Changes in Posttreatment Spleen Volume Associated with Immunotherapy Outcomes for Advanced Hepatocellular Carcinoma.

Purpose: We investigated whether spleen volume (SV) changes were associated with treatment outcomes in advanced hepatocellular carcinoma (HCC) patients who received immunotherapy or first-line sorafenib. Patients and Methods: Patients with advanced HCC who underwent immunotherapy or first-line sorafenib at our institute were retrospectively analyzed. CT was used to measure SV before and within 3 months of treatment initiation. Tumor assessment followed Response Evaluation Criteria in Solid Tumors version 1.1. The association between SV change and tumor response or progression-free survival (PFS) was analyzed. The inverse probability of treatment weighting (IPTW) was used to adjust for differences in baseline characteristics. Results: The immunotherapy group comprised 143 patients (124 men, mean age, 59.8 years ± 11.2 [standard deviation]), while the sorafenib group had 57 (47 men, mean age, 59.6 years ± 9.9). SV increased in 108 (75.5%) immunotherapy and 21 (36.8%) sorafenib patients. In the immunotherapy group, patients with increased SV were more likely than those with decreased SV to have a higher disease control rate (76.9% vs 57.1%, p = 0.024) and durable clinical benefit (52.8% vs 25.7%, p = 0.005). It was also associated with extended PFS in the immunotherapy group in both the univariate (p = 0.028) and multivariate (p = 0.014) analysis. By contrast, in the sorafenib group, an increased in SV was not associated with treatment response but was presumably associated with reduced PFS (p = 0.072) in the multivariate analysis. After IPTW adjustment, the increase in SV remained a significant predictor for DCB and PFS in the immunotherapy group. Conclusion: Most patients exhibited an increase in SV after the initiation of immunotherapy, which may be used to predict response and prognosis. However, this association was not observed in patients who received sorafenib.

The study provides significant evidence that an increase in spleen volume is associated with better treatment outcomes in advanced hepatocellular carcinoma patients undergoing immunotherapy. These findings offer oncologists a new potential biomarker for optimizing treatment strategies. Specifically, increased spleen volume could be used to predict higher rates of disease control and durable clinical benefits, allowing for more personalized care.

Effects of Early Short-Course Corticosteroids on Immune-Related Adverse Events in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

INTRODUCTION: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown. METHODS: Between January 1st, 2015, and December 31st, 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterward. The patients were categorized as either "corticosteroid group" or "non-corticosteroid group" depending on their exposure to early short-course corticosteroid. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed. RESULTS: Among 252 eligible patients, 137 patients were categorized as "corticosteroid group" and 115 patients as "non-corticosteroid group." The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35-1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12-0.85; p = 0.013). CONCLUSION: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that lead to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs.

Disparity in survival benefits of pembrolizumab between Asian and non-Asian patients with advanced cancers: A systematic review and meta-regression analysis.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of malignancies. However, disproportionate enrollment among races and ethnicities places the generalizability of global trial results in doubt. METHODS: In this systematic review, phase 3 randomized controlled trials investigating pembrolizumab in advanced cancers and providing subgroup analyses of Asian and non-Asian participants were included. The primary and secondary effect measures were the mean differences (MDs) in the natural logarithms of the hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) between these two subgroups, respectively. We used random-effects meta-analysis to calculate the pooled ratios of HRs (i.e., exp(MD)) and implemented a meta-regression analysis to identify significant covariates. RESULTS: A total of 17 and 11 trials were included in the meta-analyses of OS and PFS, respectively. These trials included 2732 (25.49%) Asian and 7000 (65.32%) non-Asian participants in the OS analysis and 1438 (22.5%) Asian and 4129 (64.61%) non-Asian participants in the PFS analysis. The pooled ratio of HRs for OS was 0.87 (95% CI: 0.76-0.99; p = 0.0391), favoring Asian participants, but no significant difference was found in PFS (pooled ratio of HRs: 0.93; 95% CI: 0.82-1.07; p = 0.2391). Both linear meta-regression analyses revealed an open-label design as a crucial covariate, which indicated more benefits for non-Asian participants. CONCLUSIONS: Compared with non-Asian patients, Asian patients with advanced cancers may derive superior OS benefits from pembrolizumab. Although the results warrant further exploration, this meta-analysis provides insight into clinical research design.

