**5. Amenability to Atezolizumab Plus Bevacizumab in Real-Life Setting**

Given the expected upcoming change in the standard of care for the treatment of patients with advanced HCC, with a preferential use of the combination of atezolizumab plus bevacizumab as first-line treatment, we aimed to explore the actual estimates of the potential applicability in clinical practice of this dual treatment in the Western HCC population. In order to do so, we applied the inclusion and exclusion criteria of the atezolizumab plus bevacizumab IMBrave-150 study to the HCC population recorded in the Italian Liver Cancer (ITA.LI.CA) database. We used this database as it is representative of the real-life setting of HCC patients in Italy: the ITA.LI.CA database, indeed, includes more than 10,000 patients with newly diagnosed or recurrent HCC, with various underlying liver disease etiologies at all stages, who are managed in a large number of Italian centers with different levels of expertise (secondary and tertiary referral centers). Thus, it provides a reliable insight into the characteristics of HCC patients in Western regions and allows for predicting figures of the potential utilization of newly available HCC drugs in real-life clinical practice [39].

In order to carry this out, within the ITA.LI.CA database, we excluded patients diagnosed before 2008—that is the year of availability of sorafenib in clinical practice in Italy—and we applied the inclusion and exclusion criteria, listed in Table 2, set forth in the Phase III IMbrave-150 trial in patients with advanced HCC. In the studied period

(2008–2019), 7529 cases of HCC were reported overall and, among them, a total of 5203 cases had a newly diagnosed HCC, whereas 2326 presented the first recurrence after surgery and/or locoregional treatment; we then calculated the eligibility rate to atezolizumab plus bevacizumab in the overall cohort and, separately, in the two subgroups of naïve patients with HCC or with an HCC recurrence after surgery or locoregional treatment (Figure 3).

**Table 2.** Criteria of eligibility for the management of unresectable HCC with atezolizumab plus bevacizumab as a first-line therapy.


**Figure 3.** (**A**,**B**) Proportion of patients with new onset HCC or with HCC recurrence after surgery or locoregional treatment, which is amenable to first-line treatment with atezolizumab plus bevacizumab, per year, in the ITA.LI.CA database.

As far as the subgroup of naive patients with HCC is concerned, the overall proportion of patients deemed eligible for atezolizumab plus bevacizumab was 7.1%, ranging from 5.3% to 5.4% (2008–2014) up to 10.7% (2019), with a median eligibility rate for the novel therapy in this group of patients of 7.5%, and with an increasing trend observed in the most recent years (Figure 3A). With regard to patients with HCC recurrence after surgery or locoregional treatment, after excluding those not eligible for the treatment with atezolizumab plus bevacizumab as per the study inclusion and exclusion criteria, the overall eligibility rate to this ICI-based therapy was 36.3%, with a median eligibility rate across the whole period of 36.5% (range, 28.9% to 44.4%), with a decreasing trend observed in the most recent years (Figure 3B).

Taking into account all the patients included in the ITA.LI.CA database in the period 2008–2019, irrespective of previous locoregional treatment, approximately 16% of cases were considered eligible for the newly approved dual treatment. This figure is in accordance with estimates from other reports on ICI-based treatments [39].

Among patients with newly diagnosed HCC, 1.4% of patients were excluded solely due to the presence of untreated, or incompletely treated, esophageal varices at high risk of bleeding, while this figure among patients with recurrence following locoregional treatment or surgery was 4.0%. However, the presence of esophageal varices at high risk of bleeding should not be considered a strict exclusion criterion, as primary prevention of variceal bleeding can and must be performed with either non-selective beta-blockers or endoscopic banding ligation as part of the standard of care of patients with cirrhosis [51,52]. Ligation, which might be preferred due to the possibility of an objective assessment of treatment success, may delay by several weeks the beginning of anti-tumor treatment due to the need to fully evaluate the eradication of varices in a proportion of patients ranging from 1.4% to 4.0%. These considerations need to be taken into account in the therapeutic decision process, as overall approximately 13% of patients with HCC harbor large esophageal varices, a finding keeping with the overall prevalence of at-risk varices in this study population (i.e., 15.0%) before the application of the inclusion/exclusion criteria of the atezolizumab plus bevacizumab study [65]. Moreover, besides representing an issue to be solved before the beginning of treatment, the presence of varices has an inherent meaning that needs to be underscored in these patients, as it pinpoints a subpopulation of patients that—despite having similar inclusion criteria—presents a more advanced liver disease, characterized by clinically significant portal hypertension. This finding is not negligible when patients' prognosis is assessed, as the presence of esophageal varices is an independent prognostic determinant, also considering the stage of liver disease and HCC stage [51,65–67]. Therefore, the prognosis of patients with advanced HCC and esophageal

varices will be poorer than that of patients without varices, regardless of the efficacy of the anti-tumoral drug (Figure 4) [65]; as such, screening and treatment (either with band ligation or beta-blockers, selected on a case by case basis) is strongly recommended and must be performed in all patients with HCC, independently from the tumor stage and prior to the initiation of any anti-tumoral treatment.

