Tislelizumab in hepatocellular carcinoma: a duet or a solo performance?

First-line treatment of unresectable hepatocellular carcinoma (HCC) has relied for many years on the use of tyrosine kinase inhibitors (TKIs), such as sorafenib and, more recently, lenvatinib. The field has considerably advanced with the exploration of the efficacy of various immune checkpoint inhibitors (ICIs), including antibodies targeting programmed death receptor-1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), alone or in combination with anti-vascular endothelial growth factor (VEGF) antibodies or TKIs. The IMbrave150 randomized controlled trial (RCT) has led to the introduction of ICIs in the landscape of systemic treatment for HCC, and resulted in the approval of the combination of atezolizumab, a monoclonal antibody targeting PD-L1 and bevacizumab, targeting VEGF (1,2). Atezolizumab-bevacizumab outperformed sorafenib in terms of overall survival (OS) (19.2 vs. 13.4 months), progression-free survival (PFS) (6.9 vs. 4.3 months), objective response rate (ORR) (30% vs. 11% according to RECIST 1.1 criteria), and patient-reported outcomes. For these reasons, this combination currently represents the recommended first-line option for patients with unresectable HCC worldwide (1,2).

Subsequently, the phase III HIMALAYA trial explored the effects of durvalumab and tremelimumab, which target PD-L1 and CTLA-4, respectively, in combination (STRIDE protocol) as compared to durvalumab alone, or sorafenib (3). STRIDE led to a significant improvement in OS compared with sorafenib (16.4 vs. 13.8 months, respectively) with an ORR of 20.1%, compared to 17.0% for durvalumab alone, and 5.1% for sorafenib (3). Good outcomes in terms of OS (median not reached vs. 10.4 months), PFS (4.6 vs. 2.8 months), and ORR (21% vs. 4%) were also achieved by the phase II/III ORIENT-32 trial conducted in China, which assessed the combination of the anti-PD-1 antibody sintilimab and a bevacizumab biosimilar (IBI 305) versus sorafenib (4). More recently, treatment of patients with advanced HCC with first-line nivolumab in combination with ipilimumab resulted in a significant and clinically meaningful improvement in OS compared with sorafenib or lenvatinib, prescribed according to the investigator’s choice. This phase 3, CheckMate 9DW trial, met its primary endpoint (NCT04039607). It is noteworthy that, in all the aforementioned trials, the OS of patients in the control group—treated with sorafenib or lenvatinib—has improved over the years, likely reflecting a better clinical management of systemic treatments for HCC and their adverse events.

The successful strategies described above are based on combination therapies having the rationale of overcoming resistance mechanisms and/or enhancing the antitumor immune response (5). These ‘duets’ may target the immune system and the tumor microenvironment, as in the case of bevacizumab, which blocks angiogenesis, reduces new vessel formation and at the same time counteracts T cell exhaustion and the accumulation of immunosuppressive cells (5). On the other hand, drugs employed in the STRIDE protocol modulate different functions with immune-stimulating effects, increasing T cell effector function and reducing Treg cell infiltration. These synergistic effects may theoretically be expanded to the combination of ICIs and tyrosine-kinase inhibitors (TKIs), which potentially act on T cells, immunosuppressive cells, and macrophage polarization, thereby enhancing and modulating the responses of the immune system (5). However, three phase III trials (COSMIC-312, LEAP-002 and SHR-1210-III-310) that evaluated the combination of ICI and TKIs did not meet their primary endpoints (6-8).

Before the combination of atezolizumab and bevacizumab was successfully tested, ICI monotherapy had provided fewer encouraging results. The CheckMate 459 trial compared nivolumab and sorafenib as first-line treatment, but despite an ORR of 15% and a favorable adverse event profile, the improvement in OS was not significant (16.4 vs. 14.7 months). These results are comparable to those of durvalumab monotherapy in the HIMALAYA trial (3) where the key secondary endpoint of non-inferiority compared to sorafenib was nonetheless met. Moreover, in a second-line setting, pembrolizumab was not superior to placebo (13.9 vs. 10.6 months) (9).

