Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. METHODS: In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon's two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. RESULTS: Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6-51.9) and 90.3% (56/62, 95% CI, 80.1-96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8-not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7-94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. CONCLUSIONS: Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04401800).

Evaluation of an artificial intelligence-based clinical trial matching system in Chinese patients with hepatocellular carcinoma: a retrospective study.

BACKGROUND: Artificial intelligence (AI)-assisted clinical trial screening is a promising prospect, although previous matching systems were developed in English, and relevant studies have only been conducted in Western countries. Therefore, we evaluated an AI-based clinical trial matching system (CTMS) that extracts medical data from the electronic health record system and matches them to clinical trials automatically. METHODS: This study included 1,053 consecutive inpatients primarily diagnosed with hepatocellular carcinoma who were referred to the liver tumor center of an academic medical center in China between January and December 2019. The eligibility criteria extracted from two clinical trials, patient attributes, and gold standard were decided manually. We evaluated the performance of the CTMS against the established gold standard by measuring the accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and run time required. RESULTS: The manual reviewers demonstrated acceptable interrater reliability (Cohen's kappa 0.65-0.88). The performance results for the CTMS were as follows: accuracy, 92.9-98.0%; sensitivity, 51.9-83.5%; specificity, 99.0-99.1%; PPV, 75.7-85.1%; and NPV, 97.4-98.9%. The time required for eligibility determination by the CTMS and manual reviewers was 2 and 150 h, respectively. CONCLUSIONS: We found that the CTMS is particularly reliable in excluding ineligible patients in a significantly reduced amount of time. The CTMS excluded ineligible patients for clinical trials with good performance, reducing 98.7% of the work time. Thus, such AI-based systems with natural language processing and machine learning have potential utility in Chinese clinical trials.

Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition).

Background: Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages: The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial.

Importance: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment. Objective: To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC. Design, Setting, and Participants: The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy-naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022. Intervention: Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily. Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety. Results: A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib. Conclusions and Relevance: In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib. Trial Registration: ClinicalTrials.gov Identifier: NCT03412773.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

GL-V9 ameliorates liver fibrosis by inhibiting TGF-ß/smad pathway.

Liver fibrosis is a wound-healing response that arises from various aetiologies. Flavonoid compounds have been proved of their anti-liver fibrosis effects. This study aimed to elucidate the protective effect and mechanism of flavonoid compound GL-V9 on CCl4-induced and DDC-induced liver fibrosis. Treatment with GL-V9 alleviated hepatic injury and exhibited a dramatic protection effect of liver fibrosis. Further experiments found that GL-V9 treatment inhibited extracellular matrix (ECM) expression. Activation of hepatic stellate cells (HSCs) is a central driver of fibrosis. GL-V9 could inhibit the activation of HSCs through directly binding to TGFßRI, subsequently inhibit TGF-ß/Smad pathway. In conclusion, this study proved that GL-V9 executed a protective effect on liver fibrosis by inhibiting TGF-ß/Smad pathway.

Ramucirumab as second-line treatment in Chinese patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib (REACH-2 China): A randomised, multicentre, double-blind study.

Background: In the global REACH-2 study, ramucirumab significantly improved overall survival (OS) compared with placebo in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP). REACH-2 China study aimed to evaluate the efficacy and safety of ramucirumab in Chinese patients with advanced HCC (NCT02435433). Methods: REACH-2 China was a randomised, double-blind, placebo-controlled, phase 3 study done at 31 centres in China between Sep 16, 2015, and March 15, 2021. Patients with advanced HCC and AFP ≥400 ng/mL after first-line sorafenib were randomly assigned (2:1) to receive ramucirumab 8 mg/kg intravenously or placebo Q2W, until disease progression or unacceptable toxicity. The primary endpoint was OS. Efficacy was assessed per intention-to-treat, and safety in patients who received any treatment. Findings: Of 104 Chinese patients enrolled (44 in the global study and 60 in the China extension study), 70 received ramucirumab and 34 received placebo. Median OS was 9·1 months in the ramucirumab group and 6·2 months in the placebo group (HR = 0·854 [95% CI: 0·536, 1·359]). The most common grade 3 or worse treatment-emergent adverse event were hypertension (5 [7·1%] of 70 patients in the ramucirumab group vs 1 [2.9%] of 34 in the placebo group), pneumonia (5 [7·1%] vs 1 [2·9%]), and hyponatraemia (4 [5·7%] vs 0 [0%]). Interpretation: Ramucirumab demonstrated clinically meaningful improvement in OS compared to placebo for Chinese patients with advanced HCC and elevated AFP, although lacking statistical superiority. Ramucirumab was well tolerated, with a manageable safety profile. The results are consistent with those of the global REACH-2 study, supporting a favourable risk-benefit profile for ramucirumab in this population. Funding: Eli Lilly and Company, USA.

