IMbrave152/SKYSCRAPER-14: a Phase III study of atezolizumab, bevacizumab and tiragolumab in advanced hepatocellular carcinoma.

Background & rationale

Hepatocellular carcinoma disease background

Primary liver cancer remains a global health challenge. Liver cancer is the third most common cause of cancer-related death and is the sixth most common in terms of incident cases worldwide [ 1 ]. Hepatocellular carcinoma (HCC) accounts for approximately 90% of liver cancer cases [ 2 , 3 ]. The development of HCC is closely related to the presence of chronic liver disease, mostly due to hepatitis B virus or hepatitis C virus, or nonviral causes such as alcohol abuse or nonalcoholic fatty liver disease, resulting in heterogeneous worldwide incidence rates [ 3 ]. Most HCC cases (80%) occur in sub-Saharan Africa and eastern Asia, where the main risk factor is chronic hepatitis B virus infection. In the USA, Europe and Japan, hepatitis C virus is the main risk factor, together with excessive alcohol intake [ 4 ].

Due to 80–90% of HCC cases developing in patients with cirrhosis, the treatment of HCC is challenging because of the patient’s overall health status, including the degree of liver dysfunction and patient performance status, in addition to tumor burden [ 3 ]. Multiple staging systems have been proposed, with no globally accepted system for HCC due to the heterogeneity of the disease [ 5 ]. Barcelona Clinic Liver Cancer and Hong Kong Liver Cancer systems include all three clinical prognostic factors with stage-dependent treatment recommendations [ 6 , 7 ].

In patients with relatively early HCC, curative treatment is recommended, including surgical resection, orthotopic liver transplant or local ablative therapies [ 8 , 9 ]. In patients with intrahepatic tumor burden beyond the early stage but without evidence of vascular invasion or distant metastases (i.e., intermediate-stage HCC), palliative therapies such as transarterial chemoembolization and transarterial radioembolization may prolong survival with a median overall survival (OS) of 26–30 months. For patients with advanced-stage HCC with extensive intrahepatic tumor burden beyond the intermediate stage or any evidence of vascular invasion or distant metastases, systemic therapy can prolong survival by slowing tumor progression, with median survival time varying from 8 to 19.2 months [ 9 , 10 ].

Current treatment options for patients with unresectable hepatocellular carcinoma

First-line treatment options for patients with HCC include single-agent tyrosine kinase inhibitors (e.g., sorafenib and lenvatinib), cancer immunotherapy (CIT) in combination with targeted agents (e.g., atezolizumab plus bevacizumab), and dual CIT regimens (e.g., durvalumab plus tremelimumab) ( Table 1 ).

In 2007, sorafenib was approved by the US FDA for first-line treatment of advanced HCC: sorafenib demonstrated a 3-month improvement in OS compared with placebo in the SHARP study [ 16 ]. Lenvatinib was the second drug approved as a first-line treatment based on the REFLECT study, which demonstrated a noninferior improved median OS for lenvatinib compared with sorafenib [ 17 ]. Both treatments are associated with grade 3–4 drug related adverse events in approximately 50% of the treated patients (e.g., hand-foot skin reaction, hypertension, asthenia, anorexia, diarrhea and weight loss), resulting in an approximately 15% withdrawal rate [ 3 ].

Atezolizumab plus bevacizumab is currently the global standard of care for this patient population in the first-line treatment setting. IMbrave150, a Phase III study evaluating atezolizumab plus bevacizumab versus sorafenib, was the first to demonstrate a statistically significant and clinically meaningful improvement in OS, progression-free survival (PFS), and confirmed objective response rate (ORR) compared with sorafenib [ 11 , 18 ].

Other treatment regimens, including dual CIT (e.g., durvalumab plus tremelimumab) and CIT plus tyrosine kinase inhibitor (e.g., camrelizumab plus rivoceranib), have recently provided additional evidence in Phase III studies validating the therapeutic targeting of multiple pathways associated with HCC pathogenesis [ 19 , 20 ].

