Hepatocellular carcinoma (HCC) is the most common malignancy worldwide, and is especially common in China. A total of 70%–80% of patients are diagnosed at an advanced stage and can receive only ...palliative care. Sorafenib has been the standard of care for a decade, and promising results for regorafenib as a second‐line and lenvatinib as a first‐line treatment were reported only 1 or 2 years ago. FOLFOX4 was recently recommended as a clinical practice guideline by the China Food and Drug Administration. All approved systemic therapies remain unsatisfactory, with limited objective response rates and poor overall survival. Immune checkpoint inhibitors (CPIs) offer great promise in the treatment of a rapidly expanding spectrum of solid tumors. Immune checkpoint molecules are involved in almost the whole process of viral‐related hepatitis with cirrhosis and HCC and in the most important resistance mechanism of sorafenib. The approval of nivolumab by the U.S. Food and Drug Administration on September 23, 2017, for the treatment of patients with HCC, based only on a phase I/II clinical trial, is a strong hint that immunotherapy will introduce a new era of HCC therapy. CPI‐based strategies will soon be a main approach in anticancer treatment for HCC, and we will observe the rapid advances in the therapeutic use of CPIs, even in an adjuvant setting, with great interest. How shall we face the opportunities and challenges? Can we dramatically improve the prognosis of patients with HCC? This review may provide some informed guidance.
Implications for Practice
Immune checkpoint molecules are involved in almost the whole process of viral‐related hepatitis with cirrhosis and hepatocellular carcinoma (HCC) and in the most important resistance mechanism of sorafenib. As all approved systemic therapies in HCC remain unsatisfactory, checkpoint inhibitor (CPI)‐based strategies will soon be a main approach in anticancer treatment for advanced stage of HCC, even in an adjuvant setting. In virus‐related HCC, especially hepatitis B virus‐related HCC, whether CPIs can control virus relapse should be further investigated. Combination strategies involving conventional therapies and immunotherapies are needed to increase clinical benefit and minimize adverse toxicities with regard to the underlying liver disease.
摘要
肝细胞癌 (HCC) 是世界上最常见的恶性肿瘤，在中国尤为普遍。高达 70% ~ 80% 的患者被确诊时已经进入晚期，只能接受姑息治疗。近十年来，索拉非尼一直是标准治疗方案，只是在一二年前才有报告称，瑞格拉非尼作为二线治疗以及乐伐替尼作为一线治疗的结果颇具前景。最近，中国食品药品监督管理总局建议将 FOLFOX4 作为临床实践指南。所有经过批准的系统疗法效果仍不理想，客观缓解率较低并且整体存活率不佳。免疫检查点抑制剂 (CPI) 在治疗迅速恶化的实体瘤方面具有大好前景。在病毒相关肝炎所致肝硬化和 HCC以及索拉非尼最重要的耐药机制中，免疫检查点分子几乎都参与整个过程。美国食品药品监督管理局于 2017 年 9 月 23 日正式批准将纳武单抗用于 HCC 患者的治疗，仅基于一项 I /II 期临床试验，这一举措强烈暗示免疫疗法将纳入 HCC 治疗的新纪元。基于 CPI 的方案很快将成为 HCC 抗癌治疗的主要方法，我们将有幸见证 CPI 治疗用途的长足进展，即便在辅助治疗中也将获益匪浅。我们将如何面对机遇与挑战?我们是否能明显改善 HCC 患者的预后?本篇综述将提供一些详细的指南。
实践意义:在病毒相关肝炎所致肝硬化和肝细胞癌 (HCC)以及索拉非尼最重要的耐药机制中，免疫检查点分子几乎都参与整个过程。所有经过批准的 HCC 系统疗法效果仍不理想，基于免疫检查点抑制剂 (CPI) 的方案将成为晚期 HCC 抗癌治疗的主要方法，即便在辅助治疗中亦是如此。在病毒引发的 HCC，尤其是乙型肝炎病毒引发的 HCC 中，对于CPI 能否扼制病毒复发，应该对其进行进一步研究。因此，需要包含常规疗法和免疫疗法的组合方案来增加临床受益，并且组合方案将最大程度减少与潜在肝病相关的不良毒性。
This review focuses on the opportunities and challenges of immune checkpoint inhibitor therapies for hepatocellular carcinoma, especially hepatitis B virus‐related hepatocellular carcinoma.
