Treatment Of Unresectable Hepatocellular Carcinoma Research Articles

Potential feasibility of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma treated with tyrosine-kinase inhibitors.

The combination of atezolizumab-bevacizumab has been proven to be superior to sorafenib for the treatment of unresectable hepatocellular carcinoma not amenable to locoregional treatments, becoming the standard of care of systemic therapy. This study aimed at assessing real-world feasibility of atezolizumab-bevacizumab in patients treated with tyrosine-kinase inhibitors. Among 1447 patients treated with tyrosine-kinase inhibitors from January 2010 to December 2020, we assessed the percentage of those potentially eligible to atezolizumab-bevacizumab (according to IMbrave-150 trial criteria), and the overall survival of eligible and non-eligible patients. 422 (29%) patients were qualified for atezolizumab-bevacizumab therapy. The main exclusion causes were Child-Pugh class and Performance Status. Adopting the more permissive inclusion criteria of SHARP trial, 535 patients became eligible. The median overall survival of tyrosine-kinase inhibitors patients was 14.9 months, longer in eligible patients than in their counterpart due to better baseline liver function and oncological features. Real-world data indicate that less than one-third of hepatocellular carcinoma patients treated with tyrosine-kinase inhibitors are potentially eligible to atezolizumab-bevacizumab according to the registration trial criteria. These patients have a longer survival than the non-eligible ones. If the selection criteria of atezolizumab-bevacizumab trial are maintained in clinical practice, tyrosine-kinase inhibitors will remain the most used systemic therapy for hepatocellular carcinoma patients.

Atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma progressing after molecular targeted therapy: A multicenter prospective observational study.

To evaluate the efficacy of atezolizumab plus bevacizumab treatment in patients with hepatocellular carcinoma (HCC) previously treated with molecular targeted agents (MTAs).Thirty-one patients treated with atezolizumab plus bevacizumab for unresectable HCC and previously treated with MTAs were enrolled in this study.The treatment lines ranged from second to sixth lines. The treatment effect on HCC differed from that during first-line treatment. The treatment effect was determined using the Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST. The treatment response was different for each MTA immediately prior to atezolizumab + bevacizumab treatment. Tumors treated with lenvatinib followed by atezolizumab + bevacizumab showed rapid growth for a short period of time followed by shrinkage. However, patients who received ramucirumab, sorafenib, and regorafenib did not show such changes. This was likely because of differences in the mechanism of action of the MTA administered immediately beforehand. The side-effect profile differed from that observed in the IMbrave150 phase 3 study of atezolizumab plus bevacizumab, which showed more adverse events related to hepatic reserve.Patients treated with the combination of atezolizumab and bevacizumab after lenvatinib therapy may experience rapid tumor growth and subsequent shrinkage.

Lenvatinib Might Induce Activation of Host Immunity in Patients with Hepatocellular Carcinoma

Introduction: Atezolizumab, an immune checkpoint inhibitor, plus bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor (VEGF), is an approved first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). Immune checkpoint inhibitors are more effective in patients with HCC when administered with anti-VEGF drugs; however, these drugs affect host immunity. Lenvatinib is an anti-VEGF agent used to treat HCC; therefore, this study evaluated the effect of treatment of HCC with lenvatinib on host immunity in patients with chronic liver disease (CLD). Methods: We studied adult Japanese patients with CLD and unresectable HCC treated with lenvatinib at our hospital. Lenvatinib was administered for 4 weeks (8 mg/day for bodyweight <60 kg; 12 mg/day for bodyweight >60 kg). Blood samples were collected at baseline and at 4 weeks of treatment and examined for immune-related changes. Results: Forty-three patients were enrolled in this study. We found a significant increase in T helper (Th) 1 cells following 4 weeks of lenvatinib treatment, although there was no significant difference in Th2 cells and regulatory T cells. We also found a significant increase in serum levels of TNF-alpha, soluble TNF-alpha receptor I, and endothelial growth factor following 4 weeks of lenvatinib treatment. Furthermore, an increase in Th1 cells and serum levels of TNF-alpha was found in patients with partial response. Conclusion: Lenvatinib might induce Th1-dominant host immunity in patients with CLD and unresectable HCC treatment in patients who showed a partial response. These changes in host immunity may be a biomarker in HCC patients treated with lenvatinib.

Efficacy and safety of lenvatinib for preventing tumor recurrence after liver transplantation in hepatocellular carcinoma beyond the Milan criteria.

