LEN therapy.

Higher Risk of Proteinuria with Atezolizumab plus Bevacizumab than Lenvatinib in First-Line Systemic Treatment for Hepatocellular Carcinoma

Introduction: Proteinuria presents a challenging complication during systemic therapy for hepatocellular carcinoma (HCC). This study aims to identify risk factors for proteinuria in patients with HCC treated with atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic treatment. Methods: A retrospective analysis was conducted on 622 consecutive patients with unresectable HCC who received Atezo/Bev or LEN as first-line systemic treatment between October 2013 and October 2022. Cumulative incidence of proteinuria was estimated using Kaplan-Meier curves and compared using log-rank tests. Risk factors for proteinuria were identified using Cox proportional-hazard models, along with propensity score-matched and subgroup analyses. Results: Among 367 patients treated with Atezo/Bev and 255 with LEN, the cumulative incidence of proteinuria at 12 months was 27.5%. In the multivariable analysis, Atezo/Bev treatment (adjusted HR [aHR]: 1.57; 95% CI: 1.03–2.42), diabetes (aHR: 1.64; 95% CI: 1.03–2.61), hypertension (aHR: 2.27; 95% CI: 1.04–4.97), Child-Pugh class B (aHR: 3.43; 95% CI: 1.34–8.78), macrovascular invasion (MVI; aHR: 1.58; 95% CI: 1.04–2.38), and an estimated glomerular filtration rate ≤60 mL/min/1.73 m2 (aHR: 3.21; 95% CI: 1.84–5.62) were identified as risk factors for proteinuria. A higher risk of proteinuria in Atezo/Bev patients compared with LEN was consistently observed in the PS-matched cohort, particularly pronounced in subgroups with MVI (HR: 2.84; 95% CI: 1.23–6.54) compared with those without MVI (HR: 1.31; 95% CI: 0.69–2.47). Conclusions: Patients treated with Atezo/Bev as first-line systemic treatment for HCC exhibited a higher risk of proteinuria compared with those with LEN, particularly when accompanied by MVI.

Prognostic Significance of Psoas Muscle Index in Unresectable Hepatocellular Carcinoma: Comparative Analysis of Lenvatinib and Atezolizumab Plus Bevacizumab.

Background and Aims: Skeletal muscle loss has been identified as a prognostic factor in patients with unresectable hepatocellular carcinoma (uHCC) undergoing treatment with lenvatinib (LEN). While atezolizumab plus bevacizumab (ATZ-BEV) is recommended as first-line therapy for uHCC, the impact of skeletal muscle loss in these patients remains unclear. Methods: We enrolled 97 patients treated with either LEN or ATZ-BEV as their first-line therapy and divided them into two groups based on the presence or absence of a low psoas muscle index (low PMI) before treatment. We compared patient characteristics and overall survival (OS) between the groups. Additionally, we investigated the transition of the PMI during drug therapy, specifically before treatment, at the initial evaluation, and after the end of treatment. Results: Seventy percent of patients in the LEN group and seventy-one percent in the ATZ-BEV group had a low PMI. Multivariate analysis across all patients revealed a low PMI (hazard ratio [HR] 3.25, p = 0.0004) as a prognostic factor for OS. The PMI decreased more in the LEN group compared to the ATZ-BEV group. In the Barcelona Clinic Liver Cancer-C group, the OS of ATZ-BEV therapy was significantly better than that of LEN therapy when a low PMI was present (p = 0.046). Conclusions: A low PMI emerges as a significant prognostic factor in uHCC patients undergoing drug therapy, not only in LEN therapy but also in ATZ-BEV therapy. Additionally, ATZ-BEV therapy may be more favorable for sarcopenic patients with advanced HCC stages.

Is atezolizumab plus bevacizumab as first-line therapy for unresectable hepatocellular carcinoma superior to lenvatinib? a systematic review and meta‑analysis.

