Second-Line TKI after First-Line Immunotherapy-based Treatment in Advanced HCC: Reconstructed IPD Meta-analysis.

Chapter 4: Chemotherapy and radiotherapy

Advanced hepatocellular carcinoma (HCC) poses a substantial global disease burden. Since the approval of sorafenib in 2007, an increasing number of treatment regimens have demonstrated encouraging survival benefits in first-line treatment of advanced HCC. However, this expansion of therapeutic options has also introduced complexity into clinical decision-making. This study aims to provide high-quality evidence to inform clinical practice by comparing all first-line treatment regimens for advanced HCC. We will systematically search PubMed, Embase (Ovid), and the Cochrane Library (Ovid) from January 1, 2007, to March 3, 2026. Supplementary searches will be performed in clinical trial platforms and conference abstracts. All randomized controlled trials (RCTs) and high-quality observational studies (for prior information only) comparing active first-line treatment regimen for advanced HCC will be included. Primary outcomes are overall survival, grade ≥3 serious adverse events, and the incremental safety-effectiveness ratio. Secondary outcomes include progression-free survival, objective response rate, the incidence of all adverse events and treatment discontinuation due to adverse events. The risk of bias of included RCTs will be assessed using the Risk of Bias 2.0 tool, and the certainty of evidence for each outcome will be evaluated with the Confidence in Network Meta-Analysis (CINeMA) application. Study selection, data extraction, and quality assessment will be performed independently by two reviewers, with any disagreements adjudicated by a third reviewer. Individual patient data will be reconstructed from published Kaplan-Meier curves, and treatment effects will be evaluated using restricted mean survival time. Subgroup analyses will be performed based on PD-L1 expression, etiology, Barcelona Clinic Liver Cancer stage, alpha-fetoprotein concentration, macrovascular invasion, and extrahepatic spread. Bayesian network meta-analysis will be performed using R with the gemtc package. Our study is expected to inform clinical guidelines and support personalized therapeutic decisions for advanced HCC. https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420251126975.

Simple SummaryFor years, the systemic therapies sorafenib and lenvatinib have represented standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). The recent approval of atezolizumab in combination with bevacizumab heralded the arrival of immunotherapy for first-line treatment of advanced HCC, and the field is growing, with other combination immunotherapies under investigation. Focusing on the Asia–Pacific region, where drug availability and reimbursement systems differ widely, this article reviews the evolving treatment landscape and summarises the authors’ expert opinion on therapeutic decision-making to optimise outcomes in advanced HCC.Hepatocellular carcinoma (HCC) is the fourth most common driver of cancer-related death globally, with an estimated 72% of cases in Asia. For more than a decade, first-line systemic treatments for advanced or unresectable HCC were limited to the multi-targeted kinase inhibitors sorafenib and, more recently, lenvatinib. Now, treatment options have expanded to include immunotherapy, as exemplified by the immune checkpoint inhibitor (ICI) atezolizumab combined with the antiangiogenic agent bevacizumab. Additional combinations of ICIs with kinase inhibitors, other ICIs, or antiangiogenic agents are under investigation, further supporting the new era of immunotherapy for first-line treatment of advanced or unresectable HCC. We describe this evolving landscape and provide expert opinion on therapeutic best practices in the Asia–Pacific region, where different costs of, and patient access to, treatment are a challenge. With the combination of atezolizumab plus bevacizumab likely to become the clinical standard of care, optimising treatment sequence and ensuring patient access to newer therapies remain priorities. Cost containment and treatment sequencing may be facilitated by characterisation of predictive positive and negative biomarkers. With these considerations in mind, this review and expert opinion focused on advanced HCC in the Asia–Pacific region offers perspectives of multiple stakeholders, including physicians, payer systems, and patients.