Lenvatinib is one of the first-line treatments for unresectable hepatocellular carcinoma (HCC). However, data are lacking on lenvatinib in the postoperative setting. This retrospective analysis enrolled 242 patients with HCC who underwent liver transplantation (LTx). Eligible patients were divided into 2 groups according to their use of adjuvant lenvatinib following LTx (lenvatinib, n=42; control, n=200). The primary outcome measures were overall survival (OS), time to recurrence (TTR), and safety. Kaplan-Meier analysis was applied to calculate the OS, while a competing risk model was used to estimate the cumulative incidence of recurrence. The lenvatinib group showed more advanced tumors and a higher proportion of HCC beyond the Milan criteria (P<0.001) than the control group. There were no significant differences in both the OS and TTR between the 2 groups. After focusing on the patients with HCC beyond the Milan criteria, baseline characteristics were similar in the lenvatinib group (n=38) and the control group (n=102). Competing risk analysis showed lenvatinib significantly prolonged TTR after LTx versus the control group [sub-hazard ratio (sHR), 0.40; 95% confidence interval (CI): 0.17 to 0.93; P=0.031]. In the multivariate competing risk model, adjuvant lenvatinib was an independent protective factor for tumor recurrence after LTx in patients with HCC beyond the Milan criteria (sHR, 0.33; 95% CI: 0.13 to 0.83; P=0.018). The rate of early recurrence within t2 years after LTx was also significantly decreased in the lenvatinib group (15.8% vs. 33.3%, P=0.041). However, the lenvatinib group exhibited comparable OS with the control group in patients with HCC beyond the Milan criteria. Treatment-related adverse events (TRAEs) and Grade ≥3 TRAEs occurred in 40 (95.2%) and 13 (31%) patients who received adjuvant lenvatinib, respectively. No treatment-related death was reported. Postoperative lenvatinib administration may provide clinical benefits and is well tolerated in patients with HCC beyond the Milan criteria who undergo LTx.

Bevacizumab and atezolizumab as first-line therapy for advanced hepatocellular carcinoma: A Taiwanese subgroup analysis on efficacy and safety

The combination of bevacizumab and atezolizumab has been established as a standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). We examined the treatment outcomes of patients in Taiwan who received the combination in 2 pivotal clinical trials. All patients who resided in Taiwan, were enrolled in the IMbrave150 and GO30140 studies, and received bevacizumab and atezolizumab as the first-line systemic therapy for unresectable HCC were included. We extracted and pooled anonymous raw data from the study records. We enrolled 40 patients, with the median age of 62.5 years; 36 (90%) had Barcelona Clinic Liver Cancer stage C disease. The response rate was 37.5%, including 3 (7.5%) complete responses. The disease control rate was 85%. The median duration of response was 21.4 months (95% confidence interval [CI], 16.6-not estimable). The median progression-free survival (PFS) and overall survival (OS) were 8.6 (95% CI, 5.6-18.6) and 24.9 months (95% CI, 14.2-not estimable), respectively. The most common adverse events of all grades were proteinuria (50%) and hypertension (37.5%), the median onset of which were 157 and 127 days, respectively. Bevacizumab and atezolizumab treatment had to be interrupted in 20 (50%) and 13 (32.5%) patients, respectively. Among patients whose treatment duration was ≥6 months, 50% of them had to skip bevacizumab, but no signal of poorer PFS or OS was observed. In Taiwanese patients with advanced HCC, the efficacy and safety outcomes of bevacizumab and atezolizumab treatment were generally consistent with the global intent-to-treat populations.

Clinical Predictor of Urinary Protein as Adverse Event Associated with Atezolizumab plus Bevacizumab Treatment for Unresectable Hepatocellular Carcinoma