This meta-analysis was dedicated to evaluating the effectiveness and safety of Atezolizumab plus Bevacizumab (Atez/Bev) and Lenvatinib (LEN) as first-line systematic therapy for unresectable hepatocellular carcinoma (u-HCC). The prospective protocol for this study was registered with the PROSPERO (Registration number: CRD42022356874). Literature searches were conducted in PubMed, EMBASE database Cochrane Library, and Web Science to determine all clinical controlled studies that reported Atez/Bev and LEN for treating u-HCC. We. evaluated as primary end-point overall survival (OS) and progression-free survival (PFS), as well as other outcomes such as tumor response and adverse events (AEs).Quality assessment and data extraction of studies were conducted independently by three reviewers. Mean difference (MD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a fixed-effects or random-effects model. The meta-analysis was performed with RevMan 5.3 software. 12 retrospective cohort studies (RCSs) involving a total of 4948 patients were finally included. The results showed that compared with LEN, Atez/Bev can improve the patient's PFS (HR = 0.80, 95% CI: 0.72 ~ 0.88; p < 0.0001) and reduce the rate of overall AEs (OR = 0.46 95% CI: 0.38 ~ 0.55, p < 0.00001) and grade ≥ 3 AEs (OR = 0.43; 95% CI: 0.36 ~ 0.51, p < 0.00001), while there is no difference between OS and treatment responses rate (objective response rate, disease control rate, complete response, partial response, progressive disease, and stable disease) between two groups. In addition, the subgroup analysis shows that Atez/Bev can promote the OS of patients with viral hepatitis. (HR = 0.79, 95% CI: 0.67 ~ 0.95; p = 0.01), while LEN has an advantage in improving OS in patients with Child-Pugh grade B liver function (HR = 1.98, 95% CI: 1.50 ~ 2.63; p < 0.00001). Current evidence shows that compared with LEN, Atez/Bev has more advantages in PFS and safety in treating u-HCC and can improve the OS of patients with viral. LEN has advantages in improving the OS of patients with grade B liver function. However, more multicenter randomized controlled experiments are needed in the future to verify our results.

Identifying risk factors of dose reduction or treatment discontinuation due to fatigue or gastrointestinal symptoms in patients receiving lenvatinib treatment for hepatocellular carcinoma

Introduction Lenvatinib (LEN) is the standard treatment for hepatocellular carcinoma (HCC). In clinical practice, gastrointestinal (GI) symptoms such as fatigue and loss of appetite often lead to dose reduction or treatment discontinuation. This study aimed to identify the predictors of patients who will experience dose reduction or treatment discontinuation owing to fatigue or GI symptoms during LEN treatment for HCC. Methods We retrospectively identified 99 patients who received LEN at the Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and December 2023. To investigate the risk factors for treatment discontinuation or dose reduction due to fatigue or GI symptoms during LEN administration, patients were divided into two groups based on whether treatment discontinuation or dose reduction occurred due to fatigue or GI symptoms during LEN administration (37 patients) or not (62 patients). We compared baseline characteristics between the two groups. Results Multivariate analysis revealed that body weight (odds ratio 4.310, 95% confidence interval 1.380–13.500; P = 0.002) was an independent risk factor that significantly contributed to treatment discontinuation or dose reduction owing to fatigue or GI symptoms during LEN administration. The cut-off value calculated using the body weight curve was 55.0 kg. Using this cutoff value, the sensitivity and specificity of body weight to detect treatment discontinuation or dose reduction due to fatigue or GI symptoms during LEN administration were 83.9% and 56.8%, respectively. Conclusion In clinical practice, patients weighing less than 55 kg who start with a full dose will likely experience weight loss or discontinuation during treatment.

Dual effects of targeting neuropilin-1 in lenvatinib-resistant hepatocellular carcinoma: inhibition of tumor growth and angiogenesis.

In the era of immunotherapy, lenvatinib (LEN) still holds an important position in the sequential treatment of advanced hepatocellular carcinoma (HCC). However, the sustained therapeutic effect of LEN is not sufficient, and there is a need to address the development of resistance. Neuropilin-1 (NRP1) is known to act as a coreceptor for epidermal growth factor receptor (EGFR), Met, and vascular endothelial growth factor receptor 2 (VEGFR2), which have been reported to be involved in LEN resistance. In this study, we used cell culture and in vivo xenograft models to evaluate the contribution of NRP1 in the acquisition of LEN resistance in HCC as well as the potential of NRP1 as a therapeutic target. LEN resistance increased EGF/EGFR and hepatocyte growth factor (HGF)/Met signaling in liver cancer cells and VEGFA/VEGFR2 and HGF/Met signaling in vascular endothelial cells, thereby promoting cell proliferation, cell migration, and angiogenesis. We found that activation of NRP1 is essential for the enhancement of these signaling. In addition, NRP1 inhibition combined with LEN therapy synergistically improved the antitumor effects against LEN-resistant HCC, indicating that NRP1 is an attractive therapeutic target.NEW & NOTEWORTHY We demonstrated that neuropilin-1 (NRP1) was an essential coreceptor mediating the activation of multiple signaling pathways in the acquisition of resistance to lenvatinib (LEN) in HCC. The addition of NRP1 inhibition to LEN had a synergistic antitumor effect on LEN-resistant HCC in culture and in vivo xenograft models.

