*Review* **Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors and Applicability of First-Line Atezolizumab/Bevacizumab in a Real-Life Setting**

**Maria Corina Plaz Torres 1, Quirino Lai 2, Fabio Piscaglia 3, Eugenio Caturelli 4, Giuseppe Cabibbo 5, Elisabetta Biasini 6, Filippo Pelizzaro 7, Fabio Marra 8, Franco Trevisani <sup>9</sup> and Edoardo G. Giannini 1,\***

	- IRCCS Azienda Ospedaliero—Universitaria di Bologna, 40138 Bologna, Italy; franco.trevisani@unibo.it

**Abstract:** Immune checkpoint inhibitors (ICIs) are the new frontier for the treatment of advanced hepatocellular carcinoma (HCC). Since the first trial with tremelimumab, a cytotoxic T-lymphocyteassociated protein 4 inhibitor, increasing evidence has confirmed that these drugs can significantly extend the survival of patients with advanced hepatocellular carcinoma (HCC). As a matter of fact, the overall survival and objective response rates reported in patients with advanced HCC treated with ICIs are the highest ever reported in the second-line setting and, most recently, the combination of the anti-programmed death ligand protein-1 atezolizumab with bevacizumab—an anti-vascular endothelial growth factor monoclonal antibody—demonstrated superiority to sorafenib in a Phase III randomized clinical trial. Therefore, this regimen has been approved in several countries as first-line treatment for advanced HCC and is soon expected to be widely used in clinical practice. However, despite the promising results of trials exploring ICIs alone or in combination with other agents, there are still some critical issues to deal with to optimize the prognosis of advanced HCC patients. For instance, the actual proportion of patients who are deemed eligible for ICIs in the real-life ranges from 10% to 20% in the first-line setting, and is even lower in the second-line scenario. Moreover, long-term data regarding the safety of ICIs in the population of patients with cirrhosis and impaired liver function are lacking. Lastly, no biomarkers have been identified to predict response, and thus to help clinicians to individually tailor treatment. This review aimed to summarize the state of the art immunotherapy in HCC and, by analyzing a large, multicenter cohort of Italian patients with HCC, to assess the potential applicability of the combination of atezolizumab/bevacizumab in the real-life setting.

**Keywords:** liver cancer; systemic treatment; immunotherapy; real-world; unresectable hepatocellular carcinoma

**Citation:** Plaz Torres, M.C.; Lai, Q.; Piscaglia, F.; Caturelli, E.; Cabibbo, G.; Biasini, E.; Pelizzaro, F.; Marra, F.; Trevisani, F.; Giannini, E.G. Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors and Applicability of First-Line Atezolizumab/Bevacizumab in a Real-Life Setting. *J. Clin. Med.* **2021**, *10*, 3201. https://doi.org/10.3390/ jcm10153201

Academic Editors: Pierluigi Toniutto and Hidekazu Suzuki

Received: 1 June 2021 Accepted: 19 July 2021 Published: 21 July 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

### **1. Introduction**

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, with approximately 800,000 deaths per year and an estimated increase to more than 1 million deaths by 2030 [1]. HCC arises predominantly in the context of liver cirrhosis, but also can be diagnosed in a not negligible proportion of patients without cirrhosis suffering from non-alcoholic steato-hepatitis who carry additional metabolic and genetic risk factors [2–5]. In the past decades, the *armamentarium* for the systemic treatment of advanced HCC was limited to the anti-vascular endothelial growth factor (VEGFR), multi-target-tyrosine kinase inhibitor (TKI) sorafenib. This drug determined a significant though modest—survival benefit in two Phase III trials and remained the sole first-line treatment option for about 10 years, during which neither an alternative drug nor effective second-line therapies became available for patients who progressed during—or were intolerant to—sorafenib [6,7]. As a fact, lenvatinib (a TKI targeting VEGFR) became an effective alternative to sorafenib as first-line therapy for HCC in 2018, while regorafenib, cabozantinib, and ramucirumab only recently have been approved in the second-line setting [8]. With the advent of second-line treatments, the survival of patients with advanced HCC has significantly improved, with a proportion (approximately 20%) of patients reaching survival times of about 2 years with the sequential use of sorafenib-regorafenib [9]. These patients, however, belong to a small subgroup of patients who, maintaining an optimal liver function, are eligible for sequential treatment and tolerate the adverse effects of the anti-neoplastic agents [9].

In this scenario, immunotherapy has emerged as an additional promising approach potentially able to obtain even longer survival times. Research in this field is steadily increasing, also fueled by the positive results obtained in other cancer types and by the evidence of efficacy demonstrated in both first- and second-line settings [10–12]. The most recent Phase I/II trials have shown a clinically meaningful survival increase in the second-line setting for the programmed cell death protein 1 (PD-1) inhibitors nivolumab and pembrolizumab [12]. Hence, these agents have been granted accelerated conditional approval for sorafenib-experienced patients in the US, while the European Medicines Agency (EMA) maintains a more cautious attitude in approving these ICIs for the treatment of HCC. Indeed, subsequent Phase III trials testing nivolumab versus sorafenib as firstline treatment, and pembrolizumab versus placebo in second-line treatment, failed to meet their primary survival endpoints [13,14]. This notwithstanding, the results from trials testing the combination of immune checkpoint inhibitors (ICIs) with other agents, among which VEGFR-targeted therapies obtained very encouraging results, so that the combinations of pembrolizumab plus lenvatinib as well as atezolizumab (monoclonal antibody against PD-L1) plus bevacizumab (monoclonal antibody against VEGF) have both received breakthrough therapy designation from the US Food and Drug Administration (FDA). Actually, in a recent Phase III trial, the latter overperformed compared to sorafenib as first-line treatment of advanced HCC in terms of both overall (OS) and progression-free survival (PFS) [15]. Therefore, atezolizumab plus bevacizumab has been approved as the first-line treatment option for advanced HCC, thus becoming the standard of care for these patients.

Overall, the results from the trials testing ICIs alone or in combination, or combined with other agents, suggest that ICIs alone are not the best option for the treatment of HCC, while combined treatments are safe and highly effective. As such, immunotherapybased treatments will probably soon change the landscape of advanced HCC therapy. In this review, we summarize the state of the art immunotherapy in advanced HCC, with a particular focus on the combination of atezolizumab plus bevacizumab, by assessing in a large cohort of Italian patients with HCC the potential applicability of this regimen to the real-life setting.

#### **2. Approved Treatments for HCC before the "Era" of Immune Checkpoint Inhibitors**

Until the approval of sorafenib in 2008, no systemic treatment was available for advanced HCC [6]. Sorafenib, an orally active multi-target TKI targeting different cell surface tyrosine kinases (e.g., VEGFR-1, -2, and -3 and platelet-derived growth factor (PDGFR)-β), at the dose of 400 mg twice daily, significantly improved OS in patients with HCC not amenable to surgery and locoregional procedures, who had well-preserved liver function (97% Child–Pugh A) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 [6]. The median OS was 10.7 months in the sorafenib group and 7.9 months in the placebo group (*p* < 0.001), whereas the median time to radiologic progression (TTP) was 5.5 months in the sorafenib arm versus 2.8 months in the placebo arm (*p* < 0.001). Of note, the median OS of patients with the Barcelona Clinic Liver Cancer (BCLC) staging system stage B HCC treated with sorafenib was 15–20 months, a finding confirmed by subsequent post-marketing studies [16,17]. In the following years, several drugs were tested against sorafenib in the first-line setting, failing to demonstrate superiority to this drug, so that sorafenib remained the sole effective systemic treatment available for HCC until 2018, when lenvatinib, an oral TKI with a biologic action similar to sorafenib, showed non-inferior OS as compared to sorafenib in the REFLECT trial, and was therefore approved as an alternative to this drug in the first-line setting [8]. Again, patients included in this trial belonged to a selected group of subjects with well-preserved liver function (Child–Pugh class A) and ECOG PS ≤ 1, while those with extensive tumor burden (≥50% of the liver), bile duct invasion, or invasion of the main portal vein were excluded. Forest plots for OS revealed that lenvatinib was more effective than sorafenib in patients with baseline AFP ≥ 200 ng/mL (Hazard ratio (HR), 0.78; 95% confidence interval (95%CI), 0.63–0.98) and less effective in patients without macrovascular invasion/extrahepatic spread and those enrolled in the Western area. Secondary endpoints (PFS, TTP, objective response rate (ORR)) were significantly and remarkably better with lenvatinib, suggesting that these surrogate endpoints poorly predict OS in HCC patients treated with these drugs.

As far as the second-line setting is concerned, regorafenib, an oral TKI targeting VEGFR-2, VEGFR-3, TIE-2, PDGFR, fibroblast growth factor receptor (FGFR)-1, and the mutant oncogenic kinases KIT, RET, and B-RAF, was the first agent able to provide a significant survival benefit in patients with tumor progression on sorafenib [18]. Compared with placebo, regorafenib improved OS with a HR of 0.63 (95%CI, 0.50–0.79; *p* < 0.0001). It has to be emphasized that this study enrolled patients who progressed on sorafenib but tolerated the drug (≥400 mg/day for ≥20 of last 28 days of treatment) and had Child–Pugh class A liver function. Median survival was 10.6 months (95%CI, 9.1–12.1) for the regorafenib group versus 7.8 months (95%CI, 6.3–8.8) for the placebo group [18]. Interestingly, the treatment sequence of the sorafenib-regorafenib group was able to determine an OS of 26 months from the start of sorafenib treatment versus 19.2 months in the sorafenib-placebo group [18]. This survival time is comparable with that of patients with intermediate stage HCC undergoing trans-arterial chemo-embolization (TACE), suggesting that in a wellselected subgroup of patients the sequential treatment with TKIs may significantly improve prognosis as compared to the standard of care [9].

Other drugs that have shown efficacy in placebo-controlled trials and have consequently been approved as second-line treatment options for HCC are cabozantinib and ramucirumab [19]. Cabozantinib is an oral TKI targeting MET in addition to VEGFR2. The CELESTIAL trial was a global Phase III trial testing cabozantinib in patients with HCC progression on sorafenib [20]. It also included patients who had received up to two prior therapies for advanced-stage HCC. The study was stopped after a second interim analysis, which revealed a median OS of 10.2 months in the cabozantinib versus 8.0 months in the placebo group (HR, 0.76; 95% CI 0.63–0.92; *p* = 0.0049). Approximately 72% of patients had received only prior sorafenib treatment and, in this subpopulation, median OS was even longer, being 11.3 months in patients in the cabozantinib group versus 7.2 months in the placebo group (HR, 0.70; 95% CI, 0.55–0.88) [20].

Ramucirumab is an anti-VEGFR2 monoclonal antibody, and its utility in subjects with advanced HCC emerged from the double-blind, Phase III REACH-2 trial comparing ramucirumab versus placebo as second-line treatment in patients progressing on sorafenib and with baseline AFP ≥ 400 ng/mL [19]. This study was designed on the basis of the results of the REACH trial that failed to demonstrate an OS advantage with ramucirumab as compared to the placebo, but in a post-hoc analysis showed a benefit of the drug—albeit small—in prolonging OS (8.5 months with ramucirumab versus 7.3 months with placebo (HR, 0.71; 95% CI, 0.53–0.95; *p* = 0.0199)) among patients with baseline AFP ≥ 400 ng/mL [21]. Ramucirumab is therefore the first agent with a biomarker-driven use for patients with HCC progression on sorafenib [22].

In summary, sorafenib and lenvatinib are the TKIs that have long been in use for the front-line treatment of advanced HCC, providing a median extension of survival of about 3 months compared to the placebo. The survival benefit for patients eligible for secondline treatment with regorafenib/cabozantinib or ramucirumab, although significant, still remains modest. Hence, novel treatments targeting different tumorigenic pathways have been studied and others are still under investigation with the aim of further improving the outcomes of these patients. In this context, ICIs have gained excellent results.