315 Background: Systemic treatment with tyrosine kinase inhibitors such as sorafenib represents the mainstay of advanced-stage hepatocellular carcinoma (HCC). However, survival outcomes remain disappointing, mostly because of the onset of acquired resistance and a suboptimal safety profile, which frequently requires treatment modifications and early discontinuation of treatment – thus, interfering with compliance and long-term outcomes of patients. With immune checkpoint inhibitors (ICIs) quickly expanding as a novel therapeutic option in advanced HCC, the toxicity profiles of these agents should be kept in mind. We performed a meta-analysis with the aim to compare all-grade (G) adverse drug events (ADEs) of ICIs (alone or in combination with other anticancer agents) versus sorafenib monotherapy across randomized controlled trials (RCTs) of first-line treatment for advanced HCC. Methods: Eligible studies included RCTs comparing ICIs versus sorafenib as first-line treatment in HCC. Safety profile from each selected study was investigated for all-G most common ADEs. Outcomes of interest were as follows: pruritus, diarrhea, hand-foot skin reaction (HFSR), fatigue, aspartate aminotransferase (AST) increase, rash, hypertension and decreased appetite. Results were compared by calculating odds ratios (ORs) with 95% confidence intervals (CIs); ORs were combined with Mantel-Haenszel method. All statistical analyses were performed using R studio software. Results: Two RCTs (CheckMate 459, IMbrave 150) involving 1,228 patients were included in the analysis. Patients treated with ICIs showed higher risk of pruritus (OR 1.99, 95% CI = 1.22-3.24) while sorafenib treatment was associated with higher risk of diarrhea (OR 0.26, 95% CI = 0.18-0.37) and HFSR (OR 0.01, 95% CI = 0-0.04). Conversely, no statistically significant differences were observed in terms of fatigue (OR 0.84, 95% CI = 0.45-1.58), AST increase (OR 1.21, 95% CI = 0.78-1.88), rash (OR 0.71, 95% CI = 0.46-1.11), hypertension (OR 0.28, 95% CI = 0.01-9.76) and decreased appetite (OR 0.41, 95% CI = 0.14-1.21) between the two groups. Conclusions: Although the substantial heterogeneities affecting our analyses, ICIs appear feasible in advanced HCC, being endowed with an acceptable safety profile. Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in advanced HCC.

8580 Background: EGFR exon 19 deletions (19Del) in non-small cell lung cancer are associated with benefit from tyrosine kinase inhibitors (TKIs), but the relative inhibitor sensitivity of individual EGFR 19Del is unknown. This study predicted the structural features and TKI sensitivity of different EGFR 19Del, compared the clinical efficacy of different TKIs in non-small cell lung cancer (NSCLC) patients harboring EGFR 19Del, and incorporated structural and clinicopathological variables into a nomogram to predict the progression-free survival (PFS) of NSCLC patients with EGFR 19Del. Methods: 1964 patients with advanced NSCLC harboring EGFR 19Del treated with EGFR TKIs from March 2016 to March 2023 were retrospectively screened. Computational model generation and molecular dynamics simulation were used to predict the structural features and TKI sensitivity of different EGFR 19Del variants. Stepwise Cox Proportional Hazards Regression was conducted to select variables for inclusion in the subsequent survival nomogram. Results: A total of 401 patients and 17 subtypes of EGFR 19Del were included in this study. For patients who received first-line 3rd generation TKIs, E746_A750>X and L746_A750>P had significantly shorter median PFS (mPFS) than other patients (10.6 months vs. 22.6 months, p = 0.0069; 12.8 months vs. 22.6 months, p = 0.027). For patients who received first-line 1st or 2nd generation TKIs and second-line TKIs, the PFS was not different among EGFR 19Del. Based on molecular dynamics simulation, E746_A750>X, E746_S752>V, E746_P753>VS and L747_P753>S were grouped into CLASS 1/2G, which had less binding affinity toward 1st or 2nd generation TKIs than other EGFR 19Del variants, while E746_A750>X, E746_S752>V, L747_A750>P and L747_T751>P were grouped into CLASS 3G, which had less binding affinity toward 3rd generation TKIs than other EGFR 19Del variants. For patients who received first-line and second-line 3rd generation TKIs, CLASS 3G showed shorter mPFS than other patients (12.8 months vs. 22.6 months, p = 0.059; 7.73 months vs. 15.1 months, p = 0.041). For patients who received first-line and second-line 1st or 2nd generation TKIs, the PFS was not different between CLASS 1/2G and other patients. For patients who received first-line 3rd generation TKIs, a survival nomogram was generated incorporating histology, degree of differentiation and CLASS 3G. For patients who received first-line 1st or 2nd generation TKIs, a survival nomogram was generated incorporating age, degree of differentiation, liver metastases and number of metastasized organs. Conclusions: We identified a group of EGFR 19Del responded poorly to 3rd generation TKIs based on structural features. Nomogram that incorporated structural and clinicopathological variables was a robust prognostic model. This study highlights the molecular structural analysis as a useful predictive tool of TKIs efficacy.