Lenvatinib Plus Camrelizumab vs. Lenvatinib Monotherapy as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Cohort Study.

Background: Combining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC). Aims: To explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC. Methods: This multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety. Results: By March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events. Conclusion: First-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC.

Association of Serum Hepatitis B Virus RNA With Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Under Nucleos(t)ide Analogues Therapy.

BACKGROUND: Whether serum hepatitis B virus (HBV) RNA associates with hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients has not been fully elucidated. METHODS: We enrolled 2974 patients receiving nucleos(t)ide analogues (NAs) from a prospective, observational CHB cohort to investigate the effect of serum HBV RNA, measured at study entry (baseline), on HCC development, using Cox regression analyses. RESULTS: During median follow-up of 4.4 years, 90 patients developed HCC. Patients with detectable baseline HBV RNA (n = 2072) exhibited significantly higher HCC risk than those with undetectable level (5-year HCC incidence estimated by Kaplan-Meier method: 4.1% versus 1.8%, P = .009; adjusted hazard ratio [aHR] = 2.21, P = .005). HBV RNA levels of 609-99 999 and ≥100 000 copies/mL were associated with incrementally increasing HCC risk (aHR = 2.15 and 3.05, respectively; P for trend = .003), compared to undetectable level (<609 copies/mL). Moreover, patients with single-detectable either HBV DNA or RNA and double-detectable DNA and RNA had 1.57- and 4.02-fold higher HCC risk, respectively, than those with double-undetectable DNA and RNA (P for trend = .001). CONCLUSIONS: High-level HBV RNA is associated with increased HCC risk in NAs-treated patients. Achieving undetectable HBV RNA may contribute to better clinical outcomes, indicating it could be a valuable endpoint of anti-HBV treatment.

Unexpected high retention of 15 N-labeled nitrogen in a tropical legume forest under long-term nitrogen enrichment.

The responses of forests to nitrogen (N) deposition largely depend on the fates of deposited N within the ecosystem. Nitrogen-fixing legume trees widely occur in terrestrial forests, but the fates of deposited N in legume-dominated forests remain unclear, which limit a global evaluation of N deposition impacts and feedbacks on carbon sequestration. Here, we performed the first ecosystem-scale 15 N labeling experiment in a typical legume-dominated forest as well as in a nearby non-legume forest to determine the fates of N deposition between two different forest types and to explore their underlying mechanisms. The 15 N was sprayed bimonthly for 1 year to the forest floor in control and N addition (50 kg N ha-1  year-1 for 10 years) plots in both forests. We unexpectedly found a strong capacity of the legume forest to retain deposited N, with 75 ± 5% labeled N recovered in plants and soils, which was higher than that in the non-legume forest (56 ± 4%). The higher 15 N recovery in legume forest was mainly driven by uptake by the legume trees, in which 15 N recovery was approximately 15% more than that in the nearby non-legume trees. This indicates higher N-demand by the legume than non-legume trees. Mineral soil was the major sink for deposited N, with 39 ± 4% and 34 ± 3% labeled N retained in the legume and non-legume forests, respectively. Moreover, N addition did not significantly change the 15 N recovery patterns of both forests. Overall, these findings indicate that legume-dominated forests act as a strong sink for deposited N regardless of high soil N availability under long-term atmospheric N deposition, which suggest a necessity to incorporate legume-dominated forests into N-cycling models of Earth systems to improve the understanding and prediction of terrestrial N budgets and the global N deposition effects.

