Search Results (77)

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide. Advances in screening, diagnosis, and management have transformed clinical practice, particularly with the integration of immunotherapy and target therapies. Methods: A systematic literature search was carried out for the period between October 2016 to September 2024. Phase II and III randomized trials evaluating ICI monotherapy, ICI–chemotherapy combinations, and dual ICI regimens in patients with advanced NSCLC were included. Outcomes of interest included overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). Results: PD-1-targeted therapies demonstrated superior OS compared to PD-L1-based regimens, with cemiplimab monotherapyranking highest for OS benefit (posterior probability: 90%), followed by sintilimab plus platinum-based chemotherapy (PBC) and pemetrexed—PBC. PFS atezolizumab plus bevacizumab and PBC, and camrelizumab plus PBC were the most effective regimens. ICI–chemotherapy combinations achieved higher ORRs but were associated with greater toxicity. The most favorable safety profiles were observed with cemiplimab, nivolumab, and avelumab monotherapy, while atezolizumab plus PBC and sugemalimab plus PBC carried the highest toxicity burdens. Conclusions: In PD-L1-unselected advanced NSCLC, PD-1 blockade—particularly cemiplimab monotherapy—and rationally designed ICI–chemotherapy combinations represent the most efficacious treatment strategies. Balancing efficacy with safety remains critical, especially in the absence of predictive biomarkers. These findings support a patient-tailored approach to immunotherapy and highlight the need for further biomarker-driven and real-world investigations to optimize treatment selection. Full article

Background: Accurately determining pediatric dosing is essential prior to initiating clinical trials or administering medications in routine clinical settings. In children, ethical considerations demand careful evaluation of both safety and effectiveness. Typically, dosing recommendations for therapeutic proteins, such as monoclonal antibodies (mAbs), are derived from adult dosages using body weight as a scaling factor. However, this method overlooks key physiological and biochemical distinctions between pediatric and adult patients. Therefore, this could lead to the underexposure of mAbs, limiting their efficacy in this population. Additional methods are necessary to predict pediatric doses mechanistically. For small molecules, physiologically based pharmacokinetic (PBPK) models have been extensively used to predict pediatric doses based on physiological age-related changes and enzymes/transporters ontogeny. This study aims to evaluate the ability of PBPK models to predict mAbs’ pediatric exposure. Methods: Three mAbs were used for model development and validation: bevacizumab, infliximab, and atezolizumab. The PBPK models were built using GastroPlus^© Biologics module. For each mAb, the PBPK model was developed based on observed data in healthy and/or patient adults. Then, the physiological parameters were scaled to describe the pediatric physiology to predict exposure to the pediatric populations. Predicted plasma concentration–time courses were overlaid with reported observed data to assess the ability of the PBPK model to predict pediatric exposure. Results: Results showed that PBPK models accurately predicted pediatric pharmacokinetics for mAbs. Conclusions: This research marks a significant step in validating mechanistic extrapolation methods for biologics exposure prediction in children using PBPK models. Full article

Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a leading cause of cancer-related mortality worldwide. Its often-silent progression results in late-stage diagnosis, limiting curative options and necessitating systemic therapy for many patients. The presence of underlying cirrhosis in most cases further complicates treatment decisions. While the approval of sorafenib in 2007 marked a major milestone in systemic therapy for HCC, the treatment landscape has since evolved significantly, particularly with the advent of immune checkpoint inhibitors and anti-angiogenic agents. Combination regimens, such as atezolizumab plus bevacizumab, have demonstrated superior outcomes and are now considered standard first-line options. Despite these advances, efforts to translate insights from HCC’s molecular pathogenesis into personalized treatments have been limited. This narrative review explores the current systemic therapy options for HCC, from first-line to subsequent-line treatments, and highlights emerging strategies, including novel immunotherapies and targeted agents. We emphasize the need for individualized treatment approaches that consider tumor biology, liver function, and performance status, and we outline future directions for research aimed at improving outcomes in this complex and evolving field. Full article