Despite advancements in the treatment of HCC through the introduction of immunotherapy combinations, including improved survival, the majority of patients do not have an objective response to CIT-based therapy. This underscores that advanced HCC remains an incurable disease with a high unmet medical need, justifying the evaluation of novel treatment combinations, such as atezolizumab plus bevacizumab plus tiragolumab, that may target CIT resistance mechanisms, with higher response rates, durable responses and improved long-term survival.

Rationale for targeting TIGIT in hepatocellular carcinoma

The TIGIT pathway

TIGIT is an immune inhibitory receptor that is a member of the immunoglobulin superfamily. TIGIT is expressed on the surface of activated T-cell and natural killer-cell subsets and interacts with high affinity with CD155 (also known as PVR) [ 21 ]. Genetic ablation of TIGIT in T cells in mice results in exacerbated T-cell responses in nonclinical models of autoimmune and viral infections, demonstrating the role of TIGIT in inhibiting T-cell responses [ 22 , 23 ].

Expression of TIGIT is elevated in the tumor microenvironment in many human tumors, is concordantly expressed with other immune checkpoint receptors such as PD-1 on the surface of T cells and is associated with impaired T-cell function and antitumor immunity [ 23 , 24 ]. Activation of TIGIT on T cells and natural killer cells limits cellular proliferation, effector cytokine production and killing of target tumor cells [ 21 , 23–26 ].

TIGIT is expressed in a wide variety of human tumors, including most solid tumors, such as non-small cell lung cancer (NSCLC), breast cancer, HCC and melanoma and hematologic tumors, such as multiple myeloma and non-Hodgkin lymphoma. Fluorescence-activated cell sorting analysis of T cells isolated from fresh tumor samples revealed that TIGIT and PD-1 are also co-expressed on tumor-infiltrating T cells [ 23 , 27–32 ]. TIGIT expression was 30–80% and 50–80% on tumor-infiltrating CD4 + and CD8 + T cells, respectively [ 23 ].

Therefore, TIGIT is a potential target for therapeutic intervention aimed at restoring the immune response against the tumor. Agents that inhibit TIGIT’s interaction with PVR may inhibit an important source of tumor-associated immune suppression and therefore may enhance the activity of other immune-based therapies. Nonclinical studies using blocking antibodies in genetically deficient mice have revealed a key role for TIGIT in regulating T-cell responses in cancer. Together, these data support the hypothesis that anti-TIGIT may reactivate antitumor immunity and provide clinical benefits to patients with cancer.

Background on tiragolumab

Tiragolumab is a human immunoglobulin G1/κ monoclonal antibody that binds TIGIT and prevents its interaction with CD155 (also known PVR). Therapeutic blockade of TIGIT by tiragolumab represents an attractive strategy for cancer therapy and is expected to enhance the magnitude and quality of tumor-specific T-cell responses, which may result in improved meaningful antitumor activity when tiragolumab is used in combination with other CITs and administered with chemotherapy. Indeed, emerging clinical evidence to support combining tiragolumab with atezolizumab has recently been reported in patients with NSCLC and esophageal squamous cell carcinoma [ 33 , 34 ].

Rationale for adding tiragolumab to atezolizumab & bevacizumab in patients with hepatocellular carcinoma

Combination treatment with atezolizumab plus bevacizumab is an approved first-line treatment regimen in the USA and over 100 countries worldwide for patients with unresectable locally advanced or metastatic HCC [ 35 ]. However, even though the combination had the highest overall response rate presented in a global Phase III study to date, durable clinical benefit is limited to a subset of patients treated with this combination. Therapies targeting mechanisms of resistance to atezolizumab and bevacizumab are needed to improve clinical outcomes in this population further.

TIGIT is believed to play an important role in HCC pathogenesis and resistance to PD-1/PD-L1 blockade [ 36 ]. Nonclinical tumor models have shown that TIGIT selectively suppresses the effector function of chronically stimulated CD8 + T cells and that inhibiting both TIGIT and PD-L1 results in superior efficacy compared with single-agent treatments [ 23 ]. In patients with advanced HCC, higher levels of PD-1 + , TIGIT + , CD8 + T cells are associated with poor clinical outcomes, including accelerated disease progression and death [ 29 ]. Targeting TIGIT and PD-L1 may enhance the efficacy of PD-L1 blockade in HCC.

