Safety and Efficacy of TACE Combined with Lenvatinib and Pembrolizumab in Advanced Hepatocellular Carcinoma (BCLC C): A Retrospective Study

This study evaluated the effectiveness and safety of tislelizumab plus lenvatinib (TL group) and tislelizumab monotherapy (T group) in patients with stage C hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer (BCLC) staging system after lenvatinib failure, and it analyzed the factors influencing the effectiveness of TL as a second-line treatment. This retrospective analysis involved 51 patients treated at a single center between January 2019 and July 2023. Survival outcomes and tumor responses were compared between the TL and T monotherapy groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were identified using Cox proportional hazard regression models. Among patients with BCLC stage C advanced HCC who experienced lenvatinib treatment failure, median PFS was significantly longer in the TL group than in the T group (6.8 months vs. 4.5 months, p = 0.003), and OS was notably extended in the TL group (14.0 months vs. 10.4 months, p = 0.012). Although the disease control rate (64% vs. 53.8%, p = 0.461) and objective response rate (20% vs. 7.7%, p = 0.202) were numerically higher in the TL group, these differences did not reach significance. Child–Pugh B liver function and tislelizumab monotherapy were independent prognostic factors for poor OS, whereas only tislelizumab monotherapy was an independent prognostic factor for poor PFS, Child-Pugh B was not a prognostic factor for PFS. Subgroup analysis demonstrated the OS benefit of tislelizumab plus lenvatinib in patients with Child–Pugh A liver function (14.0 months vs. 12.0 months, p = 0.013) but not in those with Child–Pugh B liver function (7.7 months vs. 6.1 months, p = 0.225). In the TL group, the most frequent treatment-related adverse events (AEs) were hand–foot skin reaction (32%), hypertension (28%), diarrhea (32%), and hypothyroidism (20%). Grade 3 or higher AEs occurred in 24% of patients in the TL group, and hand–foot skin reaction and diarrhea were the most frequent grade 3 or higher AEs. The incidence of AEs was comparable between the two groups. As a second-line treatment, the combination of tislelizumab and lenvatinib was well tolerated and associated with improved OS and PFS versus tislelizumab alone for patients with advanced HCC, particularly in those with Child–Pugh A liver function.

Sorafenib is the only standard treatment for unresectable hepatocellular carcinoma (HCC), but it provides modest survival benefits over placebo, necessitating predictive biomarkers of the response to sorafenib. Serum samples were obtained from 115 consecutive patients with HCC before sorafenib treatment and analyzed by multiple reaction monitoring-mass spectrometry (MRM-MS) and ELISA to quantify candidate biomarkers. We verified a triple-marker panel to be predictive of the response to sorafenib by MRM-MS, comprising CD5 antigen-like (CD5L), immunoglobulin J (IGJ), and galectin-3-binding protein (LGALS3BP), in HCC patients. This panel was a significant predictor (AUROC > 0.950) of the response to sorafenib treatment, having the best cut-off value (0.4) by multivariate analysis. In the training set, patients who exceeded this cut-off value had significantly better overall survival (median, 21.4 months) than those with lower values (median, 8.6 months; p = 0.001). Further, a value that was lower than this cutoff was an independent predictor of poor overall survival [hazard ratio (HR), 2.728; 95% confidence interval (CI), 1.312-5.672; p = 0.007] and remained an independent predictive factor of rapid progression (HR, 2.631; 95% CI, 1.448-4.780; p = 0.002). When applied to the independent validation set, levels of the cut-off value for triple-marker panel maintained their prognostic value for poor clinical outcomes. On the contrast, the triple-marker panel was not a prognostic factor for patients who were treated with transarterial chemoembolization (TACE). The discriminatory signature of a triple-marker panel provides new insights into targeted proteomic biomarkers for individualized sorafenib therapy.

Progression-free survival: Starting point or endpoint in advanced HCC trial design?

Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma

Real World Effectiveness of Atezolizumab and Bevacizumab: What Lessons Can We Learn?