Transarterial infusion chemotherapy with FOLFOX for advanced hepatocellular carcinoma: a multi-center propensity score matched analysis of real-world practice.

BACKGROUND: To compare the treatment effectiveness and safety among transarterial infusion chemotherapy (TAI) with FOLFOX regimen, transarterial chemoembolization (TACE), and sorafenib in patients with BCLC stage C hepatocellular carcinoma (HCC). METHODS: The data of consecutive patients with BCLC stage C HCC treated with TAI, TACE, or sorafenib from January 2015 to December 2018 at three centers were retrospectively analyzed. Propensity-score matched (PSM) analysis was pairwise performed to reduce selection bias. Treatment effectiveness and safety were evaluated and compared using the Kaplan-Meier method, log-rank test, Cox regression models, and χ2 test. RESULTS: The median overall survival (OS) in the matched TAI cohort was significantly longer than the sorafenib cohort (19.6 vs. 7.5 months, P=0.009), and the TACE cohort (estimated 27.8 vs. 6.6 months, P<0.001). The difference in median progression-free survival (PFS) between the matched TAI and sorafenib cohorts was not significant (5.8 vs. 2.3 months, P=0.219). The median PFS in the matched TAI cohort was significantly longer than the TACE cohort (6.5 vs. 2.8 months, P<0.001). The objective response rate (ORR) in the matched TAI cohort was significantly higher than the sorafenib cohort (36.4% vs. 0.0%, P<0.001) and the TACE cohort (48.7% vs. 4.7%, P<0.001). The incidences of adverse events (AEs) were similar among these three cohorts. CONCLUSIONS: TAI with FOLFOX regimen was an effective and safe therapy that improved survival of patients with BCLC stage C HCC.

Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

miR-1258 Attenuates Tumorigenesis Through Targeting E2F1 to Inhibit PCNA and MMP2 Transcription in Glioblastoma.

MicroRNAs are a group of endogenous small non-coding RNAs commonly dysregulated in tumorigenesis, including glioblastoma (GBM), the most malignant brain tumor with rapid proliferation, diffuse invasion, and therapeutic resistance. Accumulating evidence has manifested that miR-1258 exerts an inhibitory role in many human cancers. However, the expression pattern of miR-1258 and its potential function in GBM tumorigenesis remain unclear. In this study, we reported that miR-1258 expression decreased with the ascending pathological grade of glioma, which indicated an unfavorable prognosis of patients. Functional assays revealed an inhibitory effect of miR-1258 on malignant proliferation, therapeutic resistance, migration, and invasion of GBM in vitro. Moreover, xenograft models also suggested a repression effect of miR-1258 on gliomagenesis. Mechanistically, miR-1258 directly targeted E2F1 in 3'-untranslated regions and attenuated E2F1-mediated downstream gene PCNA and MMP2 transcriptions. Furthermore, restoration of E2F1 expression in GBM cells effectively rescued the tumor-suppressive effect of miR-1258. Our studies illustrated that miR-1258 functioned as a tumor suppressor in GBM by directly targeting E2F1, subsequently inhibiting PCNA and MMP2 transcriptions, which contributed to new potential targets for GBM therapy and other E2F1-driven cancers.

Dose escalation and expansion (phase Ia/Ib) study of GLS-010, a recombinant fully human antiprogrammed death-1 monoclonal antibody for advanced solid tumors or lymphoma.

BACKGROUND: GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. AIM: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. METHODS: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. RESULTS: Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. CONCLUSION: GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.

Baveno VI criteria and spleen stiffness measurement rule out high-risk varices in virally suppressed HBV-related cirrhosis.