Background: Atezolizumab + bevacizumab represent the current standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, direct comparison with other combination treatments including immune checkpoint inhibitors (ICI) + tyrosine kinase inhibitors (TKIs) are lacking. Objectives: This network meta-analysis (NMA) aims to indirectly compare the efficacy and the safety of first-line systemic therapies for unresectable advanced HCC. Method: A literature search of MEDLINE, Embase, and SCOPUS databases was conducted up to October 31, 2022. Phase 3 randomized controlled trials (RCTs) testing TKIs, including sorafenib and lenvatinib, or ICIs reporting overall survival (OS) and progression-free survival (PFS) were included. Individual survival data were extracted from OS and PFS curves to calculate restricted mean survival time. A Bayesian NMA was performed to compare treatments in terms of efficacy (15- and 30-month OS, 6-month PFS) and safety, represented by grade ≥3 (severe) adverse events (SAEs). The incremental safety-effectiveness ratio as measure of net health benefit was calculated as the difference in SAE probability divided by survival difference between the 2 most effective treatments. Results: Nine RCTs enrolling 6,600 patients were included. Atezolizumab plus bevacizumab showed the highest probability (88%) of achieving the 30-month OS landmark. Lenvatinib showed a probability of 86% of achieving best PFS outcomes. ICI monotherapies ranked as most tolerable. Atezolizumab plus bevacizumab showed the best net health benefit for OS, compared to durvalumab plus tremelimumab. When evaluating the net health benefit for PFS, at a willingness-to-risk threshold of 10% of SAEs for life-month gained, atezolizumab plus bevacizumab was favoured in 78% of cases, while at threshold of 30% of SAEs for life-month gained, lenvatinib was favoured in 76% of cases. Conclusions: Atezolizumab plus bevacizumab is the best treatment in terms of net benefit and therefore it should be recommended as standard of care. Compared to atezolizumab plus bevacizumab, lenvatinib monotherapy had the best net benefit for PFS when physicians and patients are available to accept a higher risk of toxicity.

Treatment Characteristics and Deep Molecular Response in Chronic Phase - Chronic Myeloid Leukemia Patients Treated with Second-Line Nilotinib or Dasatinib: A Multi-Country Retrospective Chart Review Study

Hepatocellular carcinoma (HCC) is a highly aggressive disease that is usually diagnosed at an advanced stage. Advanced HCC has limited treatment options and often has a poor prognosis. For the past decade, tyrosine kinase inhibitors have been the only treatments approved for advanced HCC that have shown overall survival (OS) benefits; however, but their clinical efficacy has been limited. Recent trials have demonstrated promising advancements in survival outcomes through immunotherapy-based treatments, such as combinations of immune checkpoint inhibitors (ICIs) with other ICIs, antiangiogenic drugs, and locoregional therapies. The atezolizumab-bevacizumab and durvalumab-tremelimumab (STRIDE) regimen has significantly improved survival rates as a first-line treatment and has become the new standard of care. Therefore, combined treatments for advanced HCC can result in better treatment outcomes owing to their synergistic effects, which requires a multidisciplinary approach. Ongoing studies are examining other therapeutic innovations that can improve disease control and OS rates. Despite improvements in the treatment of advanced HCC, further studies on the optimal treatment selection and sequences, biomarker identification, combination approaches with other therapies, and development of novel immunotherapy agents are required. This review presents the current treatment options and clinical data of the ICI-based combination immunotherapies for advanced HCC from a multidisciplinary perspective.