Intermediate-stage (BCLC-B) hepatocellular carcinoma (HCC) beyond the up-to-11 criteria represent a significant therapeutic challenge due to high and heterogeneous tumor burden. This study evaluated the effectiveness and safety of transarterial chemoembolization (TACE) in combination with lenvatinib and tislelizumab for these patients. In this retrospective cohort study, patients with unresectable intermediate-stage HCC beyond the up-to-11 criteria were enrolled and divided into TACE monotherapy (T), TACE combined with lenvatinib (TL), or TACE plus lenvatinib and tislelizumab (TLT) group based on the first-line treatment, respectively. The primary endpoint was overall survival (OS). The secondary outcomes included progression-free survival (PFS), tumor response according to RESIST1.1 and modified RECIST, and adverse events (AEs). There were 38, 45, and 66 patients in the T, TL, and TLT groups, respectively. The TLT group exhibited significantly higher ORR and DCR than the other two groups, as assessed by either mRECIST or RECIST 1.1 (all P<0.05). Median PFS and OS were significantly longer in the TLT group compared with the T group (PFS: 8.5 vs. 4.4 months; OS: 31.5 vs. 18.5 months; all P<0.001) and TL group (PFS: 8.5 vs. 5.5 months; OS: 31.5 vs. 20.5 months; all P<0.05). The incidence of TRAEs was slightly higher in the TLT and TL groups than in the T group, while all the toxicities were tolerable. No treatment-related death occurred in all groups. TACE combined with lenvatinib and tislelizumab significantly improved the survival benefit compared with TACE monotherapy and TACE plus lenvatinib in patients with intermediate-stage HCC beyond the up-to-11 criteria, with an acceptable safety profile.

ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma

Background: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the fourth leading cause of cancer death in the world. Aims: This study aimed to investigate the efficacy and safety of Lenvatinib + PD-1 inhibitor + TACEHAIC (LePTaHAIC) versus Sorafenib + TACE (SorTACE) for patients with intermediate and advanced HCC. Methods: In this retrospective study, patients diagnosed with BCLC stage B/C HCC were included. All patients were treated with LePTaHAIC (LePTaHAIC group) or SorTACE (SorTACE group) between September 2019 and September 2020. Outcomes, including progression-free survival (PFS), conversion surgical resection rate, objective remission rate (ORR), overall survival (OS), and treatment-related adverse events (AEs) were analyzed and compared between the two treatment modalities. Results: In total, 65 eligible patients were recruited, with 35 assigned to receive LePTaHAIC and 30 assigned to undergo SorTACE. Median PFS (11.4 vs. 5.13 months) and OS (26 vs. 10.08 months) in the LePTaHAIC group were significantly higher compared to the SorTACE group (both P &lt; 0.0001). The ORR (mRECIST standard) of the LePTaHAIC group was markedly higher compared to the SorTACE group (71.4% vs. 40%, P = 0.01). In the LePTaHAIC group, 11 patients underwent surgical resection (BCLC stage B: n = 4, BCLC stage C: n = 7) and 3 patients achieved complete pathological remission (pCR), while one patient in the SorTACE group underwent surgical resection. The conversion surgical resection rate of the LePTaHAIC group was significantly higher compared to the SorTACE group [31.4% (11/35) vs. 3.3% (1/30), P = 0.004]. Patients with LePTaHAIC had more frequent grade 3-4 treatmentrelated AEs, especially thrombocytopenia, compared to the SorTACE group (22.9% vs. 3.3%, P = 0.02). Conclusion: LePTaHAIC exhibited acceptable toxic effects and improved survival compared to SorTACE in intermediate and advanced HCC.