Frontline evaluation: Atezolizumab-bevacizumab versus lenvatinib for BCLC stage B hepatocellular carcinoma exceeding the up-to-seven criteria.

This study aimed to evaluate the efficacy and safety of atezolizumab combined with bevacizumab (Atez/Bev) compared to lenvatinib (LEN) as first-line systemic therapy for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) exceeding the up-to-seven criteria threshold, who are typically unsuitable for transarterial chemoembolization (TACE). A retrospective analysis was conducted on 49 consecutive patients with HCC treated at Tokyo Metropolitan Komagome Hospital between May 2018 and October 2023. The patients were divided into two groups: the Atez/Bev group (21 patients) and the LEN group (28 patients). Eligibility criteria included Child-Pugh A classification, no prior systemic therapy, and ineligibility for resection, ablation, or transplantation. Treatment outcomes were assessed through periodic imaging and laboratory tests, evaluating OS, PFS, ORR, and disease control rate (DCR). Both groups demonstrated comparable baseline characteristics, with a median follow-up of 15.4 months. No significant difference was observed in OS between the Atez/Bev and LEN groups (median OS: 19.80 vs. 22.20 months, p = 0.763). The median PFS was 10.23 months for Atez/Bev and 7.20 months for LEN (p = 0.343). There were no statistically significant differences in ORR or DCR between the two groups. Common adverse events included elevated AST and ALT levels, with no significant difference in the overall rate of adverse events between the groups. Atez/Bev and LEN demonstrated comparable efficacy and safety as first-line systemic treatments for patients with BCLC stage B HCC exceeding the up-to-seven criteria. Both therapeutic options are viable for this population, though further large-scale prospective studies are required to confirm these findings.

Comparison of Local Recurrence Between LEN-TACE and TACE for Hepatocellular Carcinoma According to Lipiodol Accumulation.

Transarterial chemoembolization (TACE) is the standard treatment for patients with hepatocellular carcinoma in the intermediate stage; however, with advances in systemic therapy, the indications for TACE have gained significance. While lenvatinib (LEN)-TACE offers the potential for good outcomes, local recurrence has not yet been adequately investigated. Therefore, this study investigated local recurrence factors for each type of TACE, focusing on the lipiodol (Lip) value in LEN-TACE and conventional TACE. Fifty patients (50 nodes) with hepatocellular carcinoma and a tumor size <7 cm who underwent LEN-TACE or TACE between January 2022 and June 2023 were included in this study to investigate local recurrence and its influencing factors. The local recurrence rate after LEN-TACE was 5.6% at 6 months and 11.5% at 12 months, whereas those after TACE were 6.4% at 6 months and 13.2% at 12 months (p=0.028). There were no significant differences in local recurrence rates according to background liver factors, alpha-fetoprotein (AFP), des-γ-carboxy prothrombin (DCP) values, sex, age, and albumin-bilirubin (ALBI) score. Lipiodol (Lip) values immediately after LEN-TACE were significantly higher than those after TACE alone (p=0.021). Multivariate analysis showed that LEN-TACE had a recurrence hazard ratio of 0.184. LEN-TACE provided good local tumor control. Local recurrence factors included LEN pretreatment, and Lip CT values were higher immediately after LEN-TACE. Thus, LEN-TACE after upfront LEN administration may increase the effectiveness of TACE.