Sarcopenia and myosteatosis are associated with survival in patients receiving immunotherapy for advanced hepatocellular carcinoma.

OBJECTIVES: To investigate the association of sarcopenia, myosteatosis, and sarcopenic obesity with survival outcomes among patients who underwent immunotherapy for advanced hepatocellular carcinoma (HCC). METHODS: In this retrospective analysis, patients who initiated immunotherapy for advanced HCC were enrolled. Sarcopenia and myosteatosis were evaluated on pretreatment CT at L3 level by skeletal muscle index and mean muscle attenuation using predefined cutoff values. Sarcopenic obesity was defined as concurrent sarcopenia and body mass index > 25 kg/m2. The log-rank test and the Cox proportional hazards model were used to compare overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 138 patients was included (discovery cohort n = 111, validation cohort n = 27). In the discovery cohort, patients with sarcopenia exhibited significantly poorer PFS (p = 0.048) and OS (p = 0.002) than patients without sarcopenia. Patients with myosteatosis exhibited significantly poorer PFS (p < 0.001) and OS (p < 0.001) than patients without myosteatosis. Patients with sarcopenic obesity compared to patients without sarcopenic obesity exhibited significantly poorer OS (p = 0.006) but not PFS (p = 0.31). In multivariate analysis adjusting for patient demographics, tumor extent, and liver function reserve, myosteatosis remained an independent predictor of poor PFS (p = 0.014) and OS (p = 0.007); sarcopenia remained an independent predictor for poor OS (p = 0.007). The prediction models for survival outcomes built by the discovery cohort showed similar performance in the validation cohort. CONCLUSIONS: Sarcopenia and myosteatosis are independent prognostic factors in patients who received immunotherapy for advanced HCC. KEY POINTS: • Sarcopenia and myosteatosis can be evaluated by CT at L3 level. • Sarcopenia, myosteatosis, and sarcopenic obesity were associated with poor survival outcomes in patients who underwent immunotherapy for advanced HCC. • Myosteatosis was an independent predictor of PFS and OS, and sarcopenia was independent for OS in these patients.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Immune checkpoint inhibitors for hepatocellular carcinoma - A game changer in treatment landscape.

Rapidly expanding armamentarium of systemic therapy for advanced hepatocellular carcinoma (HCC) occurred in the recent few years. Multikinase inhibitors (MKI) or targeted therapy with antiangiogenic properties have been the focus of clinical studies in advanced HCC in the past decade. The remarkable efficacy of single agent immune checkpoint inhibitors (ICI), including nivolumab and pembrolizumab, in early phase studies led to accelerated approvals as second-line treatment for advanced HCC. The excellent toxicity profile of single agent ICI also lends support to be developed as combination therapy with other targeted therapies. The success of combining atezolizumab and bevacizumab over sorafenib as the first-line treatment in advanced HCC marked the newest paradigm shift in advanced HCC. The combination exhibited unprecedented objective response rate of 30% and a median survival of 19.2 months. Many other similar ICI-based combinations are expected to be approved in the foreseeable future. In this narrative review, the development of ICI alone and in combination in advanced HCC were described and the potential impact in all stages of HCC, safety issues of ICI-based combinations, and future perspectives were discussed.

Targeting CD38 and PD-1 with isatuximab plus cemiplimab in patients with advanced solid malignancies: results from a phase I/II open-label, multicenter study.

