Targeted agents for second-line treatment of advanced hepatocellular carcinoma

Over the past ten years, sorafenib, a multikinase inhibitor, has been the standard of care for patients with unresectable hepatocellular carcinoma (HCC) and well-preserved liver function. Recently, lenvatinib, a different multikinase inhibitor, was shown to be non-inferior to sorafenib, in terms of survival, while all other agents previously tested failed to prove non-inferiority (or superiority) when compared to sorafenib. Similarly, in the second-line setting, most investigational drugs failed to provide better survival outcomes than placebo. However, in the last 2 years three positive phase III trials have been published in this setting. The RESORCE trial, a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib, showed better outcomes with regorafenib compared to placebo. More recently, the phase III CELESTIAL trial demonstrated the superiority of cabozantinib, a multikinase inhibitor targeting vascular endothelial growth factor receptor, MET, and AXL, vs placebo in the second- and third-line setting in patients progressing on or intolerant to sorafenib. The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels. Overall, the adverse events reported in these trials were in line with the known safety profiles of the tested agents. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.     

Comparison of the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma: a retrospective cohort study

BackgroundThere is lack of studies on sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma (HCC). This study was to explore the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib failure in HCC patients.MethodsThis study was a retrospective, real-world study that included 50 HCC patients who received sequential regrafinib after sorafenib and lenvatinib failure. The safety and prognosis of two groups were compared.ResultsThe incidence of all grade and III/IV adverse events were 68% and 24%. According to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and modified (m) RECIST standards, the objective response rates (ORRs) after receiving regorafenib were 14.0% and 22.0%, respectively. The disease control rates (DCRs) were 62.0% and 60.0%, respectively. Based on different first-line targeted drugs, 50 patients were divided into sorafenib (n=22) and lenvatinib group (n=28). There was no differences between two groups except age and bilirubin. And there was no differences in other treatments before or after regorafenib. The baseline between two groups was basically same and had good comparability. There was no difference in incidence of all grade and III/IV adverse events, ORR and DCR between two groups (P>0.05). On long-term prognosis, total overall survival (TOS) in sorafenib and lenvatinib group were 23.0 (95% CI: 15.1–30.9) vs. 29.7 (95% CI: 21.4–38.1) months. The difference was statistically significant (P=0.041). Besides, regorafenib overall survival (ROS) in sorafenib and lenvatinib group were 11.7 (95% CI: 7.1–16.3) vs. 15.9 (95% CI: 8.3–23.5) months. The difference was statistically significant ( P=0.045). The regorafenib progression-free survival (RPFS) was 5.6 (95% CI: 1.9–9.2) vs. 8.0 (95% CI: 5.1–10.9) months in sorafenib and lenvatinib group, respectively, and difference was not statistically significant (P=0.380).ConclusionsRegorafenib is an effective drug for second-line treatment of HCC, with fewer severe adverse events, ORR and DCR was 14–22% and 62–60%, respectively. Both TOS and ROS in lenvatinib group were better than those in sorafenib group. For HCC patients whose first-line targeted drug is lenvatinib, it is safe and effective to accept regorafenib after disease progresses.     

Current status of first-line therapy,anti-angiogenic therapy and its combinations of other agents for unresectable hepatocellular carcinoma

Globally, hepatocellular carcinoma (HCC) is a frequently diagnosed malignancy with rapidly increasing incidence and mortality rates. Unfortunately, many of these patients are diagnosed in the advanced stages when locoregional treatments are not appropriate. Before 2008, no effective drug treatments existed to prolong survival, until the breakthrough multi-tyrosine kinase inhibitor (TKI) sorafenib was developed. It remained the standard treatment option for advanced HCC for 10 years, with a battery of other candidate drugs in clinical trials failing to produce similar efficacy results. In 2018, the REFLECT trial introduced another multi-TKI, lenvatinib, which has non-inferior overall survival compared with sorafenib. Thus, offering patients and their treating physicians two effective treatment options. Recently, immunotherapy-based drugs, such as atezolizumab and bevacizumab, have shown promising results in patients with unresectable HCC. This review summarizes clinical trial and real-world data studies of sorafenib and lenvatinib in patients with unresectable HCC. We offer guidance on the optimal choice between the two treatments and discuss the potential of immunotherapy-based combination; when more data become available, this will likely make the choice between sorafenib and lenvatinib somewhat obsolete.     