**Figure 4.** Overall survival of patients with advanced hepatocellular carcinoma, subdivided according to the presence of esophageal varices. Reprinted with permission from ref. [65]. Copyright 2006 American Gastroenterological Association.

#### **6. Conclusions**

Immunotherapy certainly represents a new, exciting frontier in the treatment of advanced, unresectable HCC, and might play a role as an adjuvant or neo-adjuvant treatment of patients with early-stage HCC as well, giving them the chance to decrease the risk of tumor recurrence. New ICI-based treatment strategies with dual, or even triple, combinations of immune-targeting agents, or combinations of immunotherapy and TKIs or other anti-neoplastic agents, will probably be available in the foreseeable future. Thus, it is currently difficult to predict the future algorithm for the systemic treatment of advanced HCC and to state whether sorafenib and lenvatinib, as single agents, will still be listed among the first-line treatment options for this cancer. However, despite the understandable enthusiasm for immunotherapy, some unmet needs remain and require further, extensive research to be resolved. First, as many as 30–40% of patients with HCC do not respond to ICIs, and biomarkers predicting treatment response are lacking. This is a particular challenging issue as data about histological or serological biomarkers related to the effectiveness of ICIs in HCC have not been clearly identified, and, even if a histological marker was identified, biopsy sampling of HCC is not standard clinical practice for this tumor, which is mostly diagnosed on the basis of its radiological hallmarks; therefore, in the future, the role of liver biopsy in HCC might need to be revisited [68]. Secondly, we have shown that in real-life, also taking into consideration previous treatments, only approximately one-tenth to one-third of patients with HCC are eligible for the recently approved combination of atezolizumab plus bevacizumab. Moreover, the safety and utility of immunotherapy in patients with a greater impairment in liver function, such as Child–Pugh class B patients, still has to be demonstrated, as most trials have explored the safety of these drugs in

patients with well-preserved liver function (Child–Pugh class A) and, even though some reports have described an acceptable safety profile of some ICIs in Child–Pugh class B patients, consistent data regarding this topic are lacking, so that no strong recommendation can be made in this regard for the time being. Finally, ICIs are highly expensive drugs and this may represent a serious threat to the worldwide treatment implementation in clinical practice, since a large share of patients with HCC are diagnosed in developing countries, where available economic resources cannot support their use [69].

Taken together, the available evidence clearly shows that ICIs are going to play a pivotal role in the treatment of HCC and will improve the prognosis of patients with advanced HCC and, presumably, of those at earlier stages of the disease as well. We can assume that in the foreseeable future the current treatment algorithms will need revisions based on the most recent evidence. However, considering that in real-life settings a high proportion of patients will probably not be eligible for ICI-based regimens, much effort is still needed in order to optimize treatment strategies for patients with advanced, unresectable HCC.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data available on request due to restrictions. The data presented in this study are available on request from the corresponding author. The data are not publicly available due to the rules of the ITA.LI.CA consortium.