738P Global, phase Ib dose-expansion cohort of E7386 + lenvatinib (LEN) in patients (pts) with advanced (a) endometrial cancer (EC) that progressed on platinum-based chemotherapy (CTx) and an anti-PD-(L)1 immunotherapy (IO)

738P Global, phase Ib dose-expansion cohort of E7386 + lenvatinib (LEN) in patients (pts) with advanced (a) endometrial cancer (EC) that progressed on platinum-based chemotherapy (CTx) and an anti-PD-(L)1 immunotherapy (IO)

965MO Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) treatment for unresectable hepatocellular carcinoma (uHCC): Expanded analyses from CheckMate 9DW

965MO Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) treatment for unresectable hepatocellular carcinoma (uHCC): Expanded analyses from CheckMate 9DW

Impact of BMI and Body Composition on First-line Systemic Treatment for Unresectable Hepatocellular Carcinoma.

The effects of body mass index (BMI) and body composition on the outcomes of systemic treatment for unresectable hepatocellular carcinoma (uHCC) remain unclear. In this retrospective study, patients with uHCC treated with lenvatinib (LEN) or atezolizumab+bevacizumab, were classified into high- (≥25 kg/m2) and low- (<25 kg/m2) BMI groups and evaluated for prognosis. Prognostic impact of body composition was also evaluated. Patients with a high BMI had lower skeletal mass index (SMI), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) compared to those in the low-BMI cohort. The baseline Child-Pugh scores and Barcelona Clinic Liver Cancer stages were comparable between the two cohorts. The overall survival (OS) was better in the high BMI group compared to the low BMI group (median, 913 vs. 484 days; p=0.008). SMI had a strong influence on OS. Additionally, low BMI, VATI, SATI, and visceral-to-subcutaneous fat ratio (VSR) in the LEN treatment group were associated with shorter progression-free survival (PFS). Following systemic treatment for uHCC, patients with low BMI have a poor prognosis. Among anthropometric factors, low SMI is associated with poor OS. In the LEN treatment group, low VATI may impact PFS negatively.

Cryoablation versus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma with lenvatinib from a real-world study.

54 Background: Hepatocellular carcinoma (HCC) is characterized by hypovascularity, the efficacy of transcatheter arterial chemoembolization (TACE) has been suboptimal. This study sought to evaluate and compare the efficacy and safety profiles of cryoablation (CRYO) plus lenvatinib (LEN) against TACE plus LEN for unresectable hepatocellular carcinoma (u-HCC) patients within a real-world clinical practice. Methods: A prospective study was conducted involving 234 patients with u-HCC who underwent treatment with LEN plus either CRYO or TACE at the Fifth Medical Center of the Chinese PLA General Hospital from October 2018 to May 2023. Treatment selection was determined through multidisciplinary discussions among a liver cancer board, weighing the pros and cons. The final decision was made by the patients and clinicians based on consensus. Clinical characteristics were balanced using propensity score matching (PSM). The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Tumor response was based on RECIST v1.1 and mRECIST by blinded independent imaging review, AEs by CTCAE v5.0. Results: In this study, 212 (90.6%) were male, with an average age of 56 years. 206 (88%) patients were infected with hepatitis B virus (HBV), and 178 (76.1%) and 77 (32.9%) patients were classified as Child-Pugh A and BCLC B. After PSM, the clinical characteristics were comparable between the CRYO plus LEN and the TACE plus LEN group. Over a median follow-up of 31.8 months, 124 patients (53%) died. The CRYO plus LEN group demonstrated similar OS (24.2 vs. 22.0 months, P = 0.64), PFS (8.7 vs. 11.9 months, P = 0.48), ORR (53.1% vs. 53.1%, P = 1.00), and DCR (86.5% vs. 78.1%, P = 0.19) compared to the TACE plus LEN group after PSM, with consistent results observed before PSM. The two groups exhibited comparable AEs. In addition to similar LEN-related AEs, the most common CRYO-related AEs included 50% elevated ALT, 50% elevated AST, and 38.5% fever, which were consistent with the TACE related AEs. Notably, the incidence of abdominal pain was higher in the TACE plus LEN group compared to the CRYO plus LEN group (7.5% vs. 0.8%, P = 0.021), while pleural effusion was more prevalent in the CRYO plus LEN group than that in the TACE plus LEN group (6.2% vs. 0, P = 0.038). Conclusions: The CRYO plus LEN group exhibited comparable efficacy and well-tolerated safety with TACE plus LEN for u-HCC patients within a real-world clinical setting. It offers a viable alternative for HCC characterized by hypovascularity, presenting a promising therapeutic approach in the clinical management of u-HCC. Clinical trial information: ChiCTR2200058643 .

Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice.