583 Background: The IMbrave 150 study opened the door of immuno-oncology (IO) combined with targeted therapy in patients (pts) with hepatocellular carcinoma (HCC). At present, some other combination of IO and tyrosine kinase inhibitors (TKIs) had been proved as efficient regimens in China and there are many ongoing studies on this approach with preliminarily considerable efficacy. Furthermore, the efficacy of this combination still needs to be explored in real-world patients. The aim of this study is to explore the efficacy and safety of anlotinib plus PD-1 inhibitors in the treatment of HCC in real-world. Methods: This is a multi-center, prospective real-world study in pts (N=200) diagnosed as advanced HCC, who evaluated by physician would get benefits from anlotinib alone or in combination with PD-1 inhibitors. The enrolled patients received treatment according to physicians. Clinical efficacy was summarized, and adverse events were documented. Tumor response was assessed by investigators according to RECIST version 1.1. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Results: As of data cutoff date of Aug, 2022, a total of 119 patients were enrolled with a median age of 55 years (range 29-83). Among them 78% ECOG PS 0-1, 21% ECOG PS 2 and 1% ECOG PS 4. 75 pts received anlotinib plus PD-1 inhibitors as first-line treatment, 17 pts as second-line treatment and 7 pts as third-line and above. 76 patients were eligible for response evaluation. The ORR as best response was 11.8% (95%CI: 5.6%, 21.3%). The DCR was 73.7% (95%CI: 62.3%, 83.1%). The preliminarily results indicated that the median OS was 12.5 months (95%CI: 9.7, 15.4), the median PFS was 8.1 months (95%CI: 5.9, 10.3). Any grade treatment-related adverse events (TRAEs) observed in 50% of pts. The most common TRAEs were hypoalbuminemia (18.6%), hypertension (11.4%), decreased white blood cell count (11.4%) and decreased platelet count (10%). Conclusions: Present study indicated that the combination of anlotinib and PD-1 inhibitors exhibited potential efficacy and manageable adverse events in the treatment of advanced HCC in the real world. The conclusion should be validated in more patients included subsequently. Clinical trial information: NCT04954521 .

BackgroundProgrammed cell death protein 1 (PD-1) or its ligand (PD-L1) monoclonal antibody combined with bevacizumab (a monoclonal antibody targeting vascular endothelial growth factor) has been established as first-line systemic treatment for advanced hepatocellular carcinoma (HCC). Radiotherapy is a crucial local treatment for HCC. Mutual efficacy enhancement has been reported between radiotherapy, anti-angiogenesis therapy and immunotherapy in preclinical researches, but not been validated in clinical practice. Whether radiotherapy can enhance efficacy of anti-PD-1 immunotherapy plus bevacizumab for HCC remains unclear. This retrospective observational study aimed to appraise efficacy and safety of the combination of radiotherapy with pembrolizumab (a PD-1 monoclonal antibody) and bevacizumab for advanced HCC for the first time.MethodsPatients with advanced HCC treated by intrahepatic tumor-directed moderately hypo-fractionated radiotherapy combined with pembrolizumab and bevacizumab were consecutively included. Clinicopathological characteristics, therapeutic outcomes and treatment-related adverse events (TRAEs) were recorded and evaluated.ResultsA total of 23 patients were eventually enrolled. Median cycles of pembrolizumab and bevacizumab were 4 (median, 1–8) and 4 (median, 1–9) cycles. The objective response rates and disease control rates of irradiated intrahepatic HCC and non-irradiated extrahepatic HCC were 34.8% [95% confidence interval (CI), 16.4–57.3%] vs. 10.0% (95% CI, 1.2–31.7%), and 91.3% (95% CI, 72.0–98.9%) vs. 70.0% (95% CI, 45.7–88.1%), respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.6 (95% CI, 4.7–8.5) and 18.3 (95% CI, 8.2–33.6) months, and 12-month PFS and OS rates were 17.5% (95% CI, 7.0–28.0%) and 60.9% (95% CI, 50.7–71.1%). Two patients (8.7%) with locally advanced, unresectable HCC eventually underwent curative resection of tumors after this trimodal treatment. Eighteen patients (78.3%) had ≥ grade 3 TRAEs, with myelosuppression and transaminase increase as the most common.ConclusionsThis study firstly reported that combining radiotherapy with pembrolizumab and bevacizumab was preliminarily a feasible and effective therapeutic choice for advanced HCC in despite of more TRAEs. This tri-modal regimen may be a potential conversion therapy for unresectable, locally advanced HCC. The limitations of this study are its retrospective nature and small sample size; therefore, big-sample prospective studies are warranted to further investigate this tri-modal regimen.