BACKGROUND: Preclinical data suggest that concurrent treatment of anti-CD38 and antiprogrammed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies substantially reduce primary tumor growth by reversing T-cell exhaustion and thus enhancing anti-PD-1/PD-L1 efficacy. METHODS: This phase I/II study enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of phase I were to investigate the safety and tolerability of isatuximab (anti-CD38 monoclonal antibody)+cemiplimab (anti-PD-1 monoclonal antibody, Isa+Cemi) in patients with mCRPC (naïve to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase II used Simon's two-stage design with response rate as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) patients receiving Isa+Cemi were enrolled in phase II. Safety, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, and tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping. RESULTS: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. All patients experienced ≥1 treatment-emergent adverse event. Grade≥3 events occurred in 13 (54.2%) patients with mCRPC and 12 (60.0%) patients with NSCLC. Based on PCWG3 criteria, assessment of best overall response with Isa+Cemi in mCRPC revealed no complete responses (CRs), one (4.2%) unconfirmed partial response (PR), and five (20.8%) patients with stable disease (SD). Per RECIST V.1.1, patients with NSCLC receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. In post-therapy biopsies obtained from patients with mCRPC or NSCLC, Isa+Cemi treatment resulted in a reduction in median CD38+ tumor-infiltrating immune cells from 40% to 3%, with no consistent modulation of PD-L1 on tumor cells or T regulatory cells in the TME. The combination triggered a significant increase in peripheral activated and cytolytic T cells but, interestingly, decreased natural killer cells. CONCLUSIONS: The present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, such CD38 inhibition was not associated with significant antitumor activity. A lack of efficacy was observed in these small cohorts of patients with mCRPC or NSCLC. TRIAL REGISTRATION NUMBERS: NCT03367819.

Limited Predictive or Prognostic Role of Tumor-Infiltrating Tissue-Resident Memory CD8 T Cells in Patients with Hepatocellular Carcinoma Receiving Immunotherapy.

PURPOSE: Tumor-infiltrating tissue-resident memory CD8 T cells (CD8 TRM; CD103+ CD8+) are considered tumor-specific and may correlate better with the tumor response to immune checkpoint blockade (ICB). This study evaluated the association of tumor-infiltrating CD8 TRM and their subsets with the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Consecutive HCC patients who received ICB in prospective trials were analyzed. Formalin-fixed paraffin-embedded tumor sections were stained for DAPI, CD8, CD103, CD39, programmed cell death-1 (PD-1), and programmed cell death ligand 1 (PD-L1) using a multiplex immunohistochemical method. The densities of CD8 T cells, CD8 TRM, and CD39+ or PD-L1+ subsets of CD8 TRM were correlated with tumor response and overall survival (OS). RESULTS: A total of 73 patients were identified, and 48 patients with adequate pretreatment tumor specimens and complete follow-up were analyzed. A median of 32.7% (range: 0-92.6%) of tumor-infiltrating CD8 T cells were TRM. In subset analyses, 66.6% ± 34.2%, 69.8% ± 33.4%, and 0% of CD8 TRM cells coexpressed CD39, PD-L1, and PD-1, respectively. The objective response rates for CD8 T cell-high, CD8 TRM-high, CD39+ CD8 TRM-high, and PD-L1+ CD8 TRM-high groups were 41.7%, 37.5%, 37.5%, and 29.2%, respectively. Patients with CD8 T cell-high, but not those with CD8 TRM-high, CD39+ CD8 TRM-high, or PD-L1+ CD8 TRM-high, tumors, had significantly prolonged OS (p = 0.0429). CONCLUSIONS: Compared with total tumor-infiltrating CD8 T cells, tumor-infiltrating CD8 TRM or their subsets failed to provide additional advantages in predicting the efficacy of immunotherapy for HCC.

An Exploratory Study for the Association of Gut Microbiome with Efficacy of Immune Checkpoint Inhibitor in Patients with Hepatocellular Carcinoma.

BACKGROUND: Gut microbiome has been associated with the efficacy of immune checkpoint inhibitors (ICI) in patients with various types of cancers but not yet in hepatocellular carcinoma (HCC). AIMS: To investigate the association between gut microbiome and efficacy of ICI in patients with HCC. METHODS: Patients with HCC who were scheduled to receive ICI were prospectively enrolled. Fecal samples were collected within 7 days before initiation of ICI (baseline) and 8 weeks later. Gut microbiome was assessed using 16S rRNA sequencing and shotgun whole-genome sequencing and correlated with objective response (complete or partial response), disease control (objective response or stable disease for ≥16 weeks), and overall survival. RESULTS: Thirty-six patients with HCC were enrolled, and 20 of them provided both baseline and 8-week feces. Alpha diversity, richness, and compositions of baseline gut microbiome indicated no difference between responders and nonresponders or between disease control and nondisease control groups. For the 20 paired feces, immunotherapy did not change any of the major microbiome features. No specific taxa were enriched in patients with objective response. Three taxa-Bifidobacterium, Coprococcus, and Acidaminococcus-were enriched in patients with disease control. However, the baseline abundance of these three taxa did not predict overall survival benefit. CONCLUSIONS: In this exploratory study, we failed to disclose any overt association of gut microbiome with the efficacy of ICI in patients with HCC. A larger prospective study is warranted for definite conclusion.