The general idea of inefficacy of single-agent immunotherapy provided by the clinical studies outlined above has been challenged by the recent report on the effects of tislelizumab in unresectable HCC (10). Tislelizumab is a humanized monoclonal IgG4 antibody that targets PD-1 and is characterized by an engineered Fc fragment that minimally binds to the FcγR on macrophages, thereby mitigating antibody-dependent phagocytosis as a potential mechanism of treatment resistance (11). It should be noted that the pharmacodynamics of tislelizumab is not different from that of other antibodies previously or currently employed in the treatment of HCC, i.e., an action on the PD-1/PD-L1 system. Physiologically, suppression of T-cell proliferation and cytokine production resulting from the interaction between PD-1 ligands and the PD-1 receptor present on T cells prevents T cell exhaustion (5). However, this mechanism is also employed by tumor cells to dampen anti-tumor immunity, upregulating the expression of PD-1 ligands (5). Binding the extracellular domain of human PD-1, tislelizumab revitalizes T-cell functions, inducing cytokine production and thereby eliciting immune-mediated antitumor responses (11) (Figure 1). Tislelizumab has been approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a monotherapy for the treatment of unresectable, locally advanced, or metastatic squamous cell carcinoma of the esophagus, following a prior systemic therapy that did not involve a PD-(L)1 inhibitor (11).

Figure 1 Mechanism of action of tislelizumab. Through its binding to PD-1, tislelizumab restores the ability of immune cells to attack tumor cells. Created with BioRender. PD-1, programmed death-1; PD-L1, programmed death-ligand 1; MHC, major histocompatibility complex; TCR, T cell receptor.

The RATIONALE-301 trial included 674 patients that were randomized to receive 200 mg of tislelizumab intravenously once weekly (342 patients) or 400 mg of sorafenib orally twice a day (332 patients), the standard-of-care treatment at the time of trial design, considering that enrolment started at the end of 2017. The primary endpoint was the non-inferiority of tislelizumab in a first-line setting (10). The inclusion criteria were similar to those of the IMbrave150 and HIMALAYA trials. Patients had histologically confirmed HCC, belonged to stages B or C according to the Barcelona clinic liver cancer (BCLC) classification, with preserved liver function (Child-Pugh class A) and no evidence of complications of portal hypertension, with bleeding esophageal or gastric varices within 6 months before randomization. As in other trials with ICIs, patients with active or previous history of autoimmune disease or immune deficiency were not included (10). Notably, patients with vascular invasion involving the main trunk of the portal vein or inferior vena cava were excluded, similarly to the HIMALAYA trial, but in contrast to the criteria used in the IMbrave150 study (1-3). It is important to highlight that patients enrolled in different trials may vary in terms of etiology of liver disease and tumor burden, and great care should be taken when comparing outcomes across studies. Tislelizumab resulted non-inferior to sorafenib in terms of OS [HR 0.85 (95% CI: 0.71, 1.02), non-inferiority margin upper limit of hazard ratio <1.08] with a median OS of 15.9 (95% CI: 13.2–19.7) months vs.14.1 (95% CI: 12.5–17.4) months for sorafenib. These results are in line with those of other ICIs used as monotherapy in the first- (nivolumab 16.4 months, durvalumab 16.6 months) or second-line setting (pembrolizumab 17.0 months) (3,9,12). The survival rate at 36 months was 29.2% for patients in tislelizumab arm. Of note, based on the curves provided in the article, more than 20% of patients survived at 48 months, a figure similar to the one (25.2%) recently reported with the STRIDE strategy in the HIMALAYA trial (25.2%) (13). When interpreting these results, it should be noted that in both arms approximately one quarter of patients underwent radiotherapy, locoregional treatments or surgery after the trial.

Interestingly, tislelizumab did not outperform sorafenib in terms of PFS, and the median was actually longer in patients receiving the TKI (3.4 vs. 2.1 months) (10). However, a small percentage of patients experienced a prolonged PFS as it is shown by the long-term tail in Kaplan-Meier curves (10). Furthermore, while the 12-month PFS rate is similar for tislelizumab and sorafenib (19% vs. 18% respectively), at 18 and 24 months the rate is higher for patients treated with tislelizumab compared to sorafenib (16% vs. 9% and 13.9% vs. 6.1%), suggesting that patients achieving a response to tislelizumab maintain this benefit for longer time (10).

As for other strategies employing ICIs, identification of subjects which are more likely to respond in the long term will be instrumental for an adequate patient selection. The ORR was 14.3% with tislelizumab and 5.4% with sorafenib, inferior to the one observed when other drugs acting on the PD-1/PD-L1 system was used in combination with anti-VEGF (30%) or with anti-CTLA4 (20.1%) monoclonal antibodies. Interestingly, good results were recently reported when tislelizumab was used as a second- and third-line treatment option in patients previously treated with sorafenib or lenvatinib (NCT03419897) (14).