Introduction: Adverse events (AEs) of urinary protein from monoclonal antibodies against vascular endothelial growth factor are factors that often inhibit systemic therapy for unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate risk factors of urinary protein in the early period (<12 weeks) of atezolizumab plus bevacizumab treatment (Atez/Bev). Methods: From 2020 to June 2022, 193 uHCC patients treated with Atez/Bev at our affiliated hospitals were enrolled (median 73 years, 158 males, 183 Child-Pugh A, BCLC-0:A:B:C = 1:7:73:112). AEs related to urinary protein (≥G2) within 12 weeks were defined as significant, and related clinical features were analyzed retrospectively. Results: In analyses of risk factors of urinary protein-related AEs during the first 12 weeks after starting Atez/Bev using a logistic regression method, univariate analysis showed positive for hypertension (odds ratio [OR] 3.54, 95% CI: 1.28–9.80, p = 0.015) and baseline urinary protein and urine creatinine ratio (UPC: ≥0.16) (OR: 2.52, 95% CI: 1.09–5.83, p = 0.031) as pretreatment clinical factors, while elevation of urinary protein in the early period (baseline to 3 weeks) with delta UPC per 3 weeks (ΔUPC/3W) (≥0.23) (OR: 15.80, 95% CI: 6.15–40.50, p < 0.001) was a clinical factor after starting treatment. Multivariate analysis of only baseline clinical factors revealed positive for history of hypertension as the only predictive factor (OR: 3.20, 95% CI: 1.14–8.95, p = 0.027), while only ΔUPC/3W (≥0.23) (OR: 14.40, 95% CI: 4.91–42.00, p < 0.001) were noted in multivariate analysis including ΔUPC/3W. Predictive factors for ΔUPC/3W (≥0.23) were hypertension (OR: 3.50, 95% CI: 1.23–99.90, p = 0.019) and UPC (≥0.16) (OR: 6.12, 95% CI: 2.61–14.30, p < 0.001) in multiple analysis. Discussion/Conclusion: Urinary protein-related AEs are frequently observed during Atez/Bev treatment in uHCC patients with elevated ΔUPC/3W (≥0.23), and ΔUPC/3W (≥0.23) is often seen in patients with hypertension and/or UPC (≥0.16).

Population Pharmacokinetic Modeling of Lenvatinib in Chinese Patients With Advanced Hepatocellular Carcinoma Using Real-World Data.

Lenvatinib is a novel oral angiogenesis inhibitor approved in China for the treatment of unresectable hepatocellular carcinoma (HCC) without prior systemic treatment. We described the population pharmacokinetics of lenvatinib in Chinese patients with advanced HCC and explore the potential patient characteristics associated with lenvatinib pharmacokinetics using real-world data. A total of 266 samples, provided by 127 Chinese patients with advanced HCC, were analyzed by nonlinear mixed-effects modeling. Monte Carlo simulation was conducted to assess impact of covariates on the exposure to lenvatinib. The clearance of lenvatinib in Chinese patients with advanced HCC was 5.3 L/h, and alkaline phosphatase, total bilirubin, and sex were identified as important covariates associated with it. The clearance of Child-Pugh class B patients (4.82L/h) was significantly lower than that of Child-Pugh class A patients (5.53 L/h), and the systemic exposure increased with the increase of alkaline phosphatase and total bilirubin. There were sex differences in the pharmacokinetic characteristics of lenvatinib. The clearance of women was significantly lower than that of men (4.61 vs 5.6 L/h; P &lt; .001), and the area under the plasma concentration-time curve of women was ≈20% higher than that of men. In this study, a population pharmacokinetic model of lenvatinib was established, which can be used to simulate clinical trials or various dosing scenarios. Our findings provide important new insights for optimizing the use of lenvatinib in patients with advanced HCC.

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma.

Combination atezolizumab/bevacizumab is the gold standard for first-line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety of combination therapy in older patients with HCC. 191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age < 65 years) age patients. Treatment-related adverse events (trAEs) were evaluated. The elderly (n=116) had higher rates of non-alcoholic fatty liver disease (19.8% vs. 2.7%; p < .001), presenting with smaller tumours (6.2cm vs 7.9cm, p=.02) with less portal vein thrombosis (31.9 vs. 54.7%, p=.002), with fewer patients presenting with BCLC-C stage disease (50.9 vs. 74.3%, p=.002). There was no significant difference in OS (median 14.9 vs. 15.1 months; HR 1.15, 95% CI 0.65-2.02 p=.63) and PFS (median 7.1 vs. 5.5 months; HR 1.11, 95% CI 0.54-1.92; p=.72) between older age and younger age. Older patients had similar ORR (27.6% vs. 20.0%; p=.27) and DCR (77.5% vs. 66.1%; p=.11) compared to younger patients. Atezolizumab-related (40.5% vs. 48.0%; p=.31) and bevacizumab-related (44.8% vs. 41.3%; p=.63) trAEs were comparable between groups. Rates of grade ≥3 trAEs and toxicity-related treatment discontinuation were similar between older and younger age patients. Patients 75 years and older had similar survival and safety outcomes compared to younger patients. Atezolizumab and bevacizumab therapy is associated with comparable efficacy and tolerability in older age patients with unresectable HCC.