Background:Many clinical studies have demonstrated the survival benefits of oxaliplatin-based chemotherapy for advanced hepatocellular carcinoma patients. Therefore, we aim to evaluate the efficacy and safety of oxaliplatin-based chemotherapy in patients with advanced hepatocellular carcinoma by conducting a meta-analysis of prospective studies.Methods:A comprehensive literature search was performed using the PubMed, Cochrane Library, EMBASE, and Web of Science databases from their inception to June 2016. Only prospective studies evaluating oxaliplatin-based chemotherapy in patients with advanced hepatocellular carcinoma were selected. The main outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and main adverse events.Results:Ten prospective studies involving 525 patients were included. The pooled ORR, 1-year PFS, and OS were 14.4% (95% confidence interval [CI] 9.2–19.6%), 9.3% (95%CI 10–28%), and 35.7% (95%CI 27–44%), respectively, for oxaliplatin-based chemotherapy. The median PFS and OS were 4.7 and 9.4 months, respectively. The incidences of grade 3/4 toxicities of neutropenia, thrombopenia, anemia, neurotoxicity, diarrhea, and nausea/vomiting were 17.2%, 9.2%, 6.0%, 4.8%, 3.1%, and 1.8%, respectively. Subgroup analysis revealed that the pooled ORR was 13.9% (95%CI 6.8–21%) in Asian patients and 12.8% (95%CI 6.8–18.7%) in Western patients. For Asian patients, the median PFS and OS were 4.2 and 9.2 months, and the 1-year PFS and OS were 12.5% and 30.5%, respectively. For Western patients, the median PFS and OS were 4.7 and 9.5 months, and the 1-year PFS and OS were 19.6% and 42.4%, respectively. There were no significant differences in the ORR, 1-year PFS, and OS (P > 0.05) between Asian and Western patients.Conclusions:Oxaliplatin-based chemotherapy appears to be effective and safe for the treatment of advanced hepatocellular carcinoma.