Objective: This study aimed to evaluate the characteristics, clinical outcomes, and resource use of patients with unresectable hepatocellular carcinoma (uHCC) treated with first-line (1L) atezolizumab plus bevacizumab (A+B) at five United States (US) institutions: the Mayo Clinic, Houston Methodist, Moffitt Cancer Center, Mays Cancer Center, and University of Arizona. Methods: Treating oncologists extracted data from medical charts of patients with uHCC who were treated with A+B after 1 January 2019. Real-world progression-free survival (rwPFS) and overall survival (OS) were assessed using the Kaplan–Meier method for the overall cohort and for a “trial-like” subgroup with characteristics similar to those in the IMbrave150 trial (Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0–1, Child–Pugh [CP] class A, albumin–bilirubin grade 1–2). Results: Of the 300 patients in the overall cohort (median age of 68 years; 12% ECOG PS ≥ 2; 73% CP A; 26% CP B; median follow-up of 8.7 months), the median rwPFS was 6.8 (95% confidence interval [CI]: 5.8, 8.4) months, and the median OS was 14.4 (95% CI: 12.3, 18.2) months. In the trial-like subgroup (n = 194), the median rwPFS was 8.8 (95% CI: 7.6, 12.1) months and the median OS was 19.5 (95% CI: 14.6, 24.7) months. A significantly lower proportion of patients with CP A compared with CP B (39.7% vs. 73.4%) experienced hospitalization within one year of A+B initiation, whereas hospitalizations due to treatment-related adverse events were similar. Conclusions: This study provides insights into the real-world effectiveness of 1L A+B in a diverse US patient cohort, with results from trial-like patients supporting the reproducible efficacy of A+B in clinical practice. Full article

Isolated intrahepatic lymphoid follicles (ILFs), also referred to as reactive lymphoid hyperplasia, are rare benign lymphoid proliferations that can closely mimic hepatocellular carcinoma (HCC) on imaging. This case highlights the diagnostic complexity of hepatic mass lesions in chronic hepatitis B patients, particularly when radiologic and serologic features raise concern for malignancy. A 60-year-old man with chronic hepatitis B presented with a liver mass, elevated alpha-fetoprotein levels, and imaging findings of heterogeneous arterial enhancement, all suggestive of HCC. Despite initial treatment with atezolizumab plus bevacizumab, the lesion progressed, leading to an extended left hepatectomy. Histopathological examination revealed well-formed lymphoid follicles with reactive germinal centers, without evidence of malignancy or granulomatous inflammation. Serum IgG was elevated, and ANA was positive, supporting the possibility of an underlying immune-mediated process. The patient showed clinical and serologic improvement following corticosteroid therapy, with no evidence of recurrence at 10-month follow-up. This case underscores the importance of histopathological confirmation in hepatic masses with atypical features and highlights the need to consider benign immune-related mimickers in the differential diagnosis, particularly in the era of immunotherapy. Full article

Over the past several years, the therapeutic landscape for patients with advanced, unresectable, or metastatic hepatocellular carcinoma has been transformed by the incorporation of checkpoint inhibitor immunotherapy into the treatment paradigm. Frontline systemic treatment options have expanded beyond anti-angiogenic tyrosine kinase inhibitors, such as sorafenib, to a combination of immunotherapy approaches, including atezolizumab plus bevacizumab and durvalumab plus tremelimumab, both of which have demonstrated superior response and survival to sorafenib. Additionally, combination treatments with checkpoint inhibitors and tyrosine kinase inhibitors have been investigated with variable success. In this review, we discuss these advances in systemic treatment with immunotherapy, with a focus on understanding both the underlying biology and mechanism of these strategies and their efficacy outcomes in clinical trials. We also review challenges in identifying predictive biomarkers of treatments and discuss future directions with novel immunotherapy targets. Full article