Evolution of systemic treatment for advanced hepatocellular carcinoma.

Advanced hepatocellular carcinoma (HCC) was considered an inherently refractory tumor in the chemotherapy era (1950-2000). However, systemic therapy has evolved to molecular targeted therapy and immunotherapy, and nine treatment regimens have been approved worldwide during the past 20 years. The approved regimens target tumor angiogenesis or tumor immunity, the two cancer hallmarks. Recently, the combination of atezolizumab (antiprogrammed cell death ligand 1) and bevacizumab (anti-vascular endothelial growth factor) has improved the efficacy of systemic therapy in treating advanced HCC without excessive toxicities or deterioration of quality of life. This review summarizes the major advances in systemic therapy and provides future perspectives on the next-generation systemic therapy for advanced HCC.

A Multicenter Phase II Study of Second-Line Axitinib for Patients with Advanced Hepatocellular Carcinoma Failing First-Line Sorafenib Monotherapy.

LESSONS LEARNED: For patients with advanced hepatocellular carcinoma after failure of first-line sorafenib monotherapy, second-line axitinib provides modest efficacy with tolerable toxicity. The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers. BACKGROUND: Multikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second-line axitinib for advanced HCC. METHODS: Patients with advanced HCC and Child-Pugh A liver function, experiencing progression on first-line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control. RESULTS: From April 2011 to March 2016, 45 patients were enrolled. Thirty-seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression-free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment-related adverse events were compatible with previous reports of axitinib. CONCLUSION: Second-line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first-line sorafenib monotherapy.

Reliability of a single-region sample to evaluate tumor immune microenvironment in hepatocellular carcinoma.

BACKGROUND & AIMS: Intratumor heterogeneity has frequently been reported in patients with hepatocellular carcinoma (HCC). Thus, the reliability of single-region tumor samples for evaluation of the tumor immune microenvironment is also debatable. We conducted a prospective study to analyze the similarity in tumor immune microenvironments among different regions of a single tumor. METHODS: Multi-region sampling was performed on newly resected tumors. The tumor immune microenvironment was evaluated by immunohistochemical staining of PD-L1, CD4, CD8, CD20, FoxP3, DC-LAMP (or LAMP3), CD68, MPO, and tertiary lymphoid structures (TLSs). PD-L1 expression was manually quantified according to the percentage of PD-L1-stained tumor or stromal cells. The densities (number/mm2) of immune cells and the number of TLSs per sample were determined by whole-section counting. RNA-sequencing was applied in selected samples. Similarities in tumor immune microenvironments within each tumor were evaluated by multivariate Mahalanobis distance analyses. RESULTS: Thirteen tumors were collected from 12 patients. The median diameter of tumors was 9 cm (range 3-16 cm). A median of 6 samples (range 3-12) were obtained from each tumor. Nine (69.2%) tumors exhibited uniform expression of PD-L1 in all regions of the tumor. Out of 13 tumors analyzed by immunohistochemical staining, 8 (61.5%) tumors displayed a narrow Mahalanobis distance for all regions within the tumor; while 8 (66.7%) of the 12 tumors analyzed by RNA-sequencing displayed a narrow Mahalanobis distance. Immunohistochemistry and RNA-sequencing had a high concordance rate (83.3%; 10 of 12 tumors) for the evaluation of similarities between tumor immune microenvironments within a tumor. CONCLUSIONS: A single-region tumor sample might be reliable for the evaluation of tumor immune microenvironments in approximately 60-70% of patients with HCC. LAY SUMMARY: Heterogeneity in the regional immune microenvironments of tumors has been reported in patients with hepatocellular carcinoma. This heterogeneity could be an obstacle when trying to reliably evaluate the immune microenvironment of an entire tumor using only a single-region tumor sample, which may be the only option in patients with more advanced disease. Our study utilized both immunohistochemical and transcriptomic analyses to demonstrate that a single-region sample is reliable for evaluation of tumor immune microenvironments in 60-70% of patients with hepatocellular carcinoma.