Clinical trials of antiangiogenic therapy for hepatocellular carcinoma

Angiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of antiangiogenic agents in hepatocellular carcinoma. A systematic search of PubMed was performed to identify clinical trials of specific antiangiogenic agents in hepatocellular carcinoma treatment, particularly phase III trials involving treatment guidelines for advanced hepatocellular carcinoma. Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma. Two large-scale, randomized phase III trials using sorafenib involving patients with unresectable HCC showed a significant survival benefit compared with placebo control groups. However, subsequent phase III trials of antiangiogenic agents in hepatocellular carcinoma have failed to improve survival compared with standard treatment protocols using sorafenib. The efficacy of antiangiogenic agents in combination with other drugs, transarterial chemoembolization, and surgical resection is currently being investigated. Future research is expected to optimize antiangiogenic therapies in combination with standard treatment with sorafenib.     

New treatment paradigm with systemic therapy in intermediate-stage hepatocellular carcinoma

Since the approval of sorafenib for the treatment of unresectable hepatocellular carcinoma in 2007 (in 2009 in Japan), five more regimens have been approved: lenvatinib, and atezolizumab plus bevacizumab for first-line treatment, and regorafenib, cabozantinib, and ramucirumab for second-line treatment, which are currently available for clinical use. The positive results of durvalumab, a programmed cell death ligand 1 antibody, plus tremelimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, were also presented at the 2022 American Society Clinical Oncology Gastrointestinal Cancers Symposium as superior to sorafenib in prolonging the overall survival; this combination is expected to be approved by the end of 2022. These systemic therapies are changing the treatment paradigm not only for advanced hepatocellular carcinoma but also for intermediate-stage hepatocellular carcinoma. This review focuses on the role of systemic therapy in intermediate-stage hepatocellular carcinoma.

     

What is the indication for sorafenib in hepatocellular carcinoma? A clinical challenge

The incidence of hepatocellular carcinoma is rising in many countries, including the United States. Approval of sorafenib (Nexavar) as the first targeted therapy for treatment of advanced hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. The approval was based on two large randomized phase III trials from the Western and Eastern hemispheres that showed an overall survival benefit compared with placebo in patients with well-preserved liver function. The exact indication for sorafenib is unclear, however. The U.S. Food and Drug Administration (FDA) authorized use of sorafenib for "unresectable HCC", an indication which is very broad, vague, and confusing. Less is known about the effects of sorafenib in patients with decompensated liver disease, or of sorafenib in combination with local therapy or in a transplant setting. Prospective trials are lacking in these areas. We will review current data on use of sorafenib in HCC.     

仑伐替尼治疗肝细胞癌的研究进展

肝细胞癌（hepatocellular carcinoma,HCC）是严重威胁人类生命健康的疾病之一,其发病率和死亡率逐年上升,具有发展迅速、高侵袭性和高复发性等特点。大多数患者确诊时已是进展期,而靶向治疗作为进展期肝癌的主要治疗策略,已广泛应用于临床。以往该类患者的一线治疗药物仅有索拉菲尼,但其不良反应大,肿瘤应答率低,对乙型肝炎病毒（hepatitis B virus,HBV）阳性患者的总生存率并无明显改善。近年来,新的靶向治疗药物仑伐替尼在肝癌的治疗研究中取得了良好的疗效,成为继索拉菲尼后治疗进展期肝癌的第2个一线药物。本文就仑伐替尼在治疗HCC中的研究进展进行综述。      