Hepatocellular carcinoma (HCC), a liver cancer originating from hepatocytes, is a major health concern and among the most common malignancies worldwide. Sorafenib, approved by the U.S. F.D.A., is the primary first-line treatment for patients with advanced HCC. While the preferred first-line systemic regimen for HCC is immunotherapy with Atezolizumab plus bevacizumab or Tremelimumab-actl + durvalumab, Sorafenib is still an alternative recommended regimen. While some patients with advanced HCC may benefit from Sorafenib treatment, most eventually develop resistance, leading to poor prognosis. Long noncoding RNAs (lncRNAs) have been found to play a critical role in tumorigenesis and the development of HCC, as well as other cancers. They are also key players in tumor drug resistance, though the mechanisms of lncRNAs in Sorafenib resistance in HCC remain poorly understood. This review summarizes the molecular mechanisms contributing to Sorafenib resistance in HCC with their potential correlation with lncRNAs, including the roles of transporters, receptors, cell death regulation, and other influencing factors. Full article

Background and Aims: Treatment with atezolizumab and bevacizumab has been approved as one of the standards of care for patients with advanced hepatocellular carcinoma (HCC). The median overall survival (OS) upon available treatments still remains below 2 years, urgently suggesting better stratification tools to identify ideal candidates for this treatment and potentially allowing personalized approaches. In this study, we evaluated the potential role of extracellular vesicles (EVs) as a novel biomarker in patients receiving atezolizumab and bevacizumab for HCC. Methods: We characterized EVs in 212 longitudinal serum samples from an observational cohort of 53 individuals with advanced HCC, who started therapy with atezolizumab plus bevacizumab at our center between January 2020 and March 2022. Results: In our cohort, the overall efficacy of atezolizumab and bevacizumab was comparable to previously published phase III data. We detected significantly smaller EVs in treatment responders, while enlarged EVs were associated with significantly decreased efficacy of atezolizumab and bevacizumab in terms of OS. A decrease in vesicle size during immunotherapy was related to a longer progression-free survival (PFS). A univariate Cox regression analysis including various clinicopathological parameters (e.g., tumor stage, markers of inflammation, organ dysfunction, or tumor markers) revealed vesicle size as an independent prognostic marker in HCC patients receiving atezolizumab and bevacizumab. Moreover, higher vesicle concentrations and lower zeta potentials were identified as a positive prognostic factor throughout treatment. Conclusions: Distinct EV characteristics such as vesicle size, concentration, and zeta potential represent promising novel biomarkers in patients with advanced HCC receiving atezolizumab and bevacizumab, potentially helping to identify optimal candidates for checkpoint inhibitor-based treatments. Full article

Background/Objectives: Reliable biomarkers for predicting outcomes in hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Ate/Bev) are still lacking. Cytokines, which play a crucial role in immune regulation and HCC progression, have potential as predictive markers, but data supporting their use are limited. This study aimed to evaluate the impact of early changes in cytokine levels on the clinical outcomes of advanced HCC patients. Methods: We prospectively enrolled 32 advanced HCC patients, collecting blood samples before the first and second Ate/Bev treatments. These samples were analyzed for IL-2, IL-6, IL-10, IL-12, IL-17, IFN-γ, and TNF-α levels to assess changes post-treatment. The primary outcome was overall survival, with a secondary focus on progression-free survival (PFS) at 6 months. Results: The mean age of the participants was 64.2 years, with the majority being male (93.8%). Patients showing increased IL-10, IL-17, and TNF-α levels had significantly better survival (p < 0.05) and marginally improved PFS compared to those with decreased cytokine levels. Interestingly, a positive correlation was noted between changes in IL-10 and TNF-α levels (p = 0.009). Furthermore, a multivariable analysis revealed that increased levels of IL-10 and TNF-α were significant predictors of enhanced survival (hazard ratio, 0.07; 95% confidence interval, 0.01–0.46; p = 0.005). Conclusions: An early increases in IL-10 and TNF-α after Ate/Bev treatment may serve as effective biomarkers for clinical outcomes in advanced HCC patients. Full article