LBA36 Final analysis of RATIONALE-301: Randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma

Tislelizumab (TIS), an anti-PD-1 monoclonal antibody, has demonstrated durable responses and was well tolerated as monotherapy in 2L+ treatment in patients (pts) previously treated systemically for unresectable HCC (Ducreux et al, 2021). TIS has been further evaluated against sorafenib (SOR) in a global randomized Phase 3 study (RATIONALE-301; NCT03412773) as 1L treatment in adult pts with unresectable HCC. Systemic therapy-naïve adults with histologically confirmed HCC BCLC Stage B/C who were not amenable to or progressed after loco-regional therapy, Child-Pugh A, with ≥1 measurable lesion per RECIST v1.1, and an ECOG PS ≤1 were eligible. Pts were randomized 1:1 to receive TIS (200 mg IV Q3W) or SOR (400 mg PO BID) until disease progression, intolerable toxicity, withdrawal, or no longer benefiting from therapy. The primary endpoint was OS; secondary endpoints included ORR, PFS, and DOR by blinded independent review committee, and safety. Non-inferiority of OS between TIS and SOR was tested against the non-inferiority margin of 1.08. A total of 674 pts were randomized (n=342, TIS; n=332, SOR); at data cutoff (11 Jul 2022) minimum study follow up was 33 months (mo). In this final analysis, RATIONALE-301 met its primary endpoint of OS non-inferiority (mOS: 15.9 mo [TIS] vs 14.1 mo [SOR]; stratified HR: 0.85 [95.003% CI: 0.712, 1.019]). TIS was associated with higher ORR (14.3% vs 5.4%) and more durable responses (mDoR: 36.1 mo vs 11.0 mo) compared with SOR. Median PFS with TIS was 2.2 mo and 3.6 mo with SOR (HR: 1.1 [95% CI: 0.92, 1.33]). Median treatment duration was longer with TIS vs SOR (4.1 mo vs 2.7 mo). The safety profiles for both treatments were consistent with prior reports. Incidence rates of grade ≥3 AEs (48.2% vs 65.4%) and AEs leading to discontinuation (10.9% vs 18.5%) were lower with TIS compared with SOR; AEs leading to death were low across both treatments (4.4%, TIS; 5.2%, SOR). Immune-mediated AEs occurring in ≥5% TIS-treated pts were hepatitis (5.3%) and hypothyroidism (5.3%). Single-agent TIS demonstrated clinically meaningful OS benefit that was non-inferior to SOR with a favorable safety profile as a 1L treatment option for pts with unresectable HCC.

Balloon-Occluded Radiofrequency Ablation as Bridge to TACE in the Treatment of Advanced HCC with Arterioportal Shunt.

Transarterial chemoembolization is the most widely used palliative treatment for unresectable hepatocellular carcinoma; however, arterioportal shunt represents a contraindication to this treatment. The study aims to assess the feasibility of balloon-occluded radiofrequency ablation in the transitory resolution of an extensive arterioportal shunt in patients with advanced hepatocellular carcinoma as a bridge to safe and effective transarterial chemoembolization. 12 consecutive patients advanced multinodular unilobar unresectable hepatocellular carcinoma with a target lesion larger than 5 cm (mean diameter 7.7 ± 1.4 cm), not suitable to transarterial chemoembolization due to extensive arterioportal shunt, were recruited. Balloon-occluded radiofrequency ablation of the hepatic area surrounding the shunt during occlusion of the artery supplying the shunt was performed, followed by lobar conventional chemoembolization. Intra/periprocedural complications were evaluated. Technical success was defined by the result of radiofrequency ablation in terms of immediate disappearance, reduction, or persistence of the shunt. Local efficacy of chemoembolization was evaluated at 1-month computed tomography according to m-RECIST criteria. Technical success was achieved in all patients. No major complications were observed. 1- month follow-up showed a mean necrotic diameter of 6.3 cm (range: 3.8-8.7 cm), with an acceptable procedural result and persistence of the shunt. An overall response rate was obtained in all patients, with 25% complete response and 75% partial response. Balloon-occluded radiofrequency ablation of an arterioportal shunt in patients with advanced hepatocellular carcinoma can temporarily reduce shunting, allowing to perform safe and therapeutically useful chemoembolization, with satisfactory control of tumor growth.

Efficacy and Effect on Liver Functional Reserve of Atezolizumab and Bevacizumab for Unresectable Hepatocellular Carcinoma in Patients Who Do Not Meet Eligibility Criteria of IMbrave150.