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β-hydroxycortisol, deoxycholic acid, and 1β-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.

Changes in Mutations of Cell-Free DNA and Liver Tumor Tissue in Patients with Advanced Hepatocellular Carcinoma before and after Introduction of Lenvatinib.

Cell-free DNA (cfDNA) is expected to contribute to the decision for treatment and prediction of effects with minimally invasion. We investigated the correlation between gene mutations before and after lenvatinib (LEN) treatment and its effectiveness, in order to find advanced hepatocellular carcinoma (HCC) patients who would benefit greatly from the therapy. We analyzed cfDNA before and 6-8 weeks after the start of treatment in 20 advanced HCC patients who started LEN. A next-generation sequencer was used for CTNNB1 and TP53. Concerning TERT promoter, -124C&gt;T and -146C&gt;T mutations are researched using digital PCR. In addition, we examined liver tumor biopsy tissues by the same method. Computerized tomography evaluation was performed at 6-8 weeks and 3-4 months to assess the efficacy. Frequencies of TERT promoter, CTNNB1, and TP53 mutations in pretreatment cfDNA were 45%, 65%, and 65%, but 53%, 41%, and 47% in HCC tissues, respectively. There were no clear correlations between these gene mutations and the disease-suppressing effect or progression-free survival. Overall, there were many cases showing a decrease in mutations after LEN treatment. Integrating the reduction of CTNNB1 and TP53 genetic mutations increased the potential for disease suppression. This study suggests that analysis of cfDNA in advanced HCC patients may be useful for identifying LEN responders and determining therapeutic efficacy. Furthermore, it has potential for selecting responders for other molecular-targeted drugs.

Outcomes of hepatocellular carcinoma patients treated in the lenvatinib and immunotherapy era (2018-2021) compared to the sorafenib era (2008-2018).

Lenvatinib (LEN) and atezolizumab + bevacizumab (A + B) have drastically changed the treatment paradigm for advanced hepatocellular carcinoma (HCC). Before these landmark trials, sorafenib (SOR) served as the standard first-line treatment for a decade. Our study aimed to assess the outcomes of HCC patients treated during the SOR era (2008-2018) in contrast to those in the post-SOR era (2018-2021), of which the predominant first-line treatments were LEN or A + B. Inclusion criteria of the study were all HCC patients in the Canadian province of Alberta who started first-line systemic therapy at cancer centers between 1 January 2008 and 31 December 2021. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), along with clinician-assessed response rate (RR), were subject to retrospective analysis. Of 372 total patients, 230 received treatment in the SOR era and 142 in the post-SOR era. The demographic and clinical characteristics for the SOR era and post-SOR era groups are as follows, respectively: the median age was 63 and 64 years, 80% and 81% were male, and 24% and 11% were of East Asian ethnicity. Before receiving systemic treatment, 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT in the two eras, respectively. In the post-SOR era, patients received A + B (23%), LEN (51%), and SOR (23%) as first-line treatment. There was a statistically significant improvement in RR (15% vs. 26%; p = 0.02), median PFS (3.8 months vs. 7.9 months; p < 0.0001), and median OS (9.8 months vs. 17.0 months; p < 0.0001). In this retrospective multicenter real-world study, HCC patients treated in the post-SOR era, where LEN and A + B were commonly used first-line treatments, exhibited superior OS, PFS, and RR compared to patients treated in the SOR era. The findings of this study affirm the tangible progress achieved in the real world in enhancing outcomes for HCC patients through advancements in treatments over the past 15 years.

Hepatic Arterial Infusion Chemotherapy Combined with Lenvatinib and PD-1 Inhibitors for Managing Arterioportal Shunt in Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Retrospective Cohort Study.