Background/Objectives: This study evaluated comparative overall survival (OS) of United States veterans with unresectable hepatocellular carcinoma (uHCC) receiving first-line (1L) atezolizumab plus bevacizumab vs. sorafenib or lenvatinib, overall and across racial and ethnic groups. Methods: In this retrospective study, patients with uHCC who initiated atezolizumab plus bevacizumab (post-2020) or sorafenib or lenvatinib (post-2018) were identified from the Veterans Health Administration National Corporate Data Warehouse (1 January 2017–31 December 2022). Patient characteristics were evaluated in the year prior to 1L treatment initiation. Kaplan–Meier and multivariable Cox regression methods were used to compare OS starting from treatment between cohorts, both overall and by race and ethnicity. Results: Among the 1874 patients included, 405 (21.6%) received 1L atezolizumab plus bevacizumab, 1016 (54.2%) received sorafenib, and 453 (24.2%) received lenvatinib, with a median follow-up time of 8.5, 7.6, and 8.2 months, respectively. Overall, patients receiving atezolizumab plus bevacizumab had longer unadjusted median OS (12.8 [95% CI: 10.6, 17.1] months) than patients receiving sorafenib (8.0 [7.1, 8.6] months) or lenvatinib (9.5 [7.8, 11.4] months; both log-rank p < 0.001). After adjustment, atezolizumab plus bevacizumab was associated with a reduced risk of death by 30% vs. sorafenib (adjusted HR: 0.70 [95% CI: 0.60, 0.82]) and by 26% vs. lenvatinib (0.74 [0.62, 0.88]; both p < 0.001). OS trends in the White, Black, and Hispanic patient cohorts were consistent with that of the overall population. Conclusions: Atezolizumab plus bevacizumab was associated with improved survival outcomes compared with sorafenib and lenvatinib in patients with uHCC, both overall and across racial and ethnic subgroups. Full article

Background: The combination of anti-angiogenic therapy and immune checkpoint inhibitors has revolutionized the management of unresectable hepatocellular carcinoma (uHCC). While an early-phase study demonstrated promising outcomes for lenvatinib plus pembrolizumab (L+P) in treating uHCC, the LEAP-002 trial did not meet its primary endpoint. However, the comparative efficacy between L+P and atezolizumab plus bevacizumab (A+B) as first-line treatment remains a topic of uncertainty. This study aimed to assess the effectiveness and safety of L+P in contrast to A+B among patients diagnosed with uHCC. Methods: We conducted a retrospective analysis of enrolled patients with uHCC who received L+P or A+B as initial systemic treatment at Chang Gung Memorial Hospital from June 2019 to December 2022. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) by modified RECIST were compared. Results: 121 patients were recruited, with 37 receiving L+P and 84 receiving A+B. Among them, 95 (78.5%) patients were BCLC stage C, and 99 (81.8%) patients had viral etiology for HCC, predominantly chronic HBV (68.6%). Both the L+P and the A+B groups demonstrated comparable OS (18.2 months versus 14.6 months, p = 0.35) and PFS (7.3 months versus 8.9 months, p = 0.75). The ORR and DCR were similar. After propensity score matching, the results remained consistent between the matched patients. Treatment-related adverse events of any grade occurred in 30 (81.1%) in the L+P group and 62 (73.8%) in the A+B group. Conclusions: Our findings suggest that L+P and A+B exhibit comparable efficacy and safety profiles in real-world settings. Full article