Simple SummaryThe IMbrave150 trial led to the approval of atezolizumab and bevacizumab for the treatment of unresectable hepatocellular carcinoma (HCC). We performed a retrospective multicenter study including 115 patients with unresectable HCC treated with atezolizumab and bevacizumab, revealing that the combination of atezolizumab and bevacizumab is equally effective for patients meeting the IMbrave150 trial eligibility criteria and for patients not meeting these criteria, generally due to a history of systemic therapy, platelet counts < 75 × 109/L, Child-Pugh B, and 2+ proteinuria. However, liver functional reserve should be carefully monitored in patients not meeting the IMbrave150 trial eligibility criteria.The IMbrave150 trial demonstrated the high efficacy and safety of atezolizumab and bevacizumab for unresectable hepatocellular carcinoma (HCC). In this multicenter study, the efficacy of this combination and its effect on liver functional reserve were evaluated in patients not meeting the eligibility criteria of IMbrave150. Of 115 patients with unresectable HCC treated with atezolizumab and bevacizumab between October 2020 and January 2022, 72 did not meet the eligibility criteria of IMbrave150, most frequently due to a history of systemic therapy (60/72), platelet counts < 75 × 109/L (7/72), Child-Pugh B (9/72), and 2+ proteinuria (8/72). Atezolizumab and bevacizumab therapy was equally effective for patients who did or did not meet the eligibility criteria (PFS, 6.5 vs. 6.9 months, p = 0.765), consistent with subgroup analyses of histories of systemic therapy, platelet counts, Child-Pugh, and proteinuria. Baseline ALBI scores were worse in patients who did not meet the criteria than in those who did and significantly worsened after treatment initiation in patients not meeting the criteria (baseline vs. 12 weeks; 2.35 ± 0.43 vs. −2.18 ± 0.54; p = 0.007). Accordingly, atezolizumab plus bevacizumab was effective for patients not meeting the eligibility criteria of IMbrave150, although careful monitoring for changes in liver functional reserve is needed.

Expert consensus on transarterial chemoembolization refractoriness and subsequent therapies in hepatocellular carcinoma

Transarterial chemoembolization (TACE) is the fundamental method for the treatment of unresectable hepatocellular carcinoma (HCC). Nevertheless, ineffective repeat TACE may lead to damage on liver function and therefore have negative effect on long-term prognosis of HCC. The concept of "TACE failure/refractoriness" was then proposed to avoid ineffective repeat TACE. Nevertheless, whether the existing definitions of "TACE failure/refractoriness" are applicable to Chinese HCCs remains to be discussed. Combining reported clinical evidence with experts' opinion, the Chinese College of Interventionalists (CCI) TACE Refractoriness Collaboration Group proposed the CCI definition and expert consensus on TACE refractoriness in 2021. The CCI definition and expert consensus aims to make the concept of TACE refractoriness more scientific and objective, so as to better guide clinical practice of TACE for patients with HCC in China.

Efficacy of Transarterial Chemoembolization Combined with Molecular Targeted Agents for Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis.

Simple SummaryLiver cancer is the second most common cause of cancer-related death, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Transarterial chemoembolization (TACE) in combination with different tyrosine kinase inhibitors (TKIs) has recently been widely used for unresectable HCC (uHCC). However, studies investigating different combinations of agents have shown inconsistent results. Thus, we conducted a network meta-analysis to assess and compare the response of different agents in an uHCC setting. According to our results, TACE plus lenvatinib provides optimal treatment for uHCC, with the highest ranking based on OS, PFS, and DCR rates and the second-best ranking based on ORR rates.Transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) is the mainstay treatment for unresectable hepatocellular carcinoma (uHCC). However, studies investigating different combinations of agents have shown inconsistent results. Here, we used network meta-analysis (NMA) to compare different agents across 41 studies (36 cohort studies and five RCTs) in 11,540 patients. Multiple RCTs and cohort studies were searched to evaluate TACE combined with different TKIs. Outcomes of interest included overall survival (OS), progression-free survival (PFS), and tumor response. NMA used a random-effects consistency model to pool evidence from direct and indirect comparisons. Hazard ratio (HR) and relative risks (RR) with 95% confidence intervals (CI) were analyzed. Further, heterogeneity and publication bias analyses were performed and agents were ranked. TACE plus lenvatinib provided the maximal OS (Rank probability: 0.7559), PFS (Rank probability: 0.8595), CR (Rank probability: 0.4179), and DCR (Rank probability: 0.3857). TACE plus anlotinib demonstrated the highest PR (p = 0.62649) and ORR (p = 0.51158). SD was more often associated with TACE plus sorafenib (Rank probability: 0.601685). TACE plus lenvatinib provides optimal treatment for uHCC based on the highest ranking of OS, PFS, and DCR rates. However, given the lack of statistically significant OS benefit, shared decision making should include other TKIs as acceptable alternatives.