This study aimed to assess the effectiveness and safety of combining hepatic arterial infusion chemotherapy (HAIC) with lenvatinib (LEN) and PD-1 inhibitors in treating arterioportal shunt (APS) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). Conducted retrospectively, the study enrolled 54 HCC patients with APS and PVTT treated with HAIC, LEN, and PD-1 inhibitors at our center between January 2021 and October 2023. APS improvement, APS recanalization, tumor response, PVTT response rate, overall survival (OS), intrahepatic progression-free survival (InPFS), and adverse events were evaluated. APS improvement was observed in 42 patients (77.8%), with all improvement occurring within two treatment sessions. Complete APS occlusion was achieved in 40 patients (74.1%), and no recanalization occurred. The best objective response rate (ORR) and ORR after two HAIC sessions were 74.1% and 66.7%, respectively. The best PVTT response and PVTT response after two HAIC sessions were 98.1% and 94.4%, respectively. The median OS and InPFS were 10.0 months and 5.0 months, respectively. OS and InPFS were longer in patients with APS occlusion compared to those without (OS 12.1 vs 4.4 months, P<0.001, InPFS 6.2 vs 2.3 months, P=0.049). ALBI grade, extrahepatic spread, APS disappearance were potential prognostic factors for OS, while APS grade and extrahepatic spread being independently associated with InPFS. No treatment-related mortality occurred. Combining HAIC with LEN and PD-1 inhibitors proves to be both effective and safe in managing APS in HCC with PVTT, potentially improving patient survival.

Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW.

LBA4008 Background: First-line therapies based on programmed death ligand 1 (PD-L1) inhibitors are standard of care (SOC) in uHCC and demonstrate improved outcomes over SOR; however, prognosis remains poor and there is an unmet need for alternative therapies with long-term benefits. Second-line NIVO + IPI demonstrated clinically meaningful efficacy and manageable safety in SOR-treated patients (pts) with HCC in CheckMate 040, leading to its accelerated approval in the United States. We report first results from the preplanned interim analysis of the phase 3, open-label, randomized CheckMate 9DW trial evaluating the efficacy and safety of NIVO + IPI vs LEN or SOR as first-line therapy for pts with uHCC (NCT04039607). Methods: Adult pts with previously untreated HCC not eligible for curative surgical or locoregional therapies, Child-Pugh score 5–6, and ECOG performance status 0–1 were included. Pts were randomly assigned 1:1 to receive NIVO 1 mg/kg + IPI 3 mg/kg Q3W (up to 4 cycles) followed by NIVO 480 mg Q4W or investigator’s choice of LEN 8 mg or 12 mg QD or SOR 400 mg BID until disease progression or unacceptable toxicity. NIVO was given for a maximum of 2 years. The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR) and duration of response (DOR) per blinded independent central review (BICR) using RECIST v1.1. Results: In total, 668 pts were randomized to NIVO + IPI (n = 335) or LEN/SOR (n = 333); among 325 pts treated in the LEN/SOR arm, 275 (85%) received LEN. After a median (range) follow-up of 35.2 (26.8–48.9) months (mo), median OS was 23.7 mo with NIVO + IPI vs 20.6 mo with LEN/SOR (HR, 0.79; 95% CI, 0.65–0.96; P = 0.0180) (Table), with respective 24-mo OS rates (95% CI) of 49% (44–55) vs 39% (34–45). ORR was higher with NIVO + IPI (36%) vs LEN/SOR (13%; P &lt; 0.0001); complete response was observed in 7% of pts with NIVO + IPI vs 2% with LEN/SOR. Median DOR was 30.4 mo with NIVO + IPI vs 12.9 mo with LEN/SOR (Table). A summary of treatment-related adverse events (TRAEs) is shown in the Table. Conclusions: NIVO + IPI demonstrated statistically significant OS benefit vs LEN/SOR in pts with previously untreated uHCC, as well as higher ORR and durable responses with a manageable safety profile. These results support this combination as a potential new first-line SOC for uHCC. Clinical trial information: NCT04039607 . [Table: see text]

Dose-expansion part of a phase 1b global study of E7386 in combination with lenvatinib (LEN) in patients (pts) with hepatocellular carcinoma (HCC) and other solid tumors including endometrial cancer (EC).