339 Background: Nintedanib (N) is an oral, triple angiokinase inhibitor of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This randomized, multicenter, open-label, Phase II study (NCT00987935; 1199.39) evaluated the efficacy and safety of N versus sorafenib (S) in Asian patients with advanced HCC. Preliminary analysis showed similar time to progression (TTP) by independent central review (ICR). Methods: Asian patients with unresectable advanced HCC, Child–Pugh score 5–6, ECOG-PS ≤2, and alanine/aspartate aminotransferase (ALT/AST) ≤2× upper limit of normal were enrolled. Patients were randomized 2:1 to N 200 mg bid or S 400 mg bid continuously in 28-day cycles, until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. Primary endpoint was TTP by ICR (RECIST 1.0) and secondary endpoints were overall survival (OS) and investigator-assessed (IA) TTP. Results: Patients (N=95) were randomized to receive N (n=63) or S (n=32); arms were balanced except for macroscopic vascular invasion (48% vs 31%). At the final cutoff date (16 Jul 14), 88% of patients had a TTP event, and 86% had an OS event; 1 patient was on treatment beyond PD. N and S had comparable IA TTP (median 2.8 vs 3.0 months; HR 1.39 [95% CI: 0.87–2.23]) and OS (median 10.2 vs 10.7 months; HR 0.94 [95% CI: 0.59–1.49]). ICR TTP data are pending. All but 1 patient reported an AE (CTCAE 3.0). More S-treated patients had Grade ≥3 AEs (56% vs 84%), serious AEs (46% vs 56%), and AEs leading to dose reduction (19% vs 59%) and drug discontinuation (24% vs 34%). Class-specific AEs of tyrosine kinase inhibitors in &gt;15% of S-treated patients were hypertension, hand-foot skin reaction, and thrombocytopenia; only anemia was higher with N. AEs previously observed and higher with N were vomiting and nausea; ALT/AST increases and diarrhea were higher with S. Rash was reported in &gt;15% of patients only with S. Conclusions: N shows similar efficacy to S for TTP and OS. N was better tolerated than S and AEs were generally manageable. Further studies of N in Asian patients with advanced HCC are warranted. Clinical trial information: NCT00987935.

238 Background: Nintedanib (N) is an oral, triple angiokinase inhibitor of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This randomized, multicenter, open-label, phase II study (NCT01004003; 1199.37) evaluated the efficacy and safety of N versus sorafenib (S) in patients with advanced HCC. Methods: Enrolled patients had unresectable advanced HCC, ECOG-PS ≤2, Child–Pugh score 5–6, alanine/aspartate aminotransferase (ALT/AST) ≤2× upper limit of normal, and ≥1 untreated measurable lesion or a previously treated lesion with progression (by RECIST 1.0). Patients were randomized 2:1 to N 200 mg bid or S 400 mg bid continuously in 28-day cycles, until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. Primary endpoint was time to progression (TTP) by independent central review (ICR; RECIST 1.0), and secondary endpoints were overall survival (OS) and investigator-assessed (IA) TTP. Results: Ninety-three patients were randomized to receive N (n=62) or S (n=31). At the cutoff date (15 July 2014), 77% of patients had a TTP event, and 70% had an OS event; 3 patients remained on treatment with 1 patient beyond PD. IA TTP was comparable between N and S (median 5.5 vs 3.8 months; HR 1.05 [95% CI: 0.63–1.76]), as was OS (median 11.9 vs 11.4 months; HR 0.88 [95% CI: 0.52–1.47]). ICR TTP data are pending. All patients reported an AE (CTCAE 3.0); more patients treated with S had Grade ≥3 AEs (68% vs 90%). AEs leading to dose reduction were higher with S (19% vs 42%), whereas AEs leading to drug discontinuation were higher with N (45% vs 23%). The only tyrosine kinase inhibitor class-specific AE reported in &gt;15% of patients was hand-foot skin reaction in the S arm. AEs previously observed with N and higher in this arm were diarrhea, vomiting, nausea, and AST increase, while blood bilirubin increase was higher with S. Rash was reported in &gt;15% of patients only in the S arm. Conclusions: N shows similar efficacy to S with respect to TTP and OS, with a manageable safety profile. Further studies of N in patients with advanced HCC are warranted. Clinical trial information: NCT01004003.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