Myeloid and T regulatory cells (Tregs) have been identified as key immunosuppressive cell types within the hepatic tumor microenvironment and are associated with poor prognosis [ 37 , 38 ]. Tregs have also recently been implicated in resistance to atezolizumab plus bevacizumab treatment in patients with unresectable HCC [ 39 ]. Specifically, patients with a high Treg: T-effector cell-ratio at baseline had poor survival outcomes. As TIGIT is highly expressed on Tregs and may be important for their suppressive function, therapeutic targeting and depletion of TIGIT-expressing Tregs with tiragolumab may alter this ratio and overcome an important resistance mechanism to atezolizumab plus bevacizumab treatment. In patients with NSCLC, high baseline levels of Tregs and intratumoral myeloid cells were recently shown to be associated with improved clinical benefit after treatment with atezolizumab and tiragolumab compared with atezolizumab plus placebo [ 40 ]. Emerging insights into the mechanism of action of tiragolumab suggests that it promotes the generation and expansion of long-lived effector tumor-specific CD8 + T cells and reshapes the tumor microenvironment to facilitate antitumor T-cell activity [ 40 ]. Taken together, there is a compelling biological rationale to evaluate the addition of tiragolumab to atezolizumab plus bevacizumab in patients with HCC.

MORPHEUS-Liver data summary

MORPHEUS-Liver is a randomized Phase Ib/II signal-seeking clinical trial designed to accelerate the development of novel CIT combinations in patients with HCC through early identification of efficacy signals and generation of proof-of-concept data. A cohort was opened to evaluate the addition of tiragolumab to atezolizumab plus bevacizumab. The hypothesis tested was that therapeutic targeting of TIGIT with tiragolumab, in combination with atezolizumab plus bevacizumab, will augment the antitumor immune response, resulting in improved and more durable clinical benefit for patients with HCC. This study enrolled an advanced HCC population, similar to the population that enrolled in the IMbrave150 Phase Ill trial.

The addition of tiragolumab to atezolizumab plus bevacizumab indicated improved efficacy outcomes in participants with advanced HCC in the MORPHEUS-Liver trial [ 41 ]. As per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, a confirmed ORR of 43% and a median PFS of 11.1 months were observed for the tiragolumab-containing combination in this randomized Phase Ib/II study. While we acknowledge the limitations of cross-trial comparisons, the tiragolumab-containing combination also outperformed the atezolizumab plus bevacizumab experimental arm in IMbrave150 ( Table 2 ).

The triplet combination of atezolizumab plus bevacizumab plus tiragolumab was well tolerated and had an acceptable safety profile [ 41 ]. No new safety signals were identified by the addition of tiragolumab to atezolizumab and bevacizumab, and all adverse events were consistent with the known safety profiles of the individual study drugs. The incidence of serious adverse events (including Grade 5 adverse events), Grade 3 and 4 adverse events, and adverse events leading to treatment discontinuation or interruption were similar between the triplet combination arm and control arm. Immune-mediated adverse events (including Grade 3 and 4 events) were also balanced between treatment arms, although higher incidence rates of immune-mediated rash and infusion-related reactions were observed in the triplet combination arm, driven by Grade 1 and 2 events. Grade 5 immune-mediated adverse events were not reported in either arm.

The IMbrave152/SKYSCRAPER-14 study design

Study objectives

This trial will assess the efficacy and safety of the atezolizumab, bevacizumab and tiragolumab combination in untreated, unresectable, locally advanced or metastatic HCC. Primary objectives include evaluating PFS and OS against the standard care of atezolizumab and bevacizumab. The study is funded by F. Hoffmann-La Roche Ltd.

Trial design

This Phase III, randomized, double-blind, placebo-controlled study was designed to compare the efficacy of the atezolizumab, bevacizumab and tiragolumab combination with atezolizumab and bevacizumab in patients with HCC.