**Acknowledgments:** We acknowledged Italian Liver Cancer (ITA.LI.CA) Group and the Italian Association for the Study of the Liver—Hepatocellular Carcinoma Special Interest Group (AISF HCC-SIG). **Others members of the ITA.LI.CA group: Maurizio Biselli, Laura Bucci, Paolo Caraceni, Annagiulia Gramenzi, Lorenzo Lani, Davide Rampoldi, Nicola Reggidori, Valentina Santi, Benedetta Stefanini**: *Semeiotics Unit, Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy.* **Donatella Magalotti, Marco Zoli:** *Medicina Interna, Malattie neurovascolari e epatometaboliche, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy.* **Alessandro Granito, Luca Muratori, Francesco Tovoli**: *Internal Medicine, Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy.* **Francesco Azzaroli, Elton Dajti, Federico Ravaioli**: *Gastroenterology Unit, Department of Surgical and Medical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy*. **Alberta Cappelli, Rita Golfieri, Cristina Mosconi, Matteo Renzulli**: *Radiology Unit, Department of Specialist, Diagnostic and Experimental Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy*. **Fabio Farinati, Barbara Penzo**: *Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy*. **Rodolfo Sacco, Ester Marina Cela, Antonio Facciorusso**: *Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, Foggia, Italy.* **Giulia Pieri, Edoardo Casagrande, Mattia Vanello**. *Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genova, Genova, Italy.* **Antonio Gasbarrini, Gianludovico Rapaccini, Francesca Romana Ponziani, Nicoletta de Matthaeis**: *Gastroenterology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Roma, Italy.* **Gianluca Svegliati Baroni, Gloria Allegrini**: *Liver Injury and Transplant Unit, Polytechnic University of Marche, Ancona, Italy*. **Valentina Lauria, Giorgia Ghittoni, Giorgio Pelecca**: *Gastroenterology Unit, Belcolle Hospital, Viterbo, Italy.* **Fabrizio Chegai, Fabio Coratella, Mariano Ortenzi**: *Vascular and Interventional Radiology Unit, Belcolle Hospital, Viterbo, Italy*. **Serena Dell'Isola**: *Infectious Disease Unit, Belcolle Hospital, Viterbo, Italy.* **Gabriele Missale, Elisabetta Biasini, Andrea Olivani**: *Infectious Diseases and Hepatology Unit, Department of Medicine and Surgery, University of Parma and Azienda Ospedaliero-Universitaria of Parma, Parma, Italy*. **Alberto Masotto, Alessandro Inno, Fabiana Marchetti**: *Gastroenterology Unit, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Italy*. **Maria Di Marco:** *Medicine Unit, Bolognini Hospital, Seriate, Italy.* **Andrea Mega:** *Gastroenterology Unit, Bolzano Regional Hospital, Bolzano, Italy.* **Ciro Celsa, Mauro Grova, Caterina Stornello, Anita Busacca, Calogero Cammà, Giacomo Emanuele Maria Rizzo**: *Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.* **Maria Stella Franzè, Giovanni Raimondo,** **Carlo Saitta**: *Clinical and Molecular Hepatology Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy*. **Gianpaolo Vidili, Assunta Sauchella**: *Department of Medical, Surgical and Experimental Sciences, Azienda Ospedaliero-Universitaria of Sassari, Sassari, Italy*. **Francesco Giuseppe Foschi, Lucia Napoli, Vittoria Bevilacqua, Dante Berardinelli, Alberto Borghi, Andrea Casadei Gardini, Fabio Conti, Alessandro Cucchetti, Anna Chiara Dall'Aglio, Giorgio Ercolani**: *Department of Internal Medicine, Ospedale per gli Infermi di Faenza, Faenza, Italy*. **Claudia Campani, Chiara Di Bonaventura, Stefano Gitto, Valentina Adotti**: *Internal Medicine and Hepatology Unit, Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy*. **Gerardo Nardone, Pietro Coccoli, Antonio Malerba**: *Hepato-Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Napoli "Federico II", Napoli, Italy*. **Filomena Morisco, Maria Guarino, Mario Capasso**: *Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Napoli "Federico II", Napoli, Italy*. **Mauriza Rossana Brunetto, Filippo Oliveri, Veronica Romagnoli**: *Hepatology and Liver Physiopathology Laboratory, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy*. **Members of the Associazione Italiana per lo Studio del Fegato Special Interest Group on Hepatocellular Carcinoma (AISF SIG-HCC):** Aglitti A., Baccarani U.,Bhoori S., Borzio M., Brancaccio G., Burra P., Carrai P., Conti F., Cozzolongo R, Cucchetti A., D'Ambrosio R., Dell'Unto C., De Matthaeis N., Di Costanzo G.G., Di Sandro S., Famularo S, Fucilli F., Galati G., Gambato M., Giuliante F., Ghinolfi D., Grieco A., Gruttadauria S., Iavarone M., Kostandini A., Lenci I., Levi Sandri G.V., Losito F., Lupo L.G., Marasco G, Manzia T.M., Mazzocato S., Masarone M., Melandro F., Mescoli C., Miele L., Muley M., Nicolini D., Pagano D, Persico M., Pompili M., Pravisani R., Rendina M., Renzulli M., Romano F, Rossi M., Rreka E., Russo F.P., Sangiovanni A., Sessa A., Simonetti N., Sposito C., Tortora R., Viganò L., Viganò M., Villa E., Vincenzi V., Violi P., Vitale A.

**Conflicts of Interest:** The authors declare no conflict of interest.

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