BACKGROUND & AIMS: There are no data validating the performance of spleen stiffness measurement in ruling out high-risk varices in patients with HBV-related cirrhosis under maintained viral suppression. Thus, we aimed to prospectively validate the performance of spleen stiffness measurement (cut-off 46 kPa) combined with Baveno VI criteria in ruling out high-risk varices in these patients. METHODS: Patients with cirrhosis were enrolled from April to December 2019 at the hepatology unit of the Nanfang Hospital, China. Liver and spleen transient elastography and esophagogastroduodenoscopy were performed at enrollment. Antiviral regimen(s) and virological responses, evaluated every 3-6 months, were recorded. RESULTS: Overall 341 patients with HBV-related cirrhosis under maintained viral suppression were enrolled, and the prevalence of high-risk varices was 20.5% (70/341). Baveno VI criteria spared 37.0% (126/341) esophagogastroduodenoscopies and no high-risk varices were missed (0/70). Eight cases of high-risk varices (8/70, 11.4%) were misclassified in patients (208/341, 61.0%) within the expanded Baveno VI criteria. The spleen stiffness measurement cut-off (≤46.0 kPa) was shown to safely rule out high-risk varices in these patients (the percentage of missed high-risk varices was 4.3%). Over half (61.6%, 210/341) of patients met the combined model (Baveno VI criteria and spleen stiffness measurement cut-off ≤46 kPa) and 4.3% (3/70) of high-risk varices cases were misclassified. This combined model exhibited a sensitivity of 95.71%, specificity of 76.38%, negative predictive value of 98.57%, and negative likelihood ratio of 0.06 for ruling out high-risk varices. CONCLUSIONS: We validated the excellent performance of Baveno VI criteria combined with spleen stiffness measurement (cut-off 46 kPa) for safely ruling out high-risk varices in patients with HBV-related cirrhosis under viral suppression; more than half of esophagogastroduodenoscopy procedures were spared using this combination. CLINICAL TRIAL NUMBER: NCT04123509 LAY SUMMARY: Esophageal varices have important prognostic implications in patients with cirrhosis. Thus, their timely identification is important so that treatment can be initiated early. Herein, we validated the excellent performance of the combination of Baveno VI criteria with spleen stiffness measurement (cut-off 46 kPa) for ruling out high-risk esophageal varices in patients with HBV-related cirrhosis under maintained viral suppression (with antiviral treatment). This combined model was able to safely rule out high-risk varices (missed/total <5%) and over half (61.6%) of esophagogastroduodenoscopy procedures were spared.

Safety and Efficacy of Camrelizumab Combined with Apatinib for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

INTRODUCTION: Previous trials demonstrated that anti-angiogenesis or anti-programmed death protein 1 (PD-1) monotherapy showed unsatisfied effect in advanced hepatocellular carcinoma (HCC). No study existed that focus on the effects of camrelizumab and apatinib ("C+A") combination therapy for HCC patients with the location and extent of portal vein tumor thrombus (PVTT) as the main variable being assessed. This study was to compare the efficacy and tolerability of "C+A" for HCC patients with PVTT. METHODS: We retrospectively analyzed patients with advanced HCC and PVTT who underwent "C+A" therapy in a multicenter retrospective cohort from Jan 2019 to July 2020. Outcomes of patients who underwent "C+A" were analyzed by using the Kaplan-Meier method according to types of PVTT: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). RESULTS: Sixty-three patients were finally included and the mean duration of follow-up was 12.6 ± 4.5 months. The objective response rate (ORR) and disease control rate (DCR) for the whole cohort were 44.0% and 75.0%, respectively. The median overall survival (OS), progression-free survival (PFS) and time to progression (TTP) were 14.8 months, 11.8 months and not yet reached (NR), respectively. Patients with type B (OS, 15.9 months; PFS, 14.0 months; TTP, NR) or type C (OS, 16.0 months; PFS, 14.9 months; NR) PVTT appear to have better survival benefits compared with type A (OS, 5.8 months; PFS, 5.0 months; TTP, 7.0 months). Along with AFP, the absence of main PVTT was an independent predictive factor for survival at uni- and multivariate analysis. CONCLUSION: Camrelizumab and apatinib yielded a promising outcome in patients with advanced HCC who developed a tumor thrombus in the first lower-order portal vein branches and was generally safe and had manageable side effects.

Effectiveness and safety of toripalimab, camrelizumab, and sintilimab in a real-world cohort of hepatitis B virus associated hepatocellular carcinoma patients.