Evolving role of regorafenib for the treatment of advanced cancers

Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of refractory metastatic colorectal cancer (mCRC), advanced gastrointestinal stromal tumors (GIST) previously treated with imatinib and sunitinib, and unresectable hepatocellular carcinoma (HCC) following progression on sorafenib. Regorafenib was initially approved for mCRC based on improved overall survival (OS) in the randomized, placebo-controlled, phase 3 CORRECT trial, which was confirmed in an expanded population of Asian patients in the randomized, placebo-controlled phase 3 CONCUR trial. Approvals in GIST, and more recently in HCC, were based on the results from the randomized, placebo-controlled, phase 3 GRID and RESORCE trials, respectively. In this review, we provide a comprehensive summary of the clinical evidence for approval of regorafenib in mCRC, GIST, and HCC, present emerging evidence of regorafenib activity in other tumor types (namely, gastroesophageal cancer, sarcomas, biliary tract cancer, and glioblastoma), and discuss trials in progress within the context of regorafenib’s mechanism of action. We describe recent advances and key lessons learned with regorafenib, including the importance of managing common drug-related toxicities using dose-optimization strategies, the search for biomarkers to predict response to treatment, and highlight some of the unaddressed questions and future directions for regorafenib across tumors.     

Drug Treatment for Advanced Hepatocellular Carcinoma: First-Line and Beyond

Hepatocellular carcinoma (HCC) has high mortality. The option of systemic therapy has increased significantly over the past five years. Sorafenib was the first multikinase inhibitor, introduced in 2007, as a treatment option for HCC, and it was the only effective systemic treatment for more than ten years. It was not until 2017 that several breakthroughs were made in the development of systemic strategies. Lenvatinib, another multikinase inhibitor, stood out successfully after sorafenib, and has been applied to clinical use in the first-line setting. Other multikinase inhibitors such as regorafenib, ramucirumab and cabozantinib, were approved in quick succession as second-line therapies. Concurrently, immune checkpoint inhibitors (ICIs) have readily become established treatments for many solid tumors, including HCC. The most studied ICIs to date, target programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These ICIs have demonstrated efficacy in treating advanced HCC. More recently, combination of bevacizumab and atezolizumab (ICI targeting PD-L1) was approved as the gold-standard first-line therapy. Combination of ICIs with nivolumab and ipilimumab was also approved in the second-line setting for those who failed sorafenib. At the moment, numerous clinical trials in advanced HCC are underway, which will bring continuous change to the management, and increase the survival, for patients with advanced HCC. Our review article: (1) summarizes United States Food and Drug Administration (US FDA) approved systemic therapies in advanced HCC, (2) reports the evidence of currently approved treatments, (3) discusses potential drugs/drug combinations being currently tested in phase III clinical trials, and (4) proposes possible future directions in drug development for advanced HCC.     

Role of cellular,molecular and tumor microenvironment in hepatocellular carcinoma: Possible targets and future directions in the regorafenib era

Hepatocellular carcinoma (HCC) remains as one of the major causes of cancer-related mortality, despite the recent development of new therapeutic options. Regorafenib, an oral multikinase inhibitor, is the first systemic therapy that has a survival benefit for patients with advanced HCC that have a poor response to sorafenib. Even though regorafenib has been approved by the FDA, the clinical trial for regorafenib treatment does not show significant improvement in overall survival. The impaired efficacy of regorafenib caused by various resistance mechanisms, including epithelial–mesenchymal transitions, inflammation, angiogenesis, hypoxia, oxidative stress, fibrosis and autophagy, still needs to be resolved. In this review, we provide insight on regorafenib microenvironmental, molecular and cellular mechanisms and interactions in HCC treatment. The aim of this review is to help physicians select patients that would obtain the maximal benefits from regorafenib in HCC therapy.     

