Hepatocellular carcinoma is typically diagnosed late in its course, and the median survival following diagnosis is short. The recommended therapy for localized hepatocellular carcinoma is surgical resection, but most patients are not eligible because of extensive tumor or underlying liver dysfunction. New treatments and indications for various treatments are evolving rapidly. For patients who are ineligible for liver-directed therapy or for patients showing progression on locoregional therapy, systemic therapy is an option if performance status and underlying liver function are within eligible requirements. Until 2008, no effective therapy existed for patients with advanced-stage hepatocellular carcinoma or for those who did not respond to local therapies. The molecularly targeted agents sorafenib and regorafenib have been shown to improve survival compared with best supportive care alone; a survival benefit has also been shown in the second-line setting for ramucirumab and immune checkpoint inhibitors. Lenvatinib has demonstrated noninferiority to first-line sorafenib. Most recently, the combination of atezolizumab plus bevacizumab was superior to front-line sorafenib. These results have radically changed the treatment landscape for patients with advanced hepatocellular carcinoma.
Key words : Immunotherapy, Survival, Treatment, Tyrosine kinase inhibitor
Primary liver cancer is the seventh-most frequently occurring cancer in the world and the second-most common cause of cancer mortality. Hepatocellular carcinoma (HCC) represents the major histological subtype among primary liver cancers, accounting for 70% to 85% of the total burden worldwide.1 According to the World Health Organization, HCC is the fifth most common tumor and the second most common cause of cancer-related deaths worldwide.2 The recommended therapy for localized HCC is surgical resection, but most patients are not eligible because of extensive tumor or underlying liver dysfunction. For patients who are ineligible for liver-directed therapy or for patients showing progression on locoregional therapy, systemic therapy is an option if performance status and underlying liver function are eligible. Until 2008, no effective therapy existed for patients with advanced-stage HCC or for those who did not respond to local therapies.
Sorafenib (a multitargeted tyrosine kinase inhibitor [TKI]) has been studied and approved based on results of the pivotal SHARP and the Sorafenib Asia-Pacific trials in Child-Pugh class A patients with advanced HCC. In 2008, the multicenter, phase 3, double-blind, placebo-controlled SHARP trial demonstrated a modest but statistically significant survival benefit for sorafenib over supportive care alone in patients with advanced HCC. In this trial, patients with advanced HCC who had not received previous systemic treatment were randomized to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival (OS) and time to symptomatic progression.3 The results showed that patients with advanced HCC who received sorafenib treatment had nearly a 3-month median survival benefit compared with those who received placebo (patients in the sorafenib group had a median survival of 10.7 months vs 7.9 months in the placebo group). The 2 most frequent grade 3 drug-related adverse events were diarrhea (8%) and hand-foot skin reaction (8%). Sorafenib-associated adverse events led to dose reductions and interruptions in a subgroup of patients.
In the Asia-Pacific trial, which investigated sorafenib in the Asia-Pacific region,4 patients with HCC who had not received previous systemic therapy and had Child-Pugh liver function class A were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily. This investigation was the first time that an agent demonstrated improved median OS in patients with advanced, incurable HCC in a randomized phase 3 trial, and sorafenib was approved all over the world for advanced HCC. After 2008, the oral multikinase inhibitor sorafenib was used for several years as the standard of care for advanced unresectable HCC. However, one of the primary limitations of sorafenib is its toxicity. Presentations of fatigue, hand-foot skin reactions, and diarrhea can be difficult to manage, with these reactions sometimes difficult for patients to tolerate.
Advances in Second-Line Systemic Treatment
After 2008, the 10 years of investigations into additional drugs showed negative results among all trials. The next breakthrough occurred in April 2017, which was with second-line regorafenib.5 Regorafenib is a novel oral multikinase inhibitor that blocks the activity of vascular endothelial growth factor (VEGF) and epidermal growth factor protein kinases in biochemical and cellular kinase phosphorylation assays and also inhibits additional angiogenic kinases (platelet-derived growth factor receptor-β and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and BRAF.6 In the randomized, double-blind, parallel-group, phase 3 trial RESORCE, which was done in 21 countries, patients with HCC who tolerated and progressed on sorafenib and had Child-Pugh class A liver function were enrolled.5 Between 2013 and 2015, 573 were enrolled and randomized and 567 initiated treatment. The study was positive for its primary endpoint of OS, which was 10.6 months in the regorafenib group and 7.8 months in the comparison group (hazard ratio [HR] of 0.63; P < .001). These findings resulted in regorafenib being approved in 2017 for patients with HCC who were previously treated with sorafenib.7 Regorafenib, although an effective treatment strategy in HCC, is also associated with significant adverse events. The most common grade 3 or 4 events were hypertension (15%), hand-foot skin reaction (13%), fatigue (9%), and diarrhea (3%).
The CELESTIAL study, another randomized, double-blind phase 3 trial, investigated cabozantinib versus placebo after failure of a sorafenib-based first-line therapy and also second-line treatment.8 Cabozantinib is a multikinase inhibitor that inhibits MET, VEGF receptors 1, 2, and 3; AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. In the CELESTIAL study, 470 patients received cabozantinib and 237 patients received placebo (2:1 randomization). Cabozantinib led to a significant improvement in OS (10.2 mo in the cabozantinib arm vs 8.0 mo in the placebo arm) with acceptable toxicity (HR of 0.76; P = .005). Adverse events of grades 3 or 4 were reported in 68% of patients in the cabozantinib group and in 36% of patients in the placebo group. The most common grade 3 or 4 adverse events in the cabozantinib group were palmar-plantar erythrody-sesthesia (17%), hypertension (16%), increased alanine aminotransferase level (12%), fatigue (10%), and diarrhea (10%). In January 2019, the CELESTIAL study results resulted in approval from the US Food and Drug Administration (FDA) of cabozantinib for patients with HCC who were previously treated with sorafenib.9
The REACH-2 study, another randomized, double-blind, multicenter phase 3 trial, tested ramucirumab after sorafenib against placebo.10 For this phase 3 trial, which was performed in 20 countries, eligible patients had histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, good performance status, alpha-fetoprotein (AFP) concentrations of 400 ng/mL or greater, and previous first-line sorafenib treatment. Participants were randomly assigned (2:1) to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. Although the primary endpoint of OS was not met, a prespecified population of patients with baseline ≥400 ng/mL AFP and Child-Pugh class A demonstrated a significant OS advantage.
When compared with TKIs, ramucirumab therapy is generally well-tolerated, with no unexpected toxicities. Few grade 3 or 4 toxicities have been observed with ramucirumab, and thus it may be an option over the TKIs, especially for patients with AFP concentrations of more than 400 ng/mL. Grade 3 or worse treatment-related adverse events that occurred in the ramucirumab group were hypertension (13%), hyponatremia (6%), and increased alanine aminot-ransferase level (3%).
As of 2021, compared with previous standards of care (including chemotherapy, radiotherapy, and surgery), cancer immunotherapy has brought signifi-cant improvements for patients in terms of survival and quality of life and immune checkpoint inhibitor therapies are now widely indicated in numerous cancer types.11 In addition to specific antigen recognition through the T-cell receptor, T-cell activation is regulated through a balance of positive and negative signals provided by costimulatory receptors. Agonistic antibodies directed against activating costimulatory molecules and blocking antibodies against negative costimulatory molecules may enhance T-cell stimulation to promote tumor destruction. These immune checkpoint inhibitors or immunotherapies are neutralizing antibodies that target the immune checkpoint T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1). These antibodies have resulted in dramatic improvements in disease outcome and are now clinically approved in many cancers. With regard to the PD1-PD-1 ligand (PD-L1) pathway, the binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body. Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) leads T cells to kill tumor cells. Available immune checkpoint inhibitors include nivolumab, pembrolizumab, durvalumab, and atezolizumab; these drugs are now in common practice for patients with cancer.
Accelerated approval of nivolumab, which is a PD-1 monoclonal antibody, was based on the CheckMate 040 trial, a phase 1/2, open-label, multicenter trial. Patients with advanced HCC who progressed on or were intolerant to sorafenib showed favorable response rates and durable responses. The CheckMate 040 trial, which studied the first checkpoint inhibitor nivolumab, investigated its use in patients in HCC with different underlying etiologies.12 This open-label phase 1/2 trial enrolled adults with advanced HCC with Child-Pugh class A/B7 (escalation phase) and class A (expansion phase) and Eastern Cooperative Oncology Group performance status <1; in addition, previous sorafenib treatment was allowed. The investigators proceeded with this study logically, looking at patients without viral hepatitis and then with hepatitis C virus (HCV) and hepatitis B virus (HBV) infection. At the time of the study, there was still some degree of concern on whether this class of agents would cause flare up of underlying hepatitis. The study then proceeded with dose expansion to up to 214 patients in different cohorts: HBV and HCV infected, sorafenib naive, and sorafenib treated. Patients were heavily pretreated, and 77% of patients had previously been treated with sorafenib.
In the CheckMate 040 trial, the overall objective response rate was 15% in the dose-escalation phase, including 3 complete responses and 4 partial responses. The disease control rate was 58%, and the median time to progression was 3.4 months. The median duration of response was 17 months, and the 6-month and 9-month OS rates were both 66%. Median OS for patients in the dose-escalation phase was 15.0 months. An objective response was observed in 20% of patients who received nivolumab 3 mg/kg every 2 weeks in the dose-expansion phase. Objective responses included 3 complete responses and 39 partial responses. Stable disease was observed in 45% of patients, and disease control was observed in 64% of patients. The overall safety profile of nivolumab in patients in the dose-expansion phase was comparable to that observed in the dose-escalation phase. Grade 3/4 treatment-related adverse events were seen in 40 patients (19%), and grade 3/4 treatment-related serious adverse events were seen in 9 patients (4%). In the dose-escalation phase, the safety profile of nivolumab in patients with HCC was consistent with that observed in other tumor types.12
Thus, there was about a 15% to 20% response rate regardless of the specific subgroup; this was shown in both patients who progressed on sorafenib and those without sorafenib treatment, as well as in patients with underlying HCV and HBV. For patients who responded to treatment with this type of agent, 91% had responses lasting at least 6 months and 55% had responses lasting at least 12 months.
The second checkpoint inhibitor that was examined was pembrolizumab, which is also a PD-1 monoclonal antibody. The KEYNOTE-224 study, a nonrandomized, multicenter, open-label, phase 2 trial, was conducted in 10 countries. Eligible patients had previously been treated with sorafenib and were either intolerant to this treatment or showed radiog-raphic progression of their disease after treatment. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression or unacceptable toxicity. The primary endpoint was objective response.13 Among the 104 patients in this study, overall response rate was 17%. Median time to response was 2.1 months, and best responses were complete response in 1 patient (1.0%), partial response in 16 patients (15.4%), stable disease in 47 patients (45.2%), and progressive disease in 34 patients (32.7%); 77% had response duration of ≥9 months and median duration of response was not reached. The investigators concluded that pembrolizumab treatment resulted in durable responses and favorable progression-free survival (PFS) and OS in patients with advanced HCC previously treated with sorafenib. Safety was generally comparable to that established for pembrolizumab monotherapy. These findings resulted in accelerated approval of pembrolizumab from the US FDA similar to nivolumab.
Pembrolizumab was also tested in the phase 3 KEYNOTE-240 trial, which examined the coprimary endpoints of PFS and OS.14 This randomized, double-blind, phase 3 study was conducted at 119 medical centers in 27 countries. Patients with advanced HCC, previously treated with sorafenib, were randomized to receive pembrolizumab or placebo. Median OS was 13.9 months for pembrolizumab versus 10.6 months for placebo (HR of 0.781; P = .0238). Median PFS for pembrolizumab was 3.0 months versus 2.8 months for placebo (HR of 0.718; P = .0022) at final analysis. Grade 3 or higher adverse events occurred in 147 (52.7%) versus 62 patients (46.3%) for pembrolizumab versus placebo.
With regard to second-line treatment options after sorafenib failure and intolerance and the question of how to choose and sequence different drugs in HCC, the appropriate selection of each treatment should be individualized. These are summarized as follows (Table 1 and Table 2): (1) regorafenib for those with prior sorafenib tolerability, (2) cabozantinib for those with up to 2 prior regimens and sorafenib intolerance, (3) ramucirumab for those with baseline AFP ≥400 ng/mL and favorable toxicity profile, and (4) nivolumab and pembrolizumab for those with durable response.
Advances in First-Line Systemic Treatment
Because few systemic treatment options are available for patients with advanced HCC, there still exists a need to develop new drugs for effective management of this disease. Lenvatinib is an oral multikinase inhibitor that targets VEGF receptors 1 to 3, fibroblast growth factor receptors 1 to 4, platelet-derived growth factor receptor α, RET, and KIT. Lenvatinib monotherapy has been approved for treatment of radioiodine-refractory differentiated thyroid cancer, in combination with everolimus (for treatment of patients with advanced renal cell carcinoma following 1 prior antiangiogenic therapy) and in combination with pembrolizumab (for treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high or mismatch repair deficient, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation).
In a phase 2 study of patients with advanced HCC, clinical activity with an acceptable safety profile with 12 mg lenvatinib once daily was observed.15 In a first-line phase 3 randomized open-label, noninferiority trial (the REFLECT study16), lenvatinib versus sorafenib was investigated in patients with nonresectable HCC who had not received treatment for advanced disease. This was a noninferiority trial, and patients were randomized to receive oral lenvatinib (12 mg/day for body weight ≥60 kg or 8 mg/day for body weight <60 kg) or sorafenib (400 mg twice daily in 28-day cycles). The primary endpoint was OS. Although the REFLECT study showed only a slight (and not significant) improvement in median survival in the lenvatinib arm (13.6 vs 12.3 mo), there was a significant improvement in tumor response (objective response rate of 24.1% vs 9.2%; P = .001) and time to progression (8.9 vs 3.7 mo; P < .0001). Lenvatinib was associated with more frequent adverse effects than sorafenib, which might be due to the longer treatment duration in the lenvatinib arm. Important high-grade adverse events were hypertension and weight loss for lenvatinib, as well as skin toxicity and diarrhea for sorafenib, respectively. After results released in August 2018, the US FDA approved lenvatinib for the first-line treatment of patients with unresectable HCC.17
The CheckMate 459 study, another first-line phase 3, noninferiority, randomized trial, compared the efficacy of nivolumab versus sorafenib in patients with advanced, nonresectable HCC and no prior systemic therapy for advanced disease.18 This was a head-to-head comparison versus sorafenib as first-line therapy in advanced HCC, but the primary endpoint of OS did not reach statistical significance (HR of 0.84, P = .0419). Median OS was 16.4 mo for nivolumab and 14.7 mo for sorafenib (HR of 0.85; P = .0752).
Several active intrinsic immune-evasion pathways, including overexpression of VEGF, have been shown to be associated with the development and progression of liver cancer. Anti-VEGF therapies reduce VEGF-mediated immunosuppression within the tumor and its microenvironment and may enhance anti-PD-1 and anti-PD-L1 efficacy by reversing VEGF-mediated immunosuppression and promoting T-cell infiltra-tion in tumors.14 The GO30140 study was a phase 1b trial of atezolizumab plus bevacizumab in patients with untreated and unresectable HCC. Its aim was to investigate the efficacy and safety of atezolizumab alone and combined with bevacizumab in patients with unresectable HCC. Results showed longer PFS (5.6 vs 3.4 mo; HR of 0.55; P = .011) with the combination arm with acceptable adverse effects. The investigators concluded that atezolizumab plus bevacizumab might be a promising treatment option for these patients.19
The IMbrave150 study, a global, multicenter, open-label, phase 3 randomized trial, aimed to determine the safety and efficacy of atezolizumab plus bevacizumab compared with sorafenib in patients with unresectable HCC who had not previously received systemic therapy.20 The trial included subgroups of high-risk patients excluded from other contemporary phase 3 trials; about 40% of patients had macrovascular invasion, and the cohort included patients with 50% hepatic involvement or main portal vein invasion. The combined atezolizumab plus bevacizumab group received 1200 mg of atezolizumab plus 15 mg/kg of bevacizumab every 3 weeks until progression or unacceptable toxicity. At the primary analysis of median follow-up at 8.6 months, 28.6% of patients in the atezolizumab plus bevacizumab group and 39.4% of patients in the sorafenib group had died, although OS at 12 months had significantly improved in the combination arm versus the sorafenib arm (HR of 0.58; P < .001), showing 67.2% versus 54.6% OS rates. The duration of response was at least 6 months in 87.6% versus 59.1% for the combination group versus the sorafenib group.
Updated results of the IMbrave150 trial were presented at the 2021 Gastrointestinal Cancers Symposium.21 At a median follow-up of 15.6 months, the median OS was 19.2 months with the com-bination treatment versus 13.4 months with sorafenib (HR of 0.66; P = .0009). The median PFS was 6.9 versus 4.3 months, respectively (HR of 0.65; P = .0001). In terms of safety, all-grade treatment-related adverse events occurred in 86% of patients in the combination arm versus 95% of patients in the sorafenib arm. The rates of grade ¾ treatment-related adverse events were 43% and 46%, respectively. Thus, this study showed a highly active regimen superior to sorafenib as frontline therapy for the first time. In May 2020, the US FDA approved the combination for patients with unresectable or metastatic HCC who had not received prior systemic therapy based on findings from the primary analysis of the Imbrave150 trial in which both the coprimary endpoints of PFS (HR of 0.59) and OS (HR of 0.58) were met. Grade 5 treatment-related adverse events occurred in 2% of patients in the combination arm versus less than 1% in the sorafenib arm (Table 3).
There are many ongoing multicenter phase 3 trials that have investigated combined TKIs and checkpoint inhibitors and dual checkpoint inhibitors; their results are eagerly awaited. There are promising developments in advanced-stage HCC. However, due to financial reasons, our country (Turkey) has been unable to reimburse most of these drugs. Therefore, screening for high-risk patients with HCC and diagnosing at earlier stages are still important issues requiring further studies.
DOI : 10.6002/ect.2021.0478
From of Medical Oncology, Baskent University Faculty of Medicine, Ankara, Turkey
Acknowledgements: The author has not received any funding or grants in support of the presented research or for the preparation of this work and has no declarations of potential
conflicts of interest. This manuscnpt was onginaly presented as part of the International Symposum on Benign and Malinant Tumors in Liver With or Without Cirrhosis held in Ankara, Turkey
Corresponding author: Ozden Altundag, Department of Medical Oncology, Baskent University Faculty of Medicine, 06490 Bahcelievler, Ankara, Turkey
Phone: +90 5333414050
Table 1. Hepatocellular Carcinoma Treatment Landscape: Second-line Options Approved by the US Food and Drug Administration
Table 2. Approved Targeted Therapies for Patients Previously Treated With Sorafenib: Positive Phase 3 Trials
Table 3. Phase 3 Trials of First-Line Systemic Therapy in Hepatocellular Carcinoma