BACKGROUND: The clinical significance of programmed cell death protein-1 (PD-1)-targeted immunotherapy in Chinese patients is understudied. We thus aimed to evaluate the safety and efficacy of PD-1 inhibitors with toripalimab, camrelizumab or sintilimab for Chinese hepatocellular carcinoma (HCC) patients in a real-life cohort. METHODS: We analysed hepatitis B virus (HBV)-associated HCC patients treated with toripalimab, camrelizumab, or sintilimab in a retrospective single-center cohort from November 2018 to June 2020. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP), and overall survival (OS). Safety data were also recorded. RESULTS: Seventy patients were finally included in the analysis: 23 were treated with toripalimab, 33 with camrelizumab, and 14 with sintilimab. The mean duration of follow-up was 44.7 (95% CI: 39.9-49.6) weeks and the mean cycles of PD-1 at cutoff were 8.3±8.0 for all patients. The ORR and DCR for the whole cohort were 30% and 72.9%, respectively. Overall, 25 (35.7%) patients had radiological disease progression and 10 (14.3%) patients died during follow-up. Median PFS, median TTP, and median OS had not yet been reached. Most frequent drug-related adverse events (AEs) were rash (27.1%), hypertension (18.6%), fatigue (17.1%), diarrhea (17.1%), paresthesia (15.7%), and nausea (15.7%). CONCLUSIONS: Our findings suggest that (I) PD-1 targeted immunotherapy with toripalimab, camrelizumab, or sintilimab yielded a promising outcome in Chinese HBV patients with HCC and that (II) immunotherapy was well tolerated generally and had manageable side effects. This approach thus warrants further popularization and application in clinical practice.

[Effect of ozone oil for prevention and treatment of sorafenib-induced hand-foot skin reactions: a randomized controlled trial].

OBJECTIVE: To compare the effects of medical ozone oil and urea ointment for prevention and treatment of hand-foot skin reaction (HFSR) caused by sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: A total of 99 patients diagnosed with advanced HCC according to National Comprehensive Cancer Network (NCCN) who were scheduled to receive sorafenib treatment for the first time were enrolled in this study between April, 2018 and January, 2020. The patients were randomized into medical ozone oil group (n=49) and urea ointment group (control group, n=49) for treatment with local application of 1 mL medical ozone oil (experimental group) and 10% urea ointment (2 g) on the palm and plantar skin (including the fingers and joints) for 12 weeks (3 times per day) starting at the beginning of sorafenib treatment, respectively. The patients were observed for occurrence of HFSR every 2 weeks for 14 weeks. RESULTS: Eight patients were excluded for poor compliance or protocol violations, leaving a total of 91 patients for analysis, including 44 in medical ozone oil group and 47 in urea ointment group. Sixteen (36.4%) of patients in ozone oil group developed HFSR, a rate significantly lower than that in urea ointment group (57.4%; P < 0.05). The incidence of grade 2/3 HFSR was also lower in ozone oil group than in urea ointment group (15.9% [7/44] vs 27.7 [13/47]). CONCLUSIONS: Medical ozone oil can significantly reduce the incidence and severity of HFSR to improve the quality of life of HCC patients receiving sorafenib treatment.

Withdrawn: Effectiveness and safety of toripalimab, camrelizumab and sintilimab in a real-world cohort of hepatitis B virus associated hepatocellular carcinoma patients.

The above article from British Journal of Clinical Pharmacology, published online on July 5, 2020 in Wiley Online Library (http://wileyonlinelibrary.com) has been withdrawn by agreement among the authors and John Wiley & Sons Ltd on behalf of the British Pharmacology Society. The withdrawal has been agreed in accordance with the authors' decision to revise their study providing the latest data.

aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis. METHODS: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686). RESULTS: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin-bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82-0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0-0.8%, 1.5-4.8%, and 8.1-19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7-100% and a negative predictive value of 99.3-100%. The cut-off value of 60 resulted in a specificity of 56.6-95.8% and a positive predictive value of 6.6-15.7%. CONCLUSIONS: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide. LAY SUMMARY: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin-bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.