Atezolizumab plus bevacizumab versus sorafenib or atezolizumab alone for unresectable hepatocellular carcinoma: A systematic review

BACKGROUNDDespite the use of current standard therapy, the prognosis of patients with unresectable hepatocellular carcinoma (HCC) is poor, with median survival times of 40 mo for intermediate HCC (Barcelona Clinic Liver Cancer [BCLC] stage B) and 6–8 mo for advanced HCC (BCLC stage C). Although patients with early-stage HCC are usually suitable for therapies with curative intention, up to 70% of patients experience relapse within 5 years. In the past decade, the United States Food and Drug Administration has approved different immunogenic treatment options for advanced HCC, the most common type of liver cancer among adults. Nevertheless, no treatment is useful in the adjuvant setting. Since 2007, the multi-kinase inhibitor sorafenib has been used as a first-line targeted drug to address the increased mortality and incidence rates of HCC. However, in 2020, the IMbrave150 trial demonstrated that combination therapy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) and bevacizumab (anti-vascular endothelial growth factor [VEGF]) is superior to sorafenib, a single anti-programmed death 1/PD-L1 antibody inhibitor used as an anti-cancer monotherapy for HCC treatment.AIMTo conduct a systematic literature review to evaluate the evidence supporting the efficacy and safety of atezolizumab/bevacizumab as preferred first-line drug therapy over the conventional sorafenib or atezolizumab monotherapies, which are used to improve survival outcomes and reduce disease progression in patients with unresectable HCC and non-decompensated liver disease. METHODSA comprehensive literature review was conducted using the PubMed, Scopus, ScienceDirect, clinicaltrials.gov, PubMed Central, Embase, EuropePMC, and CINAHL databases to identify studies that met the inclusion criteria using relevant MeSH terms. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and risk of bias (RoB) were assessed using the Cochrane RoB 2 tool and Sevis.RESULTSIn the atezolizumab/bevacizumab group, an improvement in overall tumor response, reduction of disease progression, and longer progression-free survival were observed compared to monotherapy with either sorafenib or atezolizumab. Hypertension and proteinuria were the most common adverse events, and the rates of adverse events were comparable to those with the monotherapy. Of the studies, there were two completed trials and two ongoing trials analyzed using high quality and low bias. A more thorough analysis was only performed on the completed trials.CONCLUSIONTreatment of HCC with atezolizumab/bevacizumab combination therapy was confirmed to be an effective first-line treatment to improve survival in patients with unresectable HCC and non-decompensated liver disease compared to monotherapy with either sorafenib or atezolizumab.     

Current status of molecularly targeted therapy for hepatocellular carcinoma: clinical practice

In recent years, molecular-targeted agents have been used clinically to treat various malignant tumors. In May 2009, sorafenib (Nexavar^®) was approved in Japan for “unresectable hepatocellular carcinoma (HCC)”, and was the first molecular-targeted agent for use in liver cancer. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and it has now been approved worldwide. Phase III clinical trials are now underway to compare other molecular-targeted agents with sorafenib as first-line treatment agents, and to evaluate other multi-kinase inhibitors of the vascular endothelial growth factor and platelet-derived growth factor receptors, as well as drugs targeting the epidermal growth factor receptor, insulin-like growth factor receptor, and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. This review outlines the main pathways involved in the development and progression of HCC and the agents that target these pathways.     

Indonesian consensus on systemic therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a deadly cancer with a rising incidence in the last 20 years. Most patients are diagnosed late when curative treatment is no longer feasible. With the background of chronic liver disease in most patients, the management of HCC becomes more complicated, in which well-preserved liver function is a prerequisite for locoregional or systemic therapies. In 2008, sorafenib became the first systemic agent proven to provide survival benefit for patients with advanced-stage HCC. For nearly a decade, no treatment has succeeded in providing better results than sorafenib. However, numerous advances in systemic therapies have emerged in the last 5 years to fulfill the unmet needs of effective therapeutic options. Several agents have been approved for clinical use after positive results in phase III clinical trials, including lenvatinib, regorafenib, cabozantinib, ramucirumab, and lastly immune checkpoint inhibitor atezolizumab in combination with bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor. With various options available, knowledge on the clinical evidence of each drug, their safety profile, as well as the patient characteristics and preferences become mandatory in clinical decision making. The objective of this consensus is to help clinicians, health-care workers, and policy makers in providing best clinical care for HCC patients.     