The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.
In a global, ...open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).
The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval CI, 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent.
In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.).
Aberrant c‐Met activity has been implicated in the development of hepatocellular carcinoma (HCC), suggesting that c‐Met inhibition may have therapeutic potential. However, clinical trials of ...nonselective kinase inhibitors with c‐Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This lack of observed efficacy is likely due to several factors, including trial design, lack of patient selection according to tumor c‐Met status, and the prevalent off‐target activity of these agents, which may indicate that c‐Met inhibition is incomplete. In contrast, selective c‐Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve complete inhibition of tumor c‐Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c‐Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child‐Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c‐Met inhibition compared with standard therapy in patients with HCC that were selected based on tumor c‐Met status. Thus, c‐Met inhibition continues to be an active area of research in HCC, with well‐designed trials in progress to investigate the benefit of selective c‐Met inhibitors. (Hepatology 2018;67:1132–1149)
Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed malignancies worldwide with poor prognosis and tends to be hypervascular. Aberrant expression of the vascular endothelial growth ...factor 2 (VEGFR‐2) has been implicated in the progression of HCC and represents a valid target for anticancer therapy. Apatinib, a small molecule inhibitor of VEGFR‐2 tyrosine kinase, shows strong antitumor activity in various tumors. This study is designed to evaluate the activity of apatinib on both human umbilical vein vascular endothelial cells (HUVECs) and HCC cell lines (in vitro and in vivo), and also to investigate the characteristics and possible mechanisms underlying these effects by molecular biology methods. Following the results in our study, apatinib inhibited phosphorylation of VEGFR‐2 in HUVECs and blocked in vitro endothelial cell migration and tube formation. Concentration‐dependent antiproliferative effects of apatinib were also observed in all 6 HCC cell lines including SK‐Hep‐1, HepG2, Hep3B, Huh‐7, PLC/PRF/5, SMMC‐7721. Moreover, response to apatinib of HCC cell lines was significantly correlated with VEGFR‐2 expression level. Additionally, apatinib significantly inhibit VEGF‐triggered VEGFR‐2 phosphorylation and activation of downstream signaling molecules such as Akt and ERK1/2 in HCCs. Apatinib can also induce a cell cycle arrest at G2/M phase and promote HCC apoptosis tested in vitro. In vivo data showed that apatinib can effectively inhibit tumor growth, decreased angiogenesis, as well as induced HCC apoptosis (in some tumors), and thus prolonged animal survival in a mouse xenograft model of human HCC. Our findings suggested that apatinib is a highly potent, oral active anti‐angiogenic, and anti‐HCC agent. The results from current study provide a clear biological rationale to evaluate apatinib as a new agent in HCC in clinical setting, especially for the VEGFR‐2 overexpression ones.
This study indicated that apatinib showed antitumor activity in Hepatocellular Carcinoma (HCC) by targeting on both endothelial and tumor cells. Apatinib blocked in vitro endothelial cell migration and tube formation. In addition, apatinib significantly inhibited cell proliferation in 6 HCC cell lines in a concentration‐dependent manner. Apatinib could also induce a cell cycle arrest at G2/M phase of HCC and promote HCC apoptosis. Our findings suggested that apatinib is a highly potent, oral active anti‐angiogenic, and anti‐HCC agent.
Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas
. ...More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours
. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer
, there are preclinical
and clinical
rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma
( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer‐related deaths globally due, in part, to the majority of patients being diagnosed with intermediate or advanced stage ...disease. Our increased understanding of the heterogeneous molecular pathogenesis of HCC has led to significant developments in novel targeted therapies. Despite these advances, there remains a high unmet need for new treatment options. HCC is a complex disease with multiple pathogenic mechanisms caused by a variety of risk factors, making it difficult to characterize with a single biomarker. In fact, numerous biomarkers have been studied in HCC, but alpha‐fetoprotein (AFP) remains the most widely used and accepted serum marker since its discovery over 60 years ago. This review summarizes the most relevant studies associated with the regulation of AFP at the gene and protein levels; the pathophysiology of AFP as a pro‐proliferative protein; and the correlation of AFP with molecular HCC subclasses, the vascular endothelial growth factor pathway and angiogenesis. Also described are the historical and current uses of AFP for screening and surveillance, diagnosis, its utility as a prognostic and predictive biomarker and its role as a tumour antigen in HCC. Taken together, these data demonstrate the relevance of AFP for patients with HCC and identify several remaining questions that will benefit from future research.