Differential Organ-Specific Tumor Response to Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Immune checkpoint inhibitors (ICIs) exhibit significant clinical activity in patients with advanced hepatocellular carcinoma (HCC). This study explored whether tumor response to ICIs in HCC varies among different organs. METHODS: We reviewed the data of patients with advanced HCC who had received ICIs. Patients with measurable diseases were enrolled. Organ-specific response criteria, adapted from RECIST 1.1 and immune-related RECIST, were used to evaluate the objective response to ICIs in tumors located in the liver, lung, lymph node, and other intra-abdominal sites. RESULTS: Of the 75 enrolled patients with advanced HCC, 51 and 11 patients had chronic hepatitis B virus and chronic hepatitis C virus infection, respectively. Regarding ICI treatment, 58, 1, and 16 patients had undergone anti-PD-1/anti-PD-L1 monoclonal antibody (mAb) alone, anti-CTLA4 mAb alone, and anti-PD-1 mAb plus anti-CTLA4 mAb, respectively; 20 and 55 patients had received ICIs as first-line or ≥second-line therapy. The overall objective response rate (ORR) was 28.0%. In total, 58, 34, 19, and 18 patients had measurable hepatic tumors and lung, lymph node, and other intra-abdominal metastases, and the corresponding organ-specific ORRs were 22.4, 41.2, 26.3, and 38.9%, respectively. Of the 39 patients who had both hepatic and extrahepatic tumors, 12 had disease control in extrahepatic tumors while progressive disease (PD) in hepatic tumors, whereas only 4 exhibited disease control in hepatic tumors while PD in extrahepatic tumors (p = 0.046, McNemar test). Of the 16 patients with only evaluable tumors in the liver and lungs at baseline, 8 had disease control in the lungs while PD in the liver, and none experienced disease control in the liver while PD in the lungs (p = 0.005). CONCLUSIONS: The hepatic tumors of HCC may be less responsive to ICIs than extrahepatic lesions. Lung metastases responded most favorably to ICIs. The mechanisms underlying this differential response to ICIs warrant further investigation.

Considerations of heterogeneity in clinical trials for hepatocellular carcinoma.

Introduction: Clinical trials in hepatocellular carcinoma (HCC) exhibit a high degree of heterogeneity. These heterogeneities may lead to unexpected results among clinical trials. Area covered: In this review, we address the heterogeneity noted in early phase HCC trials, trials involving transarterial chemoembolization, and advanced HCC trials. Furthermore, we discuss possible methods to attenuate the detrimental effects of heterogeneity when conducting clinical trials. Expert opinion: Clinical trials in HCC exhibit an inherently high degree of heterogeneity because of various reasons: tumor heterogeneity, different cirrhotic backgrounds, various etiologies of cirrhosis, and geographical differences in practice and expertise. Such heterogeneity may cause imbalance among the enrolled patient population, premature withdrawal from the clinical trial, and variable response to the treatment. In addition, methodological heterogeneity also exists in designing trial protocol and response evaluation. All these factors may eventually lead to conflicting results among clinical trials. Accounting for these heterogeneities is important to foster the success of future trials. In recent years, significant progress with molecular targeted agents and immune checkpoint inhibitors was made in advanced HCC. These new agents are also being tested in clinical trials involving earlier stage HCC and will also face the challenge of these issues.

Combining intratumoral Treg depletion with androgen deprivation therapy (ADT): preclinical activity in the Myc-CaP model.