FDA Supplemental Approval Summary: Lenvatinib for the Treatment of Unresectable Hepatocellular Carcinoma

On August 16, 2018, the U.S. Food and Drug Administration approved lenvatinib (Lenvima, Eisai Inc.) for first‐line treatment of patients with unresectable hepatocellular carcinoma (HCC). Approval was based on an international, multicenter, randomized, open‐label, noninferiority trial (REFLECT; {"type":"clinical-trial","attrs":{"text":"NCT01761266","term_id":"NCT01761266"}}NCT01761266) conducted in 954 patients with previously untreated metastatic or unresectable HCC. Patients were randomized (1:1) to receive lenvatinib (12 mg orally once daily for patients with a baseline body weight ≥60 kg and 8 mg orally once daily for patients with a baseline body weight <60 kg) or sorafenib (400 mg orally twice daily) until radiological disease progression or unacceptable toxicity. REFLECT demonstrated that lenvatinib was noninferior but not statistically superior to sorafenib for overall survival (OS; hazard ratio, [HR] 0.92; 95% confidence intervals [CI], 0.79–1.06), with median OS of 13.6 and 12.3 months in the lenvatinib and sorafenib arms, respectively. REFLECT also demonstrated statistically significant improvements in investigator‐assessed progression‐free survival (PFS; HR, 0.66; 95% CI, 0.57–0.77]; p < 0.001), corresponding to median PFS of 7.4 and 3.7 months and overall response rate of 24.1% vs 9.2% per modified RECIST for HCC (mRECIST) in the lenvatinib and sorafenib arms, respectively. Consistent results were observed by an independent review facility per RECISTv1.1 and per mRECIST. The most common adverse reactions observed in the lenvatinib‐treated patients (≥20%) in decreasing frequency were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar‐plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea.Implications for PracticeThis article describes the U.S. Food and Drug Administration''s review of data from a single trial, REFLECT, that supported the approval of lenvatinib, as a single agent, for the first‐line treatment of unresectable hepatocellular carcinoma (HCC). REFLECT was an open‐label, noninferiority trial that randomized 954 patients with HCC who were ineligible for liver‐directed therapy with no prior systemic therapy for HCC to lenvatinib or sorafenib. REFLECT demonstrated that lenvatinib‐treated patients had similar survival, more responses, and longer time to progression than those receiving sorafenib. Serious side effects were more common among lenvatinib‐treated patients. Lenvatinib is an effective treatment for patients with previously untreated HCC.     

分子靶向药物在肝细胞癌治疗中的临床研究进展

肝癌是全球第六大常见的恶性肿瘤,也是第四大肿瘤相关死亡原因,其中肝细胞癌（hepatocellular carcinoma,HCC）占90%,且80%以上的HCC发生在肝炎和肝硬化等患者中。对于HCC的治疗方面,仅20%的HCC患者可进行手术切除、肝脏移植或射频消融治疗,而晚期HCC患者无法进行根治性治疗,其生存率也逐渐下降。近年来,分子靶向药物治疗已成为研究热点,该类药物可通过特异性的与致癌位点靶向结合而发挥抗癌作用。目前,抗HCC的靶向药物主要分为一线药物与二线药物,其中一线药物主要包括索拉非尼、仑伐替尼,二线药物主要包括瑞戈非尼、卡博替尼及雷莫芦单抗等。本文对此类分子靶向药物在HCC治疗中的临床研究进展进行综述。      

Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy

The phase III clinical trial of the novel molecular targeted agent (MTA) lenvatinib for patients with advanced hepatocellular carcinoma (HCC) (REFLECT trial) found that lenvatinib was non-inferior to sorafenib in overall survival. Recently, the efficacy of multiple MTAs, including lenvatinib, in practice has been reported, and therapeutic strategies for Barcelona Clinic Liver Cancer (BCLC) intermediate stage HCC are undergoing major changes. Based on these results, lenvatinib could be recommended for patients with transcatheter arterial chemoembolization (TACE)-refractory, ALBI grade 1, within the up-to-seven criteria in the BCLC intermediate stage. Lenvatinib provides a more favorable outcome than TACE, even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A. When patients meet the definitions of TACE-refractory or TACE-unsuitable, switching to systemic chemotherapy, including lenvatinib, is for favorable for preserving liver function. If initial treatment, including MTA, has a significant therapeutic effect and downstaging of HCC is obtained, additional TACE or surgical resection should be considered. Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug. Furthermore, a significant therapeutic effect is expected in tumors with more than 50% liver involvement or main portal vein invasion, which have traditionally been considered to have a poor prognosis in patients. This suggests that at the start of lenvatinib treatment, HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.     