Dosing, efficacy and safety of lenvatinb in the real‐world treatment of hepatocellular carcinoma: Results from a Canadian database

AbstractBackground and AimsA phase 3 trial showed lenvatinib to be effective and safe in the treatment of unresectable hepatocellular carcinoma (HCC), however, its performance in the real world and effect of dosing on survival are unclear.MethodsFrom July 2018 to June 2020, HCC patients treated with lenvatinib from 10 Canadian cancer centres were included. Overall survival (OS) and progression‐free survival (PFS) were retrospectively analysed and compared across first‐ and later lines use of lenvatinib. In patients receiving lenvatinib first‐line, OS between different mean dose intensities and starting doses were compared.ResultsA total of 220 patients were included, of which 79% received lenvatinib as first‐line therapy. For first‐line versus later line treatment, median OS was 12.5 versus 11.8 months (P = .83) and median PFS was 7.6 versus 4.6 months (P = .27) respectively. Of patients receiving lenvatinib first‐line, 54% started at full dose according to their weight. Median OS for patients starting lenvatinib at full‐ and reduced‐dose was 12.3 and 15.8 months (P = .75) respectively. Median OS for patients with a mean dose intensity &gt;66.7% compared ≤66.7% was 13.7 and 7.7 months (P = .01). In the multivariate analysis, dose intensity (&gt;66.7 vs ≤66.7%) did not predict for OS [HR 0.70, 95% CI 0.42–1.18; P = .18]. The most common side effects were fatigue (59%), hypertension (41%) and decreased appetite (25%).ConclusionsLenvatinib appears to be effective in real‐world practice regardless of the line of therapy. Dose modifications at the start or during treatment did not appear to significantly affect survival.

Efficacy and Safety of Lenvatinib Combined With PD-1 Inhibitors Plus TACE for Unresectable Hepatocellular Carcinoma Patients in China Real-World.

PurposeTo evaluate the efficacy and safety of lenvatinib combined with programmed death receptor-1 signaling inhibitors plus transarterial chemoembolization (LePD1-TACE) for treatment of unresectable hepatocellular carcinoma (uHCC) in a real-world setting in China.MethodsThis was a retrospective study involving consecutive patients with uHCC (n =114) receiving LePD1-TACE treatment from June 2019 to May 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were calculated to evaluate the antitumor efficacy. Treatment-related adverse events (TRAEs) were analyzed to assess the safety profiles. In addition, we also evaluated prognostic factors related to survival and disease progression.ResultsA total of 114 patients with a median age of 53 years were analyzed during a median follow-up duration of 10.6 months (95% confidence interval [CI]: 8.5 -12.8). The Kaplan-Meier analysis showed that the median OS was 18.0 months (95% CI: 14.1 - Not reached), the median PFS was 10.4 months (95% CI: 6.6 - 12.4). Based on modified Response Evaluation Criteria in Solid Tumors, the best ORR was 69.3% and DCR was 80.7%. Almost all patients suffered from TRAEs, the most common grade 3-4 TRAEs were hypertension (8.8%), proteinuria (3.6%), hyperbilirubinemia (1.8%), leukopenia (4.4%) and alanine aminotransferase elevation (3.6%) across all patients. The independent treatment factors associated with OS and PFS were tumor number, neutrophil-to-lymphocyte ratio (NLR) and the early tumor response. In the early tumor response (CR+PR) patients, median OS and PFS were 25.1 months (95% CI: 13.8 - Not reached) and 15.2 months (95% CI: 10.5 - 19.1). The patients with tumor number < 3 had a superior median OS and PFS (25.1, 16.4 months) compared to patients with tumor number ≥ 3 (14.1 months, P = 0.012; 6.6 months, P = 0.007). The patients with NLR ≤ 2.165 had a longer median OS and PFS (Not reached, 15.2 months) than those with NLR > 2.165 (17.7 months, P = 0.003; 7.5 months, P = 0.047).ConclusionIn this real-world study, LePD1-TACE triple therapy showed encouraging efficiency and manageable safety in patients with uHCC. The tumor number (< 3), NLR (≤ 2.165) and early tumor response (CR+PR) could be one of the prognostic markers.