TPS4193 Background: The combination of anti-angiogenesis and immune checkpoint blockade showed promising outcomes for advanced hepatocellular carcinoma (HCC). Hepatic artery infusion chemotherapy (HAIC) combined with apatinib and camrelizumab could augment treatment efficacy in preliminary study. But HAIC has disadvantages such as technical limitations, expensive cost, impaired liver function and poor patient comfort. Results from our previous phase II trial (NCT05412589) demonstrate that the triplet treatment of Venous Infusional FOLFOX plus camrelizumab and apatinib showed inspiring antitumor activity and acceptable safety for CNLC stage Ⅲ HCC, especially in those with main portal trunk invasion (Vp4). These results encourage us to further compare the efficacy and safety of intravenous FOLFOX with apatinib and camrelizumab versus HAIC-FOLFOX with apatinib and camrelizumab as first-line treatment in advanced HCC. Methods: This multicenter, randomized, open-label, non-inferiority phase 3 study (NCT06172205) will enroll 192 patients. Essential criteria for patient inclusion encompassed: age between 18 and 75 years; a clinical diagnosis conforms to primary hepatocellular carcinoma (HCC); classification with in BCLC stage C; no prior anti-tumor treatment exposure; presence of at least one measurable tumor as per RECIST v1.1; ECOG performance status score of either 0 or 1; and a Child-Pugh A or B. Eligible patients were randomized (1:1) into two groups. Randomization is stratified by the presence of macrovascular invasion or extrahepatic metastasis (yes vs no), and baseline alpha-fetoprotein concentration (<400 ng/mL vs ≥400 ng/mL). There are 2 arms in the study: (1) Arm A: FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2,5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 46 hours; q3w; up to 6 cycles) intravenously in combination with apatinib (250 mg po qd) and camrelizumab (200 mg iv q3w). (2) Arm B: hepatic arterial infusion FOLFOX (oxaliplatin, leucovorin and 5-fluorouracil q3w; up to 6 cycles), combined with apatinib (250 mg po qd) and camrelizumab (200 mg iv q3w). The primary endpoint is 6-month progression-free survival (PFS) rate according to RECIST v1.1. Secondary outcomes encompass the Objective response rate, Disease control rate, Duration of response, PFS, Overall survival (OS), along with 12-month PFS rate, 6-month and 12-month OS rates. The additional secondary endpoints include assessment of treatment-related adverse events. With the assumption of a median 6-month PFS rate of 85% in the Arm B and 71% in the Arm A (noninferiority margin, 14%), a total of 162 patients were required under a two-sided 5% significance level and 80% power. Allowing a dropout rate of 15%, we aimed to enroll 192 patients. The trial is currently screening eligible patients. Clinical trial information: NCT06172205 .

Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

BCR-ABL1 Transcript of 7.93% at 3 Months Is an Early Predictor for Long-Term Survival to Second-Line Therapy Using Next Generation Tyrosine Kinase Inhibitors in Imatinib-Resistant Chronic Phase Chronic Myeloid Leukemia

Introduction: The tyrosine kinase inhibitors regorafenib and cabozantinib remain the mainstay in second-line treatment of advanced hepatocellular carcinoma (HCC). There is currently no clear evidence of superiority in efficacy or safety to guide choice between the two treatments. Methods: We conducted an anchored matching-adjusted indirect comparison using individual patient data from the RESORCE trial of regorafenib and published aggregate data from the CELESTIAL trial of cabozantinib. Second-line HCC patients with prior sorafenib exposure of ≥3 months were included in the analyses. Hazard ratios (HRs) and restricted mean survival time (RMST) were estimated to quantify differences in overall survival (OS) and progression-free survival (PFS). Safety outcomes compared were rates of grade 3 or 4 adverse events (AEs), occurring in >10% of patients, and discontinuation or dose reduction due to treatment-related AEs. Results: After matching adjustment for differences in baseline patient characteristics, regorafenib showed a favorable OS (HR, 0.80; 95% CI: 0.54, 1.20) and ∼3-month-longer RMST over cabozantinib (RMST difference, 2.76 months; 95% CI: −1.03, 6.54), although not statistically significant. For PFS, there was no numerical difference in HR (HR, 1.00; 95% CI: 0.68, 1.49) and no clinically meaningful difference based on RMST analyses (RMST difference, −0.59 months; 95% CI: −1.83, 0.65). Regorafenib showed a significantly lower incidence of discontinuation (risk difference, −9.2%; 95% CI: −17.7%, −0.6%) and dose reductions (−15.2%; 95% CI: −29.0%, −1.5%) due to treatment-related AEs (any grade). Regorafenib was also associated with a lower incidence (not statistically significant) of grade 3 or 4 diarrhea (risk difference, −7.1%; 95% CI: −14.7%, 0.4%) and fatigue (−6.3%; 95% CI: −14.6%, 2.0%). Conclusion: This indirect treatment comparison suggests, relative to cabozantinib, that regorafenib could be associated with favorable OS (not statistically significant), lower rates of dose reductions and discontinuation due to treatment-related AEs, and lower rates of severe diarrhea and fatigue.