Regorafenib for the treatment of unresectable hepatocellular carcinoma

Introduction: Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC) and well preserved liver function. However, until recent approval of regorafenib by the Food and Drug Administration (FDA), no effective therapeutic options were available for patients resistant to sorafenib.

Areas covered: The present article reviews the preclinical and clinical data of regorafenib, putting them into the context of current and future landscape of treatment options for patients with HCC. Recently, the randomized, placebo-controlled, Phase III RESORCE trial, demonstrated a statistically and clinically significant increase in overall survival from 7.8 months with placebo to 10.6 months with regorafenib in patients progressing on sorafenib. Furthermore, the study showed a significant improvement in all the other efficacy endpoints. Main adverse events were hypertension, hand-foot skin reaction, fatigue and diarrhea, with no negative impact on quality of life.

Expert commentary: Regorafenib is a recently approved treatment option for HCC patients who have been previously treated with sorafenib. The RESORCE trial demonstrates the beneficial effect of a sequential approach involving two multikinase inhibitors, namely sorafenib and regorafenib, whose antitumor activity extends beyond their antiangiogenic functions.     

PD-1/PD-L1抑制剂在晚期肝细胞肝癌治疗中的研究进展

晚期原发性肝细胞肝癌(hepatocellular carcinoma,HCC)的系统治疗主要包括靶向治疗、化疗以及免疫治疗。近3年,程序性死亡受体-1(programmed death receptor-1,PD-1)/程序性死亡受体-1配体(programmed death receptor-1 ligand,PD-L1)抑制剂在晚期HCC治疗中取得突破性进展。纳武单抗(nivolumab)和帕博利珠单抗(pembrolizumab)先后被美国食品药品管理局(FDA)批准用于HCC二线治疗。多个PD-1/PD-L1抑制剂联合系统治疗的Ⅰ、Ⅱ期临床研究初步显示出较好的疗效和安全性。阿特珠单抗(atezolizumab)联合贝伐单抗一线治疗成为首个在Ⅲ期临床研究中证实优于现有标准治疗索拉非尼的全新疗法。本文就近年PD-1/PD-L1抑制剂在晚期HCC治疗中的研究进展进行概述。     

Targeted agents in older patients with gastrointestinal cancers – An overview

Targeted agents have been increasingly used in different malignancies and are associated with improved survival outcomes, including gastrointestinal cancers. Their use in the treatment of older patients is appealing given their favorable toxicity profile. In the last years, this subgroup of patients has been attracting increased interest given their representativeness and specific clinical needs. Nonetheless, the lack of data on efficacy and safety of standard treatments in older patients hinders proper evidence-based decision-making, leaving most therapeutic recommendations to be extrapolated from registration trials with low representation of older and frail patients. However, even if most decisions regarding the use of targeted agents in older patients with gastrointestinal cancer remain guided by subanalyses of large trials, data from recent older adult-specific trials are beginning to emerge, particularly in colorectal cancer. This review aims to summarize the existing evidence on treatment of older patients with gastrointestinal carcinomas (colon and rectum, stomach, esophagus, liver, and pancreas) with targeted agents (cetuximab, panitumumab, bevacizumab, ramucirumab, aflibercept, regorafenib, encorafenib, trastuzumab, sorafenib, lenvatinib, cabozantinib, erlotinib, olaparib), and place the evidence in a geriatric oncology perspective.     

Second-line therapies in hepatocellular carcinoma: emergence of resistance to sorafenib

Second-line therapies are needed for patients with advanced hepatocellular carcinoma who progress after sorafenib. Positive signals seen with brivanib in phase II studies, reported herein, have yet to be confirmed in phase III trials. Identification of the molecular mechanisms driving sorafenib resistance should guide drug development strategies in this setting.