THU599 - Efficacy and safety of Atezolizumab plus Bevacizumab-based sequential treatment for unresectable hepatocellular carcinoma: a simulation model

THU599 - Efficacy and safety of Atezolizumab plus Bevacizumab-based sequential treatment for unresectable hepatocellular carcinoma: a simulation model

Abstract 5249: Efficacy and safety of apatinib in treatment of unresectablehepatocellular carcinoma: A real-world study

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. Apatinib is a small molecule TKI inhibitor. Its efficacy and safety for unresectable HCC patients have been demonstrated in randomized controlled clinical studies. However, the efficacy and safety of apatinib in real world is lacking. We are aiming to evaluate the efficacy and safety of apatinib in real world.MethodsPatients of older than 18 years with unresectable HCC confirmed by IHC (Immunohistochemistry) or CT and MR Imaging were enrolled in the study. All patients received apatinib monotherapy or combined with other treatments including TACE and chemotherapy. The enrolled patients were treated until disease progression, death, or severe intolerable toxicity, etc. The primary endpoint was overall response rate (ORR), and secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The adverse events (AEs) were also recorded.ResultsFrom February, 2019 to May, 2020, a total of 233 patients were enrolled. Among them, 66 (28.33%) patients received apatinib monotherapy and 167 (71.67%) patients received combination therapy. Patients with a history of hepatitis accounted for 70%. 8 patients achieved complete response (CR), 64 patients achieved partial response (PR), 120 patients achieved stable disease (SD), and 41 patients had progressive disease (PD), illustrating an ORR of 30.90% and a DCR of 82.40%. Median PFS and OS were 6.93 months (95% CI, 6.19-7.68 months) and 11.36 months (95% CI, 9.96-12.77 months), respectively. The safety profile indicated that the most common drug-related adverse events were hypertension (37.90%), hand-foot-skin reaction (27.39%), fatigue (19.11%), thrombocytopenia (16.02%). Grade 3/4 treatment related AEs included thrombocytopenia (4.30%), hypertension (3.82%), neutropenia (2.73%). After symptomatic treatment, all the adverse events were treated properly, and no unexpected adverse events were observed. Conclusions In current study, apatininb showed good tolerance with acceptable toxicity and high tumor response rate that translated into promising PFS and OS in unresectable HCC patients. ChiCTR1900021822 Citation Format: Jun Liu, Guangbing Li, Qiang He, Shijun Sun, Chuanlin Zhao, Chuandong Sun, Bo Zhang, Yi Cui, Yongqiang Ye, Xuting Zhi, Shiping Li, Shiping Li, Guozheng Pan, Changlin Ma, Jinhua Hu, Jun Li, Suling Wang, Yuangang Qiao, Wanhua Ren, Qi Meng. Efficacy and safety of apatinib in treatment of unresectablehepatocellular carcinoma: A real-world study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5249.

Therapeutic efficacy of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma in patients with Child-Pugh class A or B liver function in real-world clinical practice.

Atezolizumab plus bevacizumab (Atez/Bev) treatment is recommended for unresechepatocellular carcinoma (u-HCC) patients classified as Child-Pugh A (CP-A). This study aimed to elucidate the prognosis of patients treated with Atez/Bev, especially CP-A and -B cases. From September 2020 to March 2022, 457 u-HCC patients treated with Atez/Bev were enrolled (median age 74years, male:female=368:89, CP-A:CP-B=427:30, Child-Pugh score [CPS] 5:6:7:8:9=271:156:21:8:1). Therapeutic response was evaluated using RECIST ver.1.1. Clinical features and prognosis were retrospectively evaluated. There were no significant differences between CP-A and -B patients in regard to best response (CR:PR:SD:PD=16:91:194:81 vs. 0:7:13:8, p=0.739; objective response rate/disease control rate=28.0%/78.8% vs. 25.0%/71.4%). Analysis performed using inverse probability weighting adjustments of clinical factors other than those related to hepatic reserve function with a p value<0.10 for comparisons between patients with CP-A and -B showed that the progression-free survival (PFS) rate for CP-A cases was better (6-/12-/18-month: 58.2%/36.1%/27.8% vs. 49.6%/8.7%/non-estimable [NE], p<0.001), as was overall survival (OS) rate (6-/12-/18-month: 89.9%/71.7%/51.4% versus 63.6%/18.4%/NE; p<0.001). Median PFS (mPFS) and median OS (mOS) for the CPS-5 were 9.5months/NE, and 5.1/14.0months for the CPS-6 (both p<0.001). Furthermore, for modified albumin-bilirubin grade (mALBI)-1/2a/2b, mPFS was 9.4/8.5/5.3months (p<0.001) and mOS was NE/17.8/13.4months (p<0.001). Better hepatic function, such as mALBI grade 1 or 2a are thought to indicate a better condition for obtaining sufficient prognosis with Atez/Bev treatment for u-HCC patients, whereas for CP-B patients, who mainly shown an mALBI grade of 2b or 3, Atez/Bev might have less therapeutic efficacy.