AST-3424 is a novel specific aldo-keto reductase 1C3 (AKR1C3) prodrug that releases a DNA alkylating reagent upon reduction by AKR1C3. This study aimed to evaluate the efficacy and safety of AST-3424 ...in patient-derived tumor xenograft (PDTX) model and orthotopic model against hepatocellular carcinoma (HCC).
PDTX models derived from three HCC patients and orthotopic mice models using HepG2 cells were developed. The mice were treated with AST-3424 alone or combined with other drugs (oxaliplatin, apatinib, sorafenib and elemene in PDTX models, oxaliplatin and 5- fluorouracil in orthotopic models). The tumor volume and weight, as well as the mice weight were assessed. The liver tumor and transplanted tumor were removed for histological, immunohistochemical and Western blot detection in orthotopic model experiments.
AST-3424 could inhibit tumor growth in HCC PDTX models and orthotopic models, with no difference in safety compared with other marketed drugs, and the drug combination did not increase toxicity. The inhibitory effect of combination treatment was more obvious than which used alone. The reduction of AKR1C3 expression was negatively correlated with AST-3424 dose.
AST-3424 had a promising effect against HCC in PDTX model and orthotopic model with good safety. It could promote the sensitivity of other drugs without increasing toxicity. Clinical trials are warranted to further certify its antitumor effect and safety.
To determine whether FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) administered as palliative chemotherapy to patients with advanced hepatocellular carcinoma (HCC) provides a ...survival benefit and efficacy versus doxorubicin.
This multicenter, open-label, randomized, phase III study in mainland China, Taiwan, Korea, and Thailand involved 371 patients age 18 to 75 years who had locally advanced or metastatic HCC and were ineligible for curative resection or local treatment. They were randomly assigned at a ratio of one to one to receive either FOLFOX4 (n = 184) or doxorubicin (n = 187). The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR) by RECIST (version 1.0), and safety.
At the prespecified final analysis, median OS was 6.40 months with FOLFOX4 (95% CI, 5.30 to 7.03) and 4.97 months with doxorubicin (95% CI, 4.23 to 6.03; P = .07; hazard ratio HR, 0.80; 95% CI, 0.63 to 1.02). Median PFS was 2.93 months with FOLFOX4 (95% CI, 2.43 to 3.53), and 1.77 months with doxorubicin (95% CI, 1.63 to 2.30; P < .001; HR, 0.62; 95% CI, 0.49 to 0.79). RR was 8.15% with FOLFOX4 and 2.67% with doxorubicin (P = .02). On continued follow-up, the trend toward increased OS with FOLFOX4 was maintained (P = .04; HR, 0.79; 95% CI, 0.63 to 0.99). Toxicity was consistent with previous experiences with FOLFOX4; proportions of grade 3 to 4 adverse events were similar between treatments.
Although the study did not meet its primary end point, the trend toward improved OS with FOLFOX4, along with increased PFS and RR, suggests that this regimen may confer some benefit to Asian patients, but an OS benefit cannot be concluded from these data.
Summary Background There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of ...regorafenib in patients with HCC who have progressed during sorafenib treatment. Methods In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1–3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01774344. Findings Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50–0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1–12·1) for regorafenib versus 7·8 months (6·3–8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 100% of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients 15% in the regorafenib group vs nine patients 5% in the placebo group), hand–foot skin reaction (47 patients 13% vs one 1%), fatigue (34 patients 9% vs nine patients 5%), and diarrhoea (12 patients 3% vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients 13% assigned to regorafenib and 38 20% assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. Interpretation Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib. Funding Bayer.
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