A recent post-hoc analysis of the RATIONALE-301 trial evaluated the efficacy of tislelizumab in elderly patients (15). Of the 674 randomized patients, 37.8% were ≥65 years old (134 in tislelizumab arm and 121 in sorafenib arm) (15). This subgroup of patients was more frequently from Western countries (42.4% from Europe and USA vs. 25.5% of the whole population) with a distribution of etiologies more similar to the one of the IMbrave150 and HIMALAYA trials (1,13,15) and more closely reflecting the epidemiology of HCC in Western countries [hepatitis B virus (HBV) 34.1%, hepatitis C virus (HCV) 20.4%, non-viral 41.6%]. In the ≥65 years subgroup treated with tislelizumab, the median OS was longer than in the overall population (18.2 vs. 15.9 months, respectively) and in the subgroup receiving sorafenib (14.2 months in the post-hoc analysis), where survival was similar to the overall population (14.1 months) and to that of other trials where sorafenib was used in the control arm (15). It should be noted that elderly patients belonged more frequently to the BCLC-B stage compared to the overall population (15), although this did not result in a longer survival when patients treated with sorafenib are considered. It may be speculated that for a more fragile population such as older adults, immunotherapy with a single ICI targeting the PD-1/PD-L1 system should be preferred over a TKI, particularly if there are contraindications to bevacizumab. Similar results on survival were shown in a sub-analysis of the RATIONALE-301 trial where only the European and North American population (174 patients) was included (16).

The safety profiles of tislelizumab and sorafenib were consistent with previous reports, with no new safety concerns identified (10). Severe adverse events (48.2% vs. 65.4%) and treatment discontinuation (10.9% vs. 18.5%) were less frequent with tislelizumab. The most common treatment-related adverse events were increased levels of aspartate aminotransferase (23.1%), alanine aminotransferase (16.6%), and bilirubin (12.4%) with 18.3% of patients experiencing immune-mediated adverse events of any grade (10). In agreement with the better tolerability tislelizumab demonstrated superiority in maintaining a better quality of life (QoL) according to various scales, in particular with lower fatigue and other HCC-related symptoms, impaired physical functioning, and deterioration in QoL, with the exception of pain, in comparison to sorafenib (17).

Similar to other ICIs, tislelizumab is being evaluated in combination with other drugs as first-line systemic treatment for patients with HCC (Table 1). It is currently being tested in combination with regorafenib (NCT04183088) and it has shown a promising antitumor activity and favorable safety in combination with lenvatinib, in a phase II trial (NCT04401800) (18). Similarly, the combination of anlotinib, a multi-targeted TKI, and tislelizumab showed high antitumor activity and good tolerability in unresectable HCC, with an ORR of 32%, a disease control rate of 72% and a good safety profile (19). Another phase II study (NCT04948697) evaluated the efficacy of triple therapy with ociperlimab (TIGIT-inhibitor), tislelizumab, and BAT1706 (a bevacizumab biosimilar) and of a two-drug combination of tislelizumab and BAT1706, showing that the triple therapy was not superior to the tislelizumab and BAT1706 in terms of ORR (35% vs. 37.5% respectively) (20). These results are different from those reported in the phase I/II MORPHEUS study where the addition of the TIGIT-inhibitor tiragolumab to the combination atezolizumab-bevacizumab improved the ORR and PFS of patients (42.5% vs. 11.1% and 11.0 vs. 4.2 months) (21).

The findings from the RATIONALE-301 trial, together with those from other phase III studies which evaluated ICI as monotherapy, raise the issue of the positioning of monotherapy with an ICI as opposed to combination treatment(s) with other drugs (e.g., ICIs, anti-VEGF, TKIs or even more). Tislelizumab may be considered as an alternative to TKIs as first-line monotherapy in patients ineligible to atezolizumab/bevacizumab or to the STRIDE combination, especially if the patient has relative contraindications. Further research and additional clinical trials are warranted. Undoubtedly, the current availability of multiple regimens for the treatment of unresectable HCC requires more accurate answers regarding the optimal therapeutic strategy and the best treatment sequences, possibly tailored to individual patients. Future availability of predictive biomarkers, which are the focus of many current studies, will be of clear value to define personalized treatment protocols, ultimately improving patient prognosis while reducing unnecessary adverse events and containing treatment-related costs.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-111/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-111/coif). C.C. reports honoraria for lectures from AstraZeneca, Roche, and support for attending meetings from AstraZeneca, Roche. E.P. reports honoraria for lectures from AstraZeneca, Roche, MSD/EISAI, and support for attending meetings from AstraZeneca, Roche, LEO Pharma, Advanced Accelerator Applications. F.M. reports consulting fees from AstraZeneca, MSD/EISAI, Roche, Ipsen, honoraria for lectures from AstraZeneca, MSD/EISAI, Roche, Ipsen, and support for attending meetings from AstraZeneca, Ipsen, MSD/EISAI, Roche. The authors have no other conflicts of interest to declare.

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