Immune Checkpoint Inhibitors Plus an Anti-VEGF Antibody as the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis and Cost-Effectiveness Analysis.

Background: Sintilimab + a bevacizumab biosimilar (IBI305) (SB) and atezolizumab + bevacizumab (AB) have been approved for the treatment of unresectable hepatocellular carcinoma (HCC). At present, oncologists and their patients remain indecisive on their preferred treatment regime. Therefore, assessing their efficacy via a network meta-analysis and determining their comparative cost-effectiveness is necessary. Objective: To evaluate the cost-effectiveness of SB and AB compared with sorafenib alone for the treatment of unresectable HCC. Materials and Methods: The data used in our analysis were obtained from patients in ORIENT-32 and IMbrave150 phase III randomized clinical trials. A Bayesian network meta-analysis and cost-effectiveness analysis that included 1,072 patients were performed in this study. A partitioned survival model was applied to the patients with unresectable HCC. The model was designed with a 15-year time horizon, 1-month cycle, and 5% discount rate for costs and outcomes. In China, an incremental cost-effectiveness ratio (ICER) value of less than $33,500 (three times the GDP per capita in 2020) per quality-adjusted life-year (QALY) is considered cost-effective. The influence of parameter uncertainty on the results was verified by one-way deterministic sensitivity analysis and probability sensitivity analysis. Furthermore, scenario analyses of the patient assistance program (PAP) were conducted to explore the cost-effectiveness of SB and AB. Results: For the model of 1,072 patients, treatment with SB produced an additional 0.617 QALYs compared with sorafenib, resulting in an ICER of $39,766.86/QALY. Similarly, treatment with AB produced an additional 0.596 QALYs compared with sorafenib, resulting in an ICER of $103,037.66/QALY. The probability sensitivity analysis showed that when the willingness-to-pay (WTP) threshold was $33,500/QALY, the cost-effectiveness of SB and AB was 15.4 and 0.4%, respectively. However, in the scenario analyses, the probability of SB and AB regimens being cost-effective was 65.4 and 15.8%, respectively, at a WTP of $33,500/QALY. Conclusion: The findings from our study showed that sintilimab + a bevacizumab biosimilar is a cost-effective regimen compared with sorafenib as the first-line therapy for unresectable HCC in China at a $33,500 WTP threshold if sintilimab PAP is considered. However, the atezolizumab + bevacizumab regimen is not cost-effective whether atezolizumab PAP is considered or not.

P-131 Low-dose aspirin in combination with transarterial chemoembolization in treatment of unresectable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the sixth and fourth common cancer in worldwide and Egypt. Transarterial chemoembolization (TACE) is standard treatment for unresectable HCC. Recent studies showed that TACE refractoriness impairs survival of HCC patients. Various strategies under investigation aim to improve the outcome of TACE, Aspirin demonstrated chemopreventive, antithrombotic and anti-inflammatory properties Moreover, it has been reported that aspirin may reverse apoptosis resistance in HCC cell lines. This study includes 60 patients diagnosed as unresectable HCC indicted for TACE randomized in to two arms; control arm and aspirin arm. All patients have vascular and cellular compensated liver functions; platelets count ≥ 100,000, and normal prothrombin time. We excluded patients with bleeding tendency, gastrointestinal ulcers, portal hypertension, allergy or contraindication to aspirin. Aspirin arm patients received 75 mg of aspirin daily after meal for 3 months; we assessed feasibility, toxicity of aspirin, studied treatment response and disease progression. In this study there was no significant difference between the two arms regarding baseline patients’ characteristics. Regarding compliance to aspirin, 70% of patients were regular; regarding compliance to TACE, 60% of patients were compliant to TACE in aspirin arm versus 56.7% in control arm. Most of side effects of aspirin are of grade 1 gastrointestinal side effect. According to modified RECIST criteria, better responses achieved in aspirin arm; 10% of patients in aspirin arm had complete remission versus 6.7 %in control arm and 30% had partial response in aspirin arm versus 23% in control arm, 30% of patients in aspirin arm had disease progression versus 40% in control arm; however, the difference didn’t reach statistical significant level (p=0.806). 20% of patients in control arm developed portal vein thrombosis versus only 6.7% in aspirin arm. There was an improvement in progression free survival (PFS); the median PFS was not reached for aspirin arm versus 11 months for Control arm (P=0.035). The use of adjuvant aspirin with TACE in patients with HCC is feasible and may be associated with longer PFS and a tendency of better TACE responses; however, larger sample size may yield stronger results.