Combining immune checkpoint inhibitors with locoregional therapies in hepatocellular carcinoma

KEYWORDS:

• Hepatocellular carcinoma
• HCC
• immunotherapy
• locoregional therapies
• TACE

The phase III IMbrave150 trial evaluating the combination of the PD-L1 inhibitor atezolizumab plus bevacizumab has recently represented an important step forward in the medical management of HCC [1]. According to the results of this study, advanced HCC patients receiving atezolizumab – bevacizumab reported statistically significant and clinically meaningful improvements in terms of overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and complete response rate, compared with sorafenib monotherapy [2,3]. Of note, immunotherapy seems to have find its role in the management of HCC as part of combinatorial strategies, as also witnessed by the recently published results of the phase I/II HIMALAYA trial [4]. In addition, an interesting line of research currently concerns the addition of locoregional therapies to immune checkpoint inhibitors, in order to produce a synergistic effect and improve clinical outcomes [5].

Locoregional treatments, including transarterial chemoembolization (TACE), radiofrequency ablation (RFA), selective internal radiation therapy (SIRT), and stereotactic body radiotherapy (SBRT), are considered of pivotal importance in the management of HCC patients [6]. These approaches are currently under evaluation in combination with immunotherapy, since locoregional therapies not only attack primary tumors but have been also suggested to boost antitumor immunity though the release of neoplasm antigens [7]. Recent years have seen the presentation or publication of several clinical trials combining immune checkpoint inhibitors with locoregional treatments (Table 1).

Table 1. Completed clinical trials evaluating immune checkpoint inhibitors plus locoregional therapies in advanced hepatocellular carcinoma patients.

