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Corresponding author. . Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele (Milan), Italy. Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center IRCCS. Via Manzoni 56, 20089 Rozzano (Milan), Italy. Phone: 39 02 82244573. Fax: 39 02 82244590.
Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele (Milan), ItalyMedical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy
Single-agent immune checkpoint inhibitors (ICIs) have been tested in patients with advanced hepatocellular carcinoma (HCC) showing an objective response rate of 15-20%, mostly without a significant overall survival (OS) benefit. Furthermore, approximately 30% of HCC shows intrinsic resistance to ICIs. In the absence of predictive biomarkers to identify patients likely to benefit most from immunotherapy, research has moved to exploring combinations with potential activity in broader patient populations. Basket trials, including cohorts of patients with HCC, and early phase studies tested the combination of ICIs with antiangiogenic agents as well as the combination of two different ICIs. The achieved promising results provided the rationale for the following phase 3 trials, which tested the combination of anti-PD-1/PD-L1 with bevacizumab, or tyrosine kinase inhibitors (TKIs), or anti-CTLA-4. Positive results from the IMbrave150 trial led to the practice-changing approval of atezolizumab-bevacizumab, the first regimen to demonstrate improved survival in the front-line setting, since the approval of sorafenib. More recently, the HIMALAYA trial demonstrated the superiority of durvalumab-tremelimumab (STRIDE regimen) over sorafenib, establishing a new first-line option. In contrast, inconsistent results have been achieved with combinations of ICIs and TKIs, with only one phase 3 trial showing an OS benefit. The rapidly evolving therapeutic landscape for patients with advanced HCC has left significant unmet needs to be addressed in future research. These include choice and sequencing of treatments, identification of biomarkers, combinations with locoregional therapies, and development of new immunotherapy agents. This review summarizes the scientific rationale and available clinical data for combination immunotherapy in advanced HCC.
Single-agent immune checkpoint inhibitors (ICIs) produced objective responses in around 15% of patients with advanced HCC in phase 2 and 3 trials
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Immunotherapy combinations have been developed with the aim of improving activity and broadening the patient population that could benefit
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Immunotherapy combinations tested in phase 3 trials include ICIs and bevacizumab, ICIs and tyrosine-kinase inhibitors, and the combination of two ICIs
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Atezolizumab-bevacizumab and durvalumab-tremelimumab (STRIDE regimen) are current front-line standards of care
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Future directions include definition of treatment sequences, identification of biomarkers, combinations with locoregional therapies, development of novel immunotherapy agents
Introduction
The successful development of systemic therapy for hepatocellular carcinoma (HCC) followed two important advances in our understanding of the disease: 1) an appreciation for the importance of patient selection in clinical trials and 2) the development of molecular therapeutics with activity against HCC. The first point may seem trivial now, but the utility of the Barcelona Clinic Liver Cancer (BCLC) as originally described highlighted the importance of defining the stage and natural history of these groups of patients based not only on tumor characteristics but also patient characteristics such as underlying liver disease.
. In addition, beginning in the late 1990s, cancer medicine was transforming from the development of cytotoxic chemotherapies, which never were shown to improve outcomes in advanced HCC, to molecular targeted therapeutics, both small molecules and monoclonal antibodies, that were designed to interfere with proteins important in the pathogenesis of cancer. The first to be approved in HCC was sorafenib, based on data from the SHARP study that demonstrated for the first time the ability of medical treatment to improve survival in patients with advanced HCC.
Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
. This study set the stage for future drug development in HCC. In the following years, other multi-targeted tyrosine kinase inhibitors (TKIs), such as lenvatinib in first line
Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
after sorafenib treatment, as well as ramucirumab, a monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), with activity in patients with alpha-fetoprotein (AFP) ≥400 ng/mL
Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
have been approved based on positive results of phase 3 trials.
More recently, immune checkpoint inhibitors (ICIs), such as anti-programmed death receptor-1 (PD-1), anti-programmed-death ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) mAbs, have been tested in both treatment-experienced and treatment-naïve patients. Also, immunotherapy combination strategies, such as anti-PD-1/PD-L1 plus anti-VEGF or TKIs or anti-CTLA-4, have been evaluated and are still being tested to expand the responsive population, overcome resistance, and increase efficacy.
In this review, we provide the evidence for combination immunotherapy in advanced HCC, including the scientific rationale and the clinical data. We aim to put the available data into perspective to better understand the rapidly changing treatment landscape and identify future directions that need to be addressed in clinical trials and clinical practice.
Rationale
Cancer progression requires some mechanism of evasion from immune surveillance. Checkpoint molecules provide the fine tuning of the immune response against infectious agents and cancer cells alike. Inhibitory checkpoints comprise PD-1, CTLA-4, lymphocyte-activation gene 3 (LAG-3) and others. PD-1 blocks TCR signaling and inhibits T-cell proliferation and secretion of cytotoxic mediators, and continuous PD-1 signaling leads to T-cell exhaustion.
. ICIs targeting PD-1 and its main ligand PD-L1 have an unquestionable antitumor effect in some patients with advanced HCC. PD-1 and PD-L1 inhibitors including nivolumab, pembrolizumab, camrelizumab, tislelizumab, durvalumab and atezolizumab consistently produce objective tumor responses in around 15% of patients in prospective phase 2 and 3 trials.
. Responses are consistently associated with prolonged survival, but favorable outcomes are also observed among some non-responders, including those with prolonged stable disease and even patients with tumors which initially progress and then become stable or respond.
Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): Subanalyses of CheckMate-040.
. Yet, not less than 30% of HCC tumors in this stage show intrinsic resistance to PD-1 or PD-L1 inhibitors and a few even develop increased tumor growth dynamics after treatment is initiated.
. The antitumor activity of PD-1 and PD-L1 inhibitors used as single agents was not broad enough or strong enough to significantly improve the OS of naïve patients when they were compared to sorafenib in phase 3 trials.
. Combining them with other agents that could provide additive or synergistic activity was therefore a low-hanging fruit.
Two types of strategies were ready for direct testing in combination therapies. On one hand, agents which further stimulate T cell activation through the inhibition of additional checkpoint molecules providing inhibitory signals or the stimulation of checkpoint molecules providing stimulatory signals. On the other, agents able to modify the immune tumor microenvironment rendering it less hostile for cytotoxic T cells or more favorable for antigen cross-presentation to T cells. Increasing the number of tumor-specific T cells with the use of tumor vaccines, adoptive T cell therapy or epigenetic regulators are also appealing strategies in need of more solid evidence in preclinical and clinical scenarios and will therefore not be discussed here.
CTLA-4 is expressed on the membrane of activated T cells and there it competes with CD28 to impede T cell co-stimulation.
. In animal models where the relative contributions of CTLA-4 blockade on effector T cells and Tregs can be assessed, it is the combination of direct enhancement of the effector T cell function and inhibition of Treg activity that is key for deploying the full therapeutic effects of anti-CTLA-4 antibodies.
. Dual CTLA-4 and PD-1 or PD-L1 blockade therefore results in a range of immune stimulating effects different from monotherapies including unique modulation of terminally differentiated effector CD8+ T cells
that may be important for treating immunologically cold tumors that respond poorly to PD-1 or PD-L1 inhibitors. In a murine HCC model, combined treatment with anti-PD-1 and anti-CTLA-4 antibodies produced higher CD4+ and CD8+ T cell tumor infiltration than monotherapies, together with a reduced Treg infiltration, findings that were associated with increased efficacy.
. Yet, the impact of CTLA-4 blockade on tumor Treg infiltration or immunosuppressive activity has not been demonstrated convincingly.
Angiogenesis is a key player in cancer immune evasion. Pro-angiogenic factors like VEGF inhibit cytokine-induced adhesiveness of endothelial cells inducing a state of endothelial cell anergy that is exploited by tumors to evade immune infiltration.
. Similar effects have been shown for other pro-angiogenic factors, such as angiopoietins, hepatocyte growth factor (HGF) and platelet-derived growth factor (PDGF).
and this may in turn activate an array of immunosuppressive mechanisms. Tumor hypoxia attracts Tregs, regulate the maturation and function of MDSCs, decoys tumor-associated macrophages (TAM) and differentiates them towards an M2 phenotype (which participates in tumor progression by suppressing anti-tumor immunity), and has a very potent negative effect on the function of activated T cells through adenosine accumulation (Figure 1).
. However, a significant effect of this kind seems unlikely given the observed antitumor activity of selective VEGF inhibitors in combination with PD-1
Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.
The immunological effects of TKIs have only been recently studied and are far from being completely understood. TKIs share the ability to target VEGF and PDGF receptors, largely responsible for their common antiangiogenic activity.
. As explained above, VEGF inhibition may generate some immune stimulating effects. Besides, different TKIs display different abilities to inhibit individual intracellular pathways.
. Hence, their effects on tumor stromal and cancer cells may vary from one compound to another.
Pre-clinical in vitro and in vivo models have shown some off-target effects of TKIs that may contribute to the immune response against cancer through different mechanisms. First, TKIs may modify macrophage infiltration and polarization. Sorafenib favors M1 polarization through inhibition of mitogen activated protein kinase phosphatase or MAPKp
Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway.
Second, TKIs may enhance T cell function. Sorafenib enhances the function and migration of transferred CD8+ T cells in adoptive T cell therapy through inhibition of STAT3 and other immunosuppressive factors.
. And it upregulates effector T cell functions and reduces the proportion of CD8+ T cells expressing PD-1. Lenvatinib increases the percentage of activated CD8+ T cells secreting interferon IFN-γ and granzyme B.
Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway.
. Third, TKIs may reduce the number and activity of immunosuppressive cells. Sorafenib inhibits the proliferation of Tregs, induces apoptosis and inhibits their function
. Fourth, TKIs may inhibit the local release of immunosuppressive molecules. Regorafenib and other TKIs block the expression of immune suppressive factors induced by IFN-γ, including IDO1, through inhibition of the RET-Src axis.
However, these effects are only observed under the specific experimental context of each animal model, and the studies should be analyzed with caution given the inherent difficulty in simulating the human tumor microenvironment and the differences between the murine and human immune systems. An important point to consider is the potential effect of TKI dosing, which seems to be critical in preclinical models. Pharmacologic doses of sorafenib decreased activation of effector T cells isolated from peripheral blood cells of HCC patients. Quite the reverse, lower doses led to increased activation and proliferation of effector T cells and IL-2 secretion while at the same time blocking Treg function.
. Likewise, low doses of an anti-VEGFR2 antibody switches the number and phenotype of tumor-infiltrating myeloid cells from immunosuppressive to immunostimulatory
In addition, different TKIs may exert different immune modulating effects. As an example, in liver cancer xenografts lenvatinib increased, while regorafenib decreased, the expression of PD-L1 by tumor cells.
while in four different oncogene-driven, immunocompetent murine HCC models (c-Met/β-catenin, Akt/c-Met, Akt/Ras and c-Myc), cabozantinib did not modify the tumor microenvironment in a meaningful way.
. T cell infiltration and PD-L1 expression remained unaltered, and a reduction in macrophage infiltration was not accompanied by changes in macrophage polarization.
To add to this complexity, when the possible additive or synergistic effect of the combination of TKIs with ICIs have been explored in animal models, the results have been inconsistent, with both positive
Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway.
. The results from recently reported clinical trials have also produced inconsistent results that will be detailed in the following sections. We will hopefully have a better understanding of the effects of these combinations when the biomarker analyses of the phase 3 trials are reported.
Transforming our Management of HCC: Immunotherapy in the Clinic
Single-Agent Immunotherapies
Like the development of almost all drugs in HCC, they are often first studied in other malignancies before HCC given the concern of the co-morbidity of underlying liver disease. The inability of single agent ICIs to improve OS led to the development of combination approaches.
Tremelimumab was first studied as a single agent in patients with hepatitis C virus (HCV) related liver cancer, showed an early efficacy signal but there were still concerns regarding the safety of this class in patients with underlying liver disease.
. 17 patients were evaluable for response with an objective response rate (ORR) of 17.6% and disease control rate was 76.4%. While no patients required steroids for severe immune-mediated adverse events (imAEs), almost half the patients had >3 elevations in liver enzymes. The largest single-agent experience subsequently came with the PD-1 antibody nivolumab in the CheckMate 040 study.
Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
. In this study 48 patients were treated first in a dose escalation phase followed by 214 in a dose expansion phase in patients who were intolerant to or progressed on prior sorafenib. The ORR was 20% (95% CI 15–26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6–28) in the dose-escalation phase. The safety profile in this population was consistent with nivolumab in non-HCC etiologies and provided the basis for the accelerated approval of nivolumab in second-line HCC in the United States (US) in 2017. This approval was subsequently removed in 2021 when the confirmatory open-label front-line study of nivolumab versus sorafenib did not meet its endpoint of improving OS despite confirming an ORR of 15% and a favorable side-effect profile. There have been multiple other single-agent studies with other PD-1/PD-L1 inhibitors including pembrolizumab in the second-line setting, and durvalumab and tislelizumab in the front-line setting all yielding similar ORR in the 15-20% range and similar well-tolerated side effect profiles.
Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
Pembrolizumab Versus Placebo as Second-Line Therapy in Patients from Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial.
J Clin Oncol.2022 Dec 1; (JCO2200620. Online ahead of print)
Final Analysis of RATIONALE-301: Randomized, Phase 3 Study of Tislelizumab Versus Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma.
. In front-line these agents have met non-inferiority survival endpoints compared to sorafenib, and in second line, pembrolizumab has met its OS endpoint versus placebo in some studies but not others.
Improving Survival with Combinations
The promising early results from single-arm phase 1/2 studies with ICIs were tempered as phase 3 studies began reading out. Despite confirmed single agent, durable responses that were significantly higher than reported with sorafenib, or even placebo, single ICIs did not initially meet their endpoints in phase 3 trials. To improve on these results efforts to identify a biomarker have not yielded easily translatable results. Detailed analysis from CheckMate 040 which mandated tissue collection did not identify any single biomarker, but like other studies, have identified “inflammatory signatures” that may be associated with better outcomes.
Assessment of inflammation biomarkers in relation to clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma in CheckMate 040.
. Additionally, combining ICIs with other agents has been a successful strategy in improving OS and resetting the standard of care for patients with advanced liver cancer. A summary of phase 3 clinical trials with ICI based regimens is in Table 1.
Table 1Randomized phase 3 clinical trials testing combination regimes which include at least one ICI.
Trial
Treatment
n
Etiology, %
EHD, %
BCLC B, %
ORR, %
mPFS, months
mOS, months
HR for OS
TRAE grade 3-4, %
TRAE leading to discontinuation of any drug (both drugs), %
Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): Subanalyses of CheckMate-040.
Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
. For the first time since the approval of sorafenib in 2007, a regimen demonstrated superiority for OS in front-line HCC. Based on the observation that HCC is hypervascular tumor, anti-VEGF/VEGFR therapeutics have been studied extensively in HCC and until recently, the only drugs approved in the space were linked to this pathway. Our fundamental understanding of the biologic effects of targeting the VEGF pathway have evolved over time, from one focused on “normalizing” the tumor vasculature and effecting tumor oxygenation and nourishment, to effects on the immune microenvironment that shifts it from immunosuppressive to immune activating.
The IMbrave150 study was an open-label global phase 3 study evaluating the combination of atezolizumab and bevacizumab versus sorafenib and has supported the global approval of this regimen.
. The study evolved from data from a phase 1b study that included 104 patients treated with the combination that demonstrated an ORR of 36% and an expected safety profile.
. IMbrave150 met its coprimary endpoints of improving OS and progression-free survival (PFS). At the time of the primary analysis the median survival in the combination arm was not reached vs 13.4 months with sorafenib (HR 0.58; 95% CI 0.42-0.79; P<0.001). Median PFS was 6.8 months (95% CI 5.7-8.3) and 4.3 months (95% CI 4.0-5.6) in the respective groups (HR 0.59; 95% CI 0.47-0.76; P<0.001). ORR was increased with the combination, 27.3% vs 11.9% with sorafenib and quality of life measurements favored the combination as well. More recently, with longer follow-up, the median survival in the combination arm was reached at 19.2 months and the ORR increased to 30% with no longer-term safety concerns.
. Importantly, because of concerns with bleeding risk and bevacizumab, all patients were required to have an upper endoscopy within 6 months of enrolling in the study. With this approach, the incidence of high-grade bleeding events was low, 6.4% grade 3/4 with atezolizumab-bevacizumab vs 5.8% with sorafenib; four grade 5 events with the combination vs none with sorafenib. All grade 3/4 AEs occurred in 56.5% atezolizumab–bevacizumab patients and in 55.1% on 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. As expected, there were imAEs seen, but these were generally low grade and the use of steroids to manage atezolizumab AEs was 12.2% all grades and 8.5% grade 3/4 with the combination. Overall, discontinuation rates due to AEs were 7% for the combination and 10.3% for sorafenib.
Since the publication of IMbrave150, the combination of the PD-1 antibody sintilimab and the bevacizumab biosimilar (IBI305) has resulted very similar results in a phase 2/3 study conducted in China only.
Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.
. The results of the ORIENT-32 study demonstrated a significantly longer OS for the combination than did sorafenib (median not reached [95% CI not reached-not reached] vs 10.4 months [95% CI 8.5-not reached]; HR 0.57, 95% CI 0.43-0.75; P<0.0001). Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer PFS (4.6 months; 95% CI 4.1-5.7) than did patients in the sorafenib group (2.8 months; 95% CI 2.7-3.2; stratified HR 0.56; 95% CI 046-0.70; P<0.0001) and the ORR was 21% for the combination. The safety was generally in line with IMbrave150.
ICIs and VEGF Multi-kinase Inhibitors
Combining ICIs with multi-kinase inhibitors is another VEGF-based approach at increasing activity. The difference with the TKIs is that unlike the monoclonal antibodies which are pure VEGF related, these molecules have effects on the VEGFR as well as a number of other kinases that may play a role in modulating the activity of ICIs. At this time, we have seen the results of three phase 3 studies looking at this approach.
The first phase 3 study to read out was COSMIC-312 that evaluated atezolizumab and cabozantinib versus sorafenib.
Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial.
. Though there was limited data on this specific combination, this global, open-label study did meet one of its primary endpoints of improving PFS (6.8 months in the combination group versus 4.2 months in the sorafenib group; HR 0.63; 99% CI 0.44-0.91; P=0.0012). However, the regimen did not yield a rate of objective responses typically seen with single agent ICIs and was significantly less than would be expected with a combination strategy (ORR 11% with the combination). This observation, along with the lack of an OS benefit with the combination, has persuaded the sponsor not to pursue regulatory approval.
At the ESMO 2022 annual meeting two additional phase 3 studies were presented. The global LEAP-002 study evaluated the combination of pembrolizumab and lenvatinib versus lenvatinib and placebo in patients with advanced HCC without main portal vein invasion (Vp4).
Primary results from the phase 3 LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC).
. It was the first double-blind placebo-controlled study in the front-line setting with lenvatinib as the control arm. This study built on a single-arm phase 1b study of 100 patients that demonstrated an ORR of 36% per RECIST 1.1 with a median duration of response of 12.6 months. PFS was 8.6 months per RECIST 1.1, and median OS was 22 months.
. The safety profile was similar to that of single-agent lenvatinib.
In the phase 3 study, the activity of the combination was confirmed with an ORR of 26.1% as compared to 17.5% with lenvatinib alone, with a median duration of response of 16.6 months versus 10.4 months. The dual primary endpoints were OS and PFS by blinded review. Median PFS was 8.2 months and median OS was 21.2 months with the combination versus 8.0 months (HR 0.867; 95% CI 0.734-1.024; P=0.0466) and 19.0 months lenvatinib alone (HR 0.84; 95% CI 0.708-0.997; P=0.00227), respectively. The study did not meet either endpoint as the superiority threshold for OS with the combination was a one-sided α=0.0185, and as such the study was negative. There were no new safety findings with the combination. What was new, and surprising, was the performance of lenvatinib as a single agent as compared to the PFS and OS data from the pivotal REFLECT study (7.3 months and 13.6 months, respectively).
Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
. The significant increase in median OS for lenvatinib between the two studies is likely the result of several factors including improved management of lenvatinib AEs by investigators, the double-blinded nature of the study, and the increased number of patients that went on to receive additional therapies after progression (33% in REFLECT and 44.1% in LEAP-002). In LEAP-002, this included 14.4% that got ICI-based treatments.
The other phase 3 combination study presented at ESMO 2022 was the open-label study comparing the PD-1 inhibitor camrelizumab and the VEGFR2 TKI rivoceranib (apatinib), both approved in China, versus sorafenib alone.
Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): A randomized, phase III trial.
. This study, unlike the LEAP-002 study, did not limit patients based on tumor characteristics. In a single-arm study of the combination, ORR was 34.3%, PFS 5.7 months, and the 18-month OS rate was 58.1%.
. The study met both of its primary endpoint of PFS (5.6 months with combination versus 3.7 months with sorafenib; HR 0.52; 95% CI 0.41-0.65; P<0.0001) and OS (22.1 months versus 15.2 months; HR 0.62; 95% CI 0.49-0.80; P<0.0001). These benefits were consistent across baseline clinical factors such as stage, geographic region, etiology, and among others. ORR was 25.4% versus 5.9% and responses were durable. While the discontinuation rate for all treatment components was low, 3.7% for the combination, grade 3/4 treatment-related AEs (TRAEs)were significantly higher with the combination versus sorafenib, 80.5% and 52% respectively. Some of the most common AEs with the combination included hypertension, aspartate aminotransferase (AST) increased, proteinuria, and alanine aminotransferase (ALT) increased. The unique rivoceranib toxicity of reactive cutaneous capillary endothelial proliferation (RCCEP) occurred in 29% of patients, most of it of lower grade. While the regimen is clearly very active, it does come with increased toxicity and global regulatory review is pending at this time as 83% of patients came from Asia, and only 17% were non-Asian with over 70% of patients having hepatitis B virus (HBV) related liver cancer. This raises the question of whether the results are driven by the enrichment of patients with HBV related liver disease. When we look at the results of other positive global phase 3 studies, we see a consistent survival benefit for both HBV and HCV and similar ORRs. This is seen in the IMbrave150 study intent-to-treat populations
IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC).
Co-targeting the immune priming phase with CTLA-4 inhibition in combination with the immune effector phase with PD-1/PD-L1 inhibition has become an attractive approach in cancer medicine. The first combination to assess this approach in HCC was the combination of ipilimumab and nivolumab in the second-line setting after prior sorafenib.
Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial.
. Three different dosing strategies were assessed, all of which included: 1 mg/kg plus ipilimumab 3 mg/kg (arm A), administered every 3 weeks (4 doses), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses) (arm B), and nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). Both arms A and B were followed by single agent nivolumab. While all three arms performed similarly in regard to ORR, 32%, 27% and 29%, respectively, arm A had a median OS of 22.8 months as compared to a little over 12 months for the other two arms and received accelerated approval by the US Food and Drug Administration (FDA) on March 10, 2020, for second-line treatment of advanced HCC. The confirmatory CheckMate 9DW is comparing the regimen versus sorafenib or lenvatinib in the front-line setting (NCT 04039607). In regard to tolerability, the addition of CTLA-4 inhibition significantly increased imAEs with 50% of patients in the study requiring corticosteroids to manage these events. Any-grade TRAEs were reported in 46 of 49 patients (94%) of patients in Arm A. Most of these were low-grade though the most frequent grade 3/4 event was AST increased but there was 1 treatment-related death (grade 5 pneumonitis).
The HIMALAYA study was a global open-label phase 3 study evaluating a single high-dose of the CTLA-4 antibody tremelimumab in combination with the PD-L1 antibody durvalumab versus sorafenib.
. Like the LEAP-002 study, this study excluded the poor prognostic group of patients with tumor invasion of the main portal vein. The dosing of the combination, called the STRIDE regimen, was established from a multi-arm phase 1/2 expansion trial.
Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study.
. This multi-arm study evaluated STRIDE versus a multi-low dose regimen with tremelimumab and durvalumab versus single agent durvalumab and tremelimumab. The STRIDE regimen was chosen to move forward in the phase 3 study as it had a more favorable safety profile and improved efficacy. In addition, pharmacodynamic studies demonstrated that the addition of the single high dose of tremelimumab increased the CD8+ T cell population. The HIMALAYA study met its primary endpoint of improving OS of the combination versus sorafenib (median OS 16.43 months versus 13.77 months, HR 0.78; 96.02% CI 0.65-0.93; P=0.0035). As discussed earlier, a secondary endpoint of non-inferiority of single-agent durvalumab versus sorafenib was also met (median OS durvalumab alone 16.56 months versus 13.77 months; HR 0.86; 95.67% CI 0.73-1.03). PFS was not significantly different between the three arms. Both durvalumab containing arms had a higher ORR with 20.1%, 17%, and 5.1% responding in the STRIDE, durvalumab, and sorafenib arms, respectively. The study was not designed to compare the STRIDE regimen to single agent durvalumab. However, it is interesting to note that the survival curves of these two arms do not separate until about 24 months. This suggests that there is a subgroup of patients that benefit from the addition of CTLA-4 inhibition which results in a group of patients with longer-term survival for the combination. While any TRAE was lower in the durvalumab arms as compared to sorafenib, serious TRAEs were higher in the ICI arms and as seen with other ICI combinations, the addition of CTLA-4 inhibition doubled these events. This includes imAEs that occurred in 35.8 % of the combination arm vs 16.5 % in the durvalumab alone arm (all grades) and grade 3/4 12.5% versus 6.4%, respectively. Those needing high dose steroids were 20.1 % versus 9.5%. Like the ipilimumab and nivolumab combination, hepatic events were the most common higher-grade imAEs. As expected, given the known mechanism of action of the regimen, there is no significant bleeding risk.
Future Directions
The rapid transformation of the therapeutic arsenal for patients has left significant knowledge gaps that identifies areas of future research.
. For one, now that ICI-based therapy has moved to the front-line setting, the optimal management at progression is not defined. For patients that do not get a benefit from one ICI combination, is there a role for another? In addition, with various front-line combinations available, further biomarker development that would help identify patients more likely to benefit from one combination over the other would be of value.
So far, a post-hoc tissue biomarker analysis from patients treated with nivolumab in the CheckMate 040 trial has identified a 4-gene signature as a potential predictor of response.
. Similarly, data from the phase 1/2 study of durvalumab and tremelimumab showed that an increase in proliferating peripheral CD8+ T cells during treatment correlated with treatment response.
Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study.
. More recently, a comprehensive biomarker analysis from patients treated with atezolizumab-bevacizumab in the phase 1 and 3 trials showed that pre-existing immunity was associated with better outcomes with atezolizumab-bevacizumab, and high expression of VEGFR2, Tregs and myeloid inflammation signatures were associated with better outcomes with the combination compared to atezolizumab single agent. On the other hand, high Treg/Teff (effector T cell) and expression of glypican 3 and AFP were associated with reduced clinical benefit with atezolizumab-bevacizumab.
justifying the exploitation of the intestinal microbiota to increase ICI efficacy, for instance by combining immunotherapy with antibiotics or probiotics. However, further prospective studies are needed to better define the predictive role of inflammatory markers and better understand the contribution of the microbiota to anticancer immunity.
Furthermore, despite some evidence of a correlation between on-treatment AFP reductions and better outcomes in patients treated with atezolizumab-bevacizumab
Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice.
the potential role of these factors remains to be clarified.
Further insights can be obtained by implementing radiomics and radiogenomics, a new research area that seeks to correlate the imaging features with the genetic profiles.
Deep Learning Radiomics Based on Contrast-Enhanced Ultrasound Might Optimize Curative Treatments for Very-Early or Early-Stage Hepatocellular Carcinoma Patients.
. Hopefully, tumor and circulating biomarker analyses included in the ongoing immunotherapy studies, along with non-invasive, imaging-based metrics will provide the foundation for precision medicine in HCC.
Recent preclinical and clinical data suggest that non-viral-HCC, and particularly non-alcoholic steatohepatitis (NASH)/ non-alcoholic fatty liver disease (NAFLD)-related HCC, might be less responsive to immunotherapy.
Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial.
and redefinition of stratification factors beyond viral/non-viral etiology should be encouraged to consider NASH/NAFLD as an independent factor.
Furthermore, hepatitis delta virus (HDV) co-infection and active HBV-HCV co-infection represent exclusion criteria for ICIs, and this needs to be further evaluated to expand the population who could benefit from combination immunotherapy. Likewise, prospective evidence for patients living with human immunodeficiency virus (HIV) is lacking. Since this is a population where HCC is responsible for nearly 40% of liver-related deaths
it is a welcome news that ongoing studies are enrolling HIV-positive patients, provided they are receiving antiretroviral therapy with CD4+ T cell count ≥200/μL and undetectable viral load.
Another major challenge concerns Child-Pugh B patients.
. Further evaluation of immunotherapy in this population should be encouraged, as nivolumab, tested in this setting, showed reassuring safety and efficacy.
. Recently, a real-world collaborative effort showed preliminary evidence for the safety and efficacy of atezolizumab plus bevacizumab in Child-Pugh B patients, with tolerability similar to Child-Pugh A.
Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: a real-world study.
As previously mentioned, since second-line treatments have been tested after sorafenib, treatment sequencing represents an open issue. There is no scientific evidence to support any drug after first-line ICI combinations, and treatment sequence decisions incorporate patients’ characteristics, tolerability of prior therapy, and labelling and regulatory approvals in each country.
Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: A multinational, multicenter retrospective study.
and the IMbrave251 is evaluating atezolizumab-lenvatinib/sorafenib versus sorafenib or lenvatinib after progression on atezolizumab-bevacizumab (NCT04770896). In addition, other ongoing studies are testing single-agent TKIs after ICIs (e.g., phase 2 studies with cabozantinib after ICIs, NCT04435977).
Another future direction is represented by the combination of ICIs and locoregional treatments in earlier HCC stages, and ongoing trials (Table 2) may address unmet needs, such as increasing the percentage of patients eligible for curative therapies, including liver transplant in the frame of an extreme stage migration, and reducing relapse rates.
Table 2Ongoing international randomized clinical trials testing combinations of immunotherapy in HCC at stages earlier than advanced.
Trial
Phase
Treatment
Comparator
Primary endpoint
NCT number
Early stages at high-risk of recurrence after resection or ablation
CHECKMATE 9DX
3
Nivolumab
Placebo
RFS
NCT03383458
KEYNOTE-937
Pembrolizumab
Placebo
RFS
NCT03867084
EMERALD-2
3
Durvalumab + Bevacizumab
Placebo
RFS
NCT03847428
IMbrave050
3
Atezolizumab + Bevacizumab
Placebo
RFS
NCT04102098
Candidates for TACE
EMERALD-1
3
TACE + Durvalumab + Bevacizumab
TACE
PFS
NCT03778957
EMERALD-3
3
TACE + Durvalumab + Tremelimumab + Lenvatinib
TACE
PFS
NCT05301842
LEAP-012
3
TACE + Pembrolizumab + Lenvatinib
TACE
PFS, OS
NCT04246177
ML-42612
3
TACE + Atezolizumab + Bevacizumab
TACE
TACE PFS, OS
NCT04712643
ABC-HCC
3
Atezolizumab + Bevacizumab
TACE
TTFTS
NCT04803994
RENOTACE
3
Nivolumab + Regorafenib
TACE
PFS by mRECIST
NCT04777851
Candidates for SIRT
ROWAN
2
SIRT + Durvalumab + Tremelimumab
SIRT
ORR, DoR by mRECIST
NCT05063565
Phase 2 and 3 studies were retrieved from clinicaltrials.gov based on having a) recurrence-free survival; or b) progression-free survival or time to progression as endpoints, provided they involved TACE or SIRT in one of the treatment arms.
HCC, hepatocellular carcinoma. NCT, national clinical trial. RFS, recurrence-free survival. TACE, transarterial chemoembolization. PFS, progression-free survival. OS, overall survival. TTFTS, time to failure of treatment strategy. mRECIST, modified response evaluation criteria in solid tumors. SIRT, selective internal radiation therapy. ORR, overall response rate. DoR, duration of response.
In the intermediate stage, ongoing studies are testing ICIs in combination with synchronous or on-demand (DEMAND study, NCT04224636) intra-arterial therapies, or versus intra-arterial therapies, as in the ABC-HCC trial (NCT04803994) which compares atezolizumab plus bevacizumab to transarterial chemoembolization. While in the early-stage ongoing studies are combining immunotherapy with ablation, the potential abscopal effect induced by radiotherapy makes the combination of ICIs with stereotactic body radiotherapy of great interest.
Preliminary results from a phase Ib study of neoadjuvant ipilimumab plus nivolumab prior to liver resection for hepatocellular carcinoma: The PRIME-HCC trial.
and phase 2 trials are evaluating the role of adjuvant immunotherapy (CheckMate 9DX, NCT03383458; KEYNOTE-937, NCT03867084; IMbrave050, NCT04102098). In addition, neoadjuvant studies represent an unprecedented opportunity for the in vivo study of tumor biology and identification of biomarkers of response.
Preliminary results from a phase Ib study of neoadjuvant ipilimumab plus nivolumab prior to liver resection for hepatocellular carcinoma: The PRIME-HCC trial.
Finally, other immune checkpoints may regulate T cell function and play important roles in tumor immune escape. Trials of ICIs targeting LAG-3, TIM-3 (T-cell immunoglobulin and mucin domain 3) or TIGIT (T cell immunoreceptor with Ig and ITIM domains) in combination with PD-1/PD-L1 or CTLA-4 inhibitors in various cancer types are ongoing and need further exploration to potentially expand immunotherapy options also in HCC.
The prognosis for patients with advanced HCC has changed significantly with the development of combination regimens that are building on single-agent immunotherapy data. While we are seeing significant improvements in survival, with more patients achieving durable responses, with favorable side-effect profiles, there remain unmet needs for our patients. Active research is trying to better understand mechanisms of intrinsic and acquired resistance to these regimens that will then direct the next generation of studies. Already there are numerous early phase studies evaluating new “triplet” regimens in front-line as well as new molecular targets in second line, in an effort to reverse ICI resistance. Results of ongoing phase 3 studies incorporating immune based combinations into earlier lines of therapy are awaited and, if positive, will be practice changing. In sum, the incorporation of immunotherapy combinations into the HCC landscape is changing the natural history of the disease and will be the backbone of future drug development.
References
Author names in bold designate shared co-first authorship
Llovet JM
Bru C
Bruix J
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Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial.
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Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study.
Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice.
Deep Learning Radiomics Based on Contrast-Enhanced Ultrasound Might Optimize Curative Treatments for Very-Early or Early-Stage Hepatocellular Carcinoma Patients.
Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: a real-world study.
Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: A multinational, multicenter retrospective study.
Preliminary results from a phase Ib study of neoadjuvant ipilimumab plus nivolumab prior to liver resection for hepatocellular carcinoma: The PRIME-HCC trial.
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