TPS3169 Background: E7386, a first-in-class anticancer agent, inhibits protein-protein interaction between β-catenin and the CREB-binding protein, thus modulating Wnt/β-catenin signaling. E7386 is being tested in combination with LEN in the open-label global phase 1b Study 102. The dose-escalation part of Study 102 determined the recommended dose of E7386 + LEN in pts with HCC and other solid tumors. Here we describe the ongoing dose-expansion part in pts with HCC or EC. Methods: Eligible pts ≥18 years old should have an ECOG PS of 0-1 and a confirmed diagnosis of advanced, unresectable, or recurrent solid tumor. Pts with HCC will have a Child-Pugh score of A and a categorization of BCLC Stage B (not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment) or Stage C. Pts with HCC should also have received 1 prior immuno-oncology (IO)-based regimen and have progressed on/after prior treatment with IO therapy. If ineligible for IO therapy, pts should not have received prior systemic therapy; pts who previously received LEN are ineligible. In the EC subpart, pts should have disease progression after receiving prior platinum-based chemotherapy (PBT) and an IO-based therapy for EC. Pts may have received 1 additional line of PBT if given in the neoadjuvant/adjuvant setting, but not exceeding 3 lines of therapies. Pts with EC who are ineligible for IO therapy may have received only 1 prior systemic therapy including PBT. Pts who have received prior LEN therapy will be eligible if they meet protocol-specified criteria. Pts with HCC (n≈60) will be randomized in a 2:1 ratio into 1 of 2 treatment arms and will receive either the combination E7386 + LEN or LEN monotherapy in 28-day cycles. E7386 will be administered at 100 mg BID in the combination arm and LEN will be administered QD at 8 mg (if body weight &lt;60 kg) or 12 mg (if body weight ≥60 kg) in both arms. Pts with HCC will be stratified by geographical region (Western Europe and North America vs Japan vs other countries). Pts with EC (n≈30) will receive only the combination E7386 120 mg BID + LEN 14 mg QD. The expansion part of Study 102 aims to assess safety and tolerability (primary endpoints), and pharmacokinetics and preliminary efficacy (secondary endpoints), of E7386 in combination with LEN for pts with HCC and EC. Efficacy of LEN monotherapy will be assessed for HCC (secondary endpoint). Tumors will be assessed by investigator per RECIST v1.1 every 8 weeks from the date of the first dose. Adverse events will be monitored and recorded for up to 30 days after the last dose or until initiation of a new anticancer therapy, whichever occurs first. Study sites will include the United States, France, Republic of Korea, Japan, and Taiwan. As of February 5, 2024, 46 pts with HCC and 16 pts with EC have enrolled. Clinical trial information: NCT04008797 .

Envafolimab combined with lenvatinib and gemcitabine plus cisplatin in advanced biliary tract cancer as first-line treatment: A single-arm, open-label, phase II study (ENLIGHTEN study).

e16188 Background: The prognosis of advanced biliary tract cancer (BTC) remains unsatisfactory despite first-line treatment with PD-1/PD-L1 inhibitors in combination with gemcitabine and cisplatin. Lenvatinib (LEN), an anti-angiogenic multi-kinase inhibitor, has recently demonstrated promising antitumor activity in various tumors. This study aimed to determine the efficacy and safety of envafolimab (PD-L1 inhibitor) and LEN in combination with gemcitabine and cisplatin as first-line treatment in advanced BTCs. Methods: This prospective, open-label, single-arm, Simon’s two-stage, phase II study in patients with advanced BTC is ongoing at two centers. All patients received subcutaneous envafolimab (400mg, Q3W) and LEN (8 mg/day, orally once daily) combined with gemcitabine (1000mg/m2, IV, days 1, 8, Q3W) plus cisplatin (25mg/m2, IV, days 1, 8, Q3W) up for 6-8 cycles, followed by maintenance envafolimab and LEN until disease progression (PD) or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). A Simon’s two-stage phase II optimal design was used with following statistical assumptions: If 4 or more patients had partial response (PR) in 10 patients in stage 1, the cohort would expand to a total of 39 patients, and the outcomes would be positive if 15 or more patients achieved PR. The secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and safety. Results: Between October 2022 and October 2023, 20 patients were enrolled, and included for efficacy and safety analysis. All patients received at least two doses of study medication. Of the first 10 patients enrolled, confirmed responses were noted in 4 patients, and the trial continued to accrual. The ORR and DCR were 45% and 80%, respectively. Nine patients (9/20, 45%) exhibited PR, seven patients (7/20, 35%) showed stable disease (SD), and four patients (4/20, 20%) experienced PD. The most common grade 3/4 treatment-related adverse events (TRAEs) were GGT increased (n = 3, 15%) and platelet decreased (n = 2, 10%). No unacceptable toxicity or treatment-related deaths occurred. Conclusions: Envafolimab and LEN in combination with gemcitabine and cisplatin seems to be an effective and tolerable treatment option in advanced BTC. Survival data is immature and will be updated in the future. Clinical trial information: NCT05410197 .