Atezolizumab and bevacizumab show promise for treating hepatocellular carcinoma (HCC), but identifying responsive patients remains challenging, due to tumor heterogeneity. This study explores immune dynamics following this combination therapy. Between 2020 and 2023, 29 patients with advanced HCC who received atezolizumab plus bevacizumab at Severance Hospital, Seoul, were enrolled in this study. Peripheral blood mononuclear cells were analyzed using flow cytometry and statistical methods to assess immune alterations and identify biomarkers. Baseline characteristics showed a diverse HCC cohort with a mean age of 64 years and 82.8% male predominance. Absence of extrahepatic metastasis was associated with better overall survival. Immune responses revealed distinct CD4⁺ T-cell phenotypes between the ‘partial response (PR) + stable disease (SD)’ and ‘progressive disease (PD)’ groups, with an overall increase in CD8⁺ T-cell phenotypes. Patients with higher frequencies of CD8⁺PD-1⁺Ki-67⁺ T cells experienced significantly improved overall survival, while those with lower frequencies of CD4⁺Foxp3⁺PD-1⁺LAG3⁺ T cells also had notable survival benefits. These findings enhance the overall understanding of immune responses to this combination therapy, facilitating improved patient stratification and personalized therapeutic approaches for HCC. Full article

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. Full article

This retrospective study aimed to evaluate the impact of atezolizumab plus bevacizumab–transcatheter arterial chemoembolization (TACE) sequential therapy in unresectable hepatocellular carcinoma (HCC), especially in patients with intermediate-stage HCC. A total of 212 patients were enrolled and categorized into the Atez/Bev-TACE sequential therapy (n = 23) or Atez/Bev monotherapy group (n = 189) between 2020 and 2024. Of these, patients with intermediate-stage HCC were categorized into the Atez/Bev-TACE sequential (n = 18) or Atez/Bev monotherapy group (n = 91). The best objective response rate, disease control rate, and median progression-free survival (PFS) after TACE were 73.9%, 82.6%, and 6.1 months, respectively. The PFS after TACE was significantly higher in the Atez/Bev sequential therapy group than in the no-Atez/Bev-administration group after TACE (6.9 months vs. 5.0 months, p = 0.025). The median overall survival (OS) was significantly higher in the Atez/Bev-TACE sequential therapy group than in the Atez/Bev monotherapy group for intermediate-stage HCC (34.9 months vs. 17.8 months; p = 0.016). Independent factors associated with OS were low alpha-fetoprotein levels, modified albumin–bilirubin 1 or 2a levels, and Atez/Bev-TACE sequential therapy. Atez/Bev-TACE sequential therapy improved prognosis compared with Atez/Bev monotherapy in patients with intermediate-stage HCC. Moreover, Atez/Bev should be readministered after TACE. Full article

To assess the impact of adverse event (AE) severity, caused by targeted therapy, on overall survival (OS) and progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (HCC), a total of 183 patients with HCC treated with atezolizumab plus bevacizumab (40), lenvatinib (57), sorafenib (79), cabozantinib (3), ramucirumab (3), and regorafenib (1) were included in this study. Age-, AFP-, and ALBI score-adjusted hazard ratios (HRs) of AE grades 1 to 3 versus grade 0 for OS and PFS were calculated using Cox proportional hazards models. The linear trend of the HRs was assessed by calculating the p values for this trend. The most common AEs were appetite loss (AE grade 0/1/2/3 = 97/23/55/12), general fatigue (102/31/44/6), hypertension (120/6/40/17), hand-foot syndrome (HFS) (135/21/24/3), proteinuria (140/13/16/14), and hypothyroidism (148/12/23/0). The adjusted HRs for OS of these AEs were 0.532–1.450–2.361 (p for trend 0.037), 1.057–1.691–3.364 (p for trend 0.004), 1.176–0.686–0.281 (p for trend 0.002), 0.639–0.759–1.820 (p for trend 0.462), 1.030–0.959–0.147 (p for trend 0.011), and 0.697–0.609 (p for trend 0.119), respectively. Those for PFS of the corresponding AEs were 0.592–1.073–2.811 (p for trend 0.255), 1.161–1.282–4.324 (p for trend 0.03), 0.965–0.781–0.655 (p for trend 0.095), 0.737–0.623–2.147 (p for trend 0.153), 1.061–0.832–0.800 (p for trend 0.391), and 1.412–0.560 (p for trend 0.081), respectively. Appetite loss and general fatigue negatively affected clinical outcomes, whereas hypertension, HFS, proteinuria, and hypothyroidism had positive effects. Full article