403 Background: Time to progression (TTP) is widely used as the endpoint in early-phase trials for advanced hepatocellular carcinoma (HCC). However, the relevance of using TTP as a surrogate marker for overall survival (OS) in pivotal trials remains uncertain. Methods: The PubMed database and ASCO meeting library were searched for reports of randomized controlled trials that investigated patients with advanced HCC, included data for both OS and TTP, and were launched between 2009 and 2016. Correlation between hazard ratios (HRs) for TTP and OS was determined using weighted linear regression. Correlations between median OS and TTP, and between median OS and post-progression survival (PPS), defined as the period obtained by subtracting median TTP from median OS, were also evaluated. Results: The database search yielded 24 trials with 50 arms. Overall, TTP HR correlated with OS HR (R = 0.73); however, the coefficient in the regression equation was 0.48. When trials were stratified by treatment line, TTP HR was more strongly correlated with OS HR in second-line (R = 0.91) than in first-line (R = 0.77) settings. Correlation between median OS and median TTP was weak (R = 0.50), whereas the correlation between median OS and median PPS was strong (R = 0.78). Conclusions: In advanced HCC, the OS HR can be predicted from the TTP HR, especially in second-line trials, which is useful when considering whether to proceed to a pivotal trial based on the results of early-phase trials. However, TTP may not be appropriate as a primary endpoint in a pivotal trial if the trial aims to evaluate the survival benefit of novel agents because improvement of TTP cannot fully reflect improvement of OS because of the impact of PPS on OS.

160 Background: In Asia, where hepatitis B is very common, patients often present with locally advanced or metastatic hepatocellular carcinoma (HCC), and their prognosis is poor. The EACH study was designed to evaluate the efficacy and safety of FOLFOX4 vs. doxorubicin as palliative systemic chemotherapy in advanced HCC. Methods: The open-label, randomized, multicenter phase III study was conducted in 371 patients in China, Taiwan, Korea and Thailand, who had locally advanced or metastatic HCC and were ineligible for resection. Patients were randomized 1:1 to receive either FOLFOX4 (oxaliplatin 85 mg/m2 i.v. d1; LV 200 mg/m2 i.v. h0–h2 d1 and d2; 5FU 400 mg/m2 i.v. bolus h2, then 600 mg/m2 over 22 hours d1 and d2 q2w) or doxorubicin (50 mg/m2 i.v. q3w). The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), response rate (RR) by RECIST and safety. Data from final and follow-up analyses of the intent-to-treat (ITT) population and selected subgroup analyses are presented. Results: At the final analysis, median OS with FOLFOX4 (N = 184) was 6.40 months (95% CI: 5.30, 7.03) vs. 4.97 months (95% CI: 4.23, 6.03) with doxorubicin [N = 187; p = 0.0695 using a stratified log-rank test; statistical significance (p = 0.0425) was achieved at the post hoc follow-up analysis conducted 7 months later]. Median PFS with FOLFOX4 was 2.93 months (95% CI: 2.43, 3.53) vs. 1.77 months with doxorubicin (95% CI: 1.63, 2.30; p = 0.0002). The RR was 8.2% vs. 2.7% of patients with FOLFOX4 and doxorubicin, respectively (p = 0.0233), and the disease control rate (DCR) was 52.2% vs. 31.6% (p &lt; 0.0001). In the Chinese sub-population, OS, PFS, RR and DCR were significantly improved with FOLFOX4 vs. doxorubicin at both the final and follow-up analyses. In the other subgroups analyzed, the OS and PFS benefits of FOLFOX4 vs. doxorubicin were generally consistent. Conclusions: In the ITT population, median OS was greater with FOLFOX4 than doxorubicin throughout the study and statistical significance was achieved after continued follow-up. FOLFOX4 can benefit patients with advanced HCC, as it significantly increases median OS, PFS, RR and DCR compared with doxorubicin. [Table: see text]

Sequencing of systemic therapy in unresectable hepatocellular carcinoma: A systematic review and Bayesian network meta-analysis of randomized clinical trials

Atezolizumab plus bevacizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma: a cost-effectiveness analysis.