BACKGROUND: Immune checkpoint blockade has shown promising antitumor activity against a variety of tumor types. However, responses in castration-resistant prostate cancer remain relatively rare-potentially due to low baseline levels of infiltration. Using an immunocompetent cMyc-driven model (Myc-CaP), we sought to understand the immune infiltrate induced by androgen deprivation therapy (ADT) and to leverage that infiltration toward therapeutic benefit. METHODS: Using flow cytometry, qPCR and IHC, we quantified ADT-induced immune infiltration in terms of cell type and function. Preclinical treatment studies tested the combinatorial effects of ADT and immune checkpoint blockade using tumor outgrowth and overall survival as end points. RESULTS: ADT induces a complex pro-inflammatory infiltrate. This pro-inflammatory infiltrate was apparent in the early postcastration period but diminished as castration resistance emerged. Combining ADT with tumor-infiltrating regulatory T cell (Treg) depletion using a depleting anti-CTLA-4 antibody significantly delayed the development of castration resistance and prolonged survival of a fraction of tumor-bearing mice. Immunotherapy as a monotherapy failed to provide a survival benefit and was ineffective if not administered in the peri-castration period. CONCLUSIONS: The immune infiltrate induced by ADT is diverse and varies over time. Therapeutic strategies focusing on depleting Tregs in the peri-castration period are of particular interest.

Phase II multicentered study of low-dose everolimus plus cisplatin and weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin as first-line treatment for patients with advanced gastric cancer.

OBJECTIVE: This phase II trial investigates the efficacy and safety of low-dose everolimus in combination with cisplatin-fluorouracil chemotherapy in patients with advanced gastric cancer. METHODS: Eligible patients with chemotherapy-naïve advanced gastric cancer received low-dose everolimus (10 mg p.o. on days 1, 8 and 15) plus cisplatin and a weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin (HDFL) chemotherapy (cisplatin 35 mg/m(2) intravenous infusion for 24 h on days 1 and 8, 5-fluorouracil 2,000 mg/m(2) and leucovorin 300 mg/m(2) intravenous infusion for 24 h on days 1, 8 and 15) every 28 days. The primary endpoint was objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.0. RESULTS: Forty patients (19 men; 21 women; median age, 54.1 years; range, 33.7-73.3 years) received a median of 6 (range, 1-30; 95% CI, 4.9-8.0) cycles of study treatment. The ORR was 52.5% (21 confirmed partial response). The median progression-free survival and overall survival were 6.9 (95% CI, 4.9-8.4) and 10.5 (95% CI, 8.6-12.3) months, respectively. Most adverse events were mild. CONCLUSION: Adding low-dose everolimus to cisplatin-HDFL chemotherapy failed to increase the ORR as in a preplanned statistical assumption but may prolong progression-free survival in treatment-naïve advanced gastric cancer patients.

Sorafenib in advanced hepatocellular carcinoma: current status and future perspectives.

The approval of sorafenib, a multikinase inhibitor targeting primarily Raf kinase and the vascular endothelial growth factor receptor, in 2007 for treating advanced hepatocellular carcinoma (HCC) has generated considerable enthusiasm in drug development for this difficult-to-treat disease. However, because several randomized Phase III studies testing new multikinase inhibitors failed, sorafenib remains the standard of first-line systemic therapy for patients with advanced HCC. Field practice studies worldwide have suggested that in daily practice, physicians are adopting either a preemptive dose modification or a ramp-up strategy to improve the compliance of their patients. In addition, accumulating data have suggested that patients with Child-Pugh class B liver function can tolerate sorafenib as well as patients with Child-Pugh class A liver function, although the actual benefit of sorafenib in patients with Child-Pugh class B liver function has yet to be confirmed. Whether sorafenib can be used as an adjunctive therapy to improve the outcomes of intermediate-stage HCC patients treated with transcatheter arterial chemoembolization or early-stage HCC patients after curative therapies is being investigated in several ongoing randomized Phase III studies. An increasing number of studies have reported that sorafenib exerts "off-target" effects, including the modulation of signaling pathways other than Raf/MEK/ERK pathway, nonapoptotic cell death mechanisms, and even immune modulation. Finally, although sorafenib in combination with chemotherapy or other targeted therapies has the potential to improve therapeutic efficacy in treating HCC, it also increases toxicity. Additional clinical studies are warranted to determine useful sorafenib-based combinations for the treatment of advanced HCC.

Clinical trials in hepatocellular carcinoma: an update.

The success of sorafenib has spurred an explosive increase of clinical trials testing novel molecular targets and other agents in the treatment of hepatocellular carcinoma (HCC). The paradigm of the studies has been characterized by three noticeable changes. First, the molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for advanced HCC treatment. Agents targeting EGFR, FGFR, PI3K/Akt/mTOR, TGF-ß, c-Met, MEK, IGF signaling, and histone deacetylase have been actively explored. Second, the target indication has shifted from advanced stage to early or intermediate stages of disease. The feasibility of combining locoregional therapies and targeted agents, and the use of novel agents after curative treatments are currently under active investigation. Finally, the therapeutic strategy has shifted from monotherapy to combination targeted therapy. We aim to provide a comprehensive overview of newly disclosed and ongoing clinical trials for the treatment of HCC.

Geographic difference in safety and efficacy of systemicchemotherapy for advanced gastric or gastroesophagealcarcinoma: a meta-analysis and meta-regression.

BACKGROUND: The standard of chemotherapy regimens for advanced or metastatic gastric cancer and the clinical outcome were heterogeneous in Asian versus non-Asian countries. This study aimed to explore predictors of safety and efficacy of chemotherapy for patients with advanced or metastatic gastric cancer. METHODS: Treatment group-based meta-analysis and met a regression were performed to analyze results of randomized trials published since 2005 for advanced or metastatic gastric cancer patients who received systemic chemotherapy as first-line treatment. Data were extracted and synthesized according to the Cochrane guidelines. RESULTS: Twenty-five trials (8 Asian, 17 Western or international) with 56 treatment groups were analyzed. Asian trials reported a lower percentage of gastroesophageal junctional carcinoma, higher percentage of diffuse type histology, and more frequent use of second-line chemotherapy. Meta-analysis revealed significant heterogeneity both in treatment safety (grade 3­4 neutropenia and diarrhea) and efficacy [6-month progression-free survival(PFS) and 1-year overall survival (OS)]. Meta-regression analyses indicate that Asian trials are associated with an 8.2% lower incidence of grade 3­4 neutropenia and 2.1%lower incidence of grade 3­4 diarrhea. A lower percentage of patients with gastroesophageal junction carcinoma and the use of combination regimens predicted better PFS. The use of second-line chemotherapy predicts better 1-year OS,which will increase by 10% for every 10% increase inpatients who received second-line chemotherapy. CONCLUSION: Geographic region (Asian vs. non-Asian) is an independent predictor of safety in systemic therapy for gastric cancer.

A critical evaluation of the preventive effect of antiviral therapy on the development of hepatocellular carcinoma in patients with chronic hepatitis C or B: a novel approach by using meta-regression.

BACKGROUND: The extent of the effect of antiviral therapy and its predictors in preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C (CHC) or B (CHB) remain unclear. METHODS: We conducted a systemic review and meta-analysis of published randomized controlled trials (RCTs) and cohort studies (CSs) up to December 2010. Preventive efficacy was measured as absolute reduction in 3- and 5-year cumulative incidence of HCC with antiviral therapy. Predictors for efficacy were identified by using meta-regression. RESULTS: Twenty-two studies (5 RCTs; 17 CSs) were included for analysis. Antiviral therapy reduced 5-year cumulative incidence of HCC by 7.8% (95% CI 4.6-11.1; p < 0.0001) in patients with CHC and by 7.1% (95% CI 4.1-10.2; p < 0.0001) in patients with CHB. The efficacy was significant as early as 3 years after antiviral therapy. While adjusting for available study-level, patient and virological factors, RCT and higher sustained virological response were identified as pertinent predictors of superior preventive efficacy in patients with CHC, whereas lower hepatitis B virus e antigen seropositivity was identified in patients with CHB. Antiviral therapy did not result in differential preventive efficacy between cirrhotic and noncirrhotic patients with CHC or CHB. CONCLUSION: Antiviral therapy can reduce 3- and 5-year cumulative incidence of HCC in patients with CHC or CHB.