Methods

Approximately 650 participants with untreated locally advanced or metastatic HCC will be randomized in a 1:1 ratio to either atezolizumab plus bevacizumab plus tiragolumab or atezolizumab plus bevacizumab plus placebo ( Figure 1 ). Randomization will be stratified by geographic region (Asia [excluding Japan] and Africa vs the rest of the world [including Japan]), macrovascular invasion and/or extrahepatic spread (presence vs absence), baseline α-fetoprotein (<400 vs ≥400 ng/ml) and HCC etiology (viral vs nonviral). Africa has been included with Asia given that hepatitis B is the main etiological cause of HCC in both of these regions. HCC etiology determination will be based on the investigator’s judgment. The trial is conducted globally at approximately 181 sites in 20 countries with expertise in managing HCC and facilitating broad and diverse participant enrollment. Recruitment strategies are designed to ensure a broad and diverse participant population reflective of the global burden of HCC.

Eligibility criteria

Key eligibility criteria are described in Box 1 . All patients (men or women) must be aged ≥18 years with a confirmed diagnosis of HCC, classified as unresectable, locally advanced or metastatic. Patients must also be Child Pugh A and have undergone an esophagogastroduodenoscopy within the last 6 months. Although not a requirement for enrollment in the study, a baseline tumor tissue sample (either fresh or archival) is highly desired from all patients to support a comprehensive biomarker research program that aims to understand how these different study treatments work within the context of HCC.

Abbreviated eligibility criteria [ 42 ].

Inclusion criteria:

Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with diagnosis confirmed by histology/cytology or clinically by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic participants

Disease that is not amenable to curative surgical and/or locoregional therapies

No prior systemic treatment for locally advanced or metastatic and/or unresectable HCC

Measurable disease according to RECIST v1.1

ECOG performance status of 0 or 1 within 7 days prior to randomization

Child-Pugh Class A within 7 days prior to randomization

Adequate hematologic and end-organ function

Female participants of childbearing potential must be willing to avoid pregnancy within 5 months after the final dose of atezolizumab, within 6 months after the final dose of bevacizumab, and within 90 days after the final dose of tiragolumab/placebo

Male participants with a female partner of childbearing potential or pregnant female partner must remain abstinent or use a condom during the treatment period and for 6 months after the final dose of bevacizumab and for 90 days after the final dose of tiragolumab/placebo to avoid exposing the embryo

Exclusion criteria:

Pregnancy or breastfeeding within 5 months after the final dose of atezolizumab, within 6 months after the final dose of bevacizumab, and within 90 days after the final dose of tiragolumab/placebo

Prior treatment with CD137 agonists or immune checkpoint blockade therapies

Treatment with investigational therapy within 28 days prior to initiation of study treatment

Treatment with locoregional therapy to liver within 28 days prior to initiation of study treatment, or nonrecovery from side effects of any such procedure

Treatment with systemic immunostimulatory agents

Treatment with systemic immunosuppressive medication

Untreated or incompletely treated esophageal and/or gastric varices with bleeding or that are at high risk for bleeding

A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment

Active or history of autoimmune disease or immune deficiency

History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis or idiopathic pneumonitis or evidence of active pneumonitis on screening chest CT scan

History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death

Mixed histology or other subtypes/variants of HCC, including, but not limited to, known liver adenocarcinoma, fibrolamellar HCC, sarcomatoid HCC, other rare HCC variant or mixed cholangiocarcinoma and HCC

Co-infection with hepatitis B virus and hepatitis C virus

Acute Epstein–Barr virus infection or known or suspected chronic active Epstein–Barr virus infection

Symptomatic, untreated or actively progressing central nervous system metastases

Study procedures & treatment intervention

Participants randomized to the treatment arm are given atezolizumab 1200 mg intravenously (iv.) every 3 weeks (Q3W) plus bevacizumab 15 mg/kg iv. Q3W plus tiragolumab 600 mg iv. Q3W. Participants randomized to the control arm are given atezolizumab 1200 mg iv. Q3W plus bevacizumab 15 mg/kg iv. Q3W plus placebo iv. Q3W. Participants will continue to receive treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Outcomes, statistical methodology & independent data monitoring committee monitoring

The primary end points of this trial are investigator-assessed PFS and OS. Both PFS and OS have been selected as primary end points in this first-line study due to the risk of bias for OS due to second-line treatment options that patients may receive. In addition, PFS is an important end point and may provide earlier evidence of improved clinical activity for the experimental treatment arm. Investigator-assessed PFS is defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST 1.1. OS is defined as the time from randomization to death from any cause.

Other selected secondary end points of the study include investigator-assessed ORRs, duration of response, landmark OS and PFS rates, as well as HCC-modified RECIST criteria for PFS, confirmed ORR, duration of response and time to confirmed deterioration. Safety will also be analyzed. With the use of dual immune checkpoint inhibitors, adverse events of special interest in the IMbrave152/SKY-14 study are immune-mediated adverse events that could impact multiple organs and systems of the human body, including the lung, liver, heart, kidney, muscle, skin, gastrointestinal tract, blood vessels, blood and immune system, endocrine system and nervous system.

PFS analysis will be performed on all randomized participants according to the treatment to which they were assigned, using the Kaplan–Meier method to estimate the median PFS for each arm. A stratified Cox proportional hazards model will be used to estimate the hazard ratio and its 95% confidence interval. Methods for comparison of OS between treatment arms will be the same as the methods for treatment comparison of the PFS analysis. An independent data monitoring committee will monitor safety data during the study, and ensure the integrity of trial outcomes.

Ethics & dissemination

Ethical approval is obtained from institutional review boards or ethics committees at each participating center. Findings will be disseminated through peer-reviewed publications and conference presentations.

Conclusion

Advanced HCC remains a disease with a high unmet medical need, justifying the need for additional clinical research that targets mechanisms of resistance to standard of care. While the MORPHEUS Phase Ib/II study will continue to evaluate novel CIT-based treatment combinations, the addition of the anti-TIGIT tiragolumab to atezolizumab plus bevacizumab has been identified as a promising candidate that warrants evaluation in a large Phase III study. Through a rigorous evaluation of the efficacy and safety of tiragolumab plus atezolizumab plus bevacizumab compared with an established standard-of-care regimen, the Phase III IMbrave152/SKYSCRAPER-14 study aims to improve clinical outcomes in patients with unresectable HCC, which have historically faced a considerable unmet medical need. The findings of this trial have the potential to redefine the standard of care, offering therapeutic advances for individuals with this challenging oncological condition.

Funding Statement

The study is funded by F. Hoffmann-La Roche Ltd. The study sponsor participated in the study design; the writing of the report; and the decision to submit the article for publication.

Author contributions

All authors contributed to the conception or design of the work and participated in drafting or revising the manuscript.

Financial disclosure

The study is funded by F. Hoffmann-La Roche Ltd. The study sponsor participated in the study design; the writing of the report; and the decision to submit the article for publication. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

D Li has received honoraria and advisory/consultancy fees from AbbVie, AstraZeneca, Ipsen, Eisai, Exelixis, Coherus, Genentech, QED, Merck, Adagene, Delcath, Servier, Sumitomo, Transthera and TerSera; and received institutional research funding from Brooklyn Immunotherapeutics and AstraZeneca. M Kudo reports the following conflicts of interest: honoraria payment to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eli Lilly, Eisai and Takeda; research funding to institution from AbbVie, Chugai Pharmaceutical Co. Ltd., EA Pharma, Eisai, F. Hoffmann-La Roche Ltd, GE HealthCare, Gilead Sciences, Otsuka, Sumitomo Dainippon Pharma, Taiho and Takeda; and Editor in Chief of Liver Cancer . S Badhrinarayanan, C Cotter, H Zhu and Y-C Lin are employees of Roche/Genentech. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

Third-party editorial support for this manuscript was funded by F. Hoffmann-La Roche and provided by Kristi Allard of Nucleus Global, an Inizio Company.

Ethical conduct of research

Ethical approval is obtained from institutional review boards (IRB) or ethics committees at each participating center. The central IRB is WCG IRB. The study approval number is 20231856. All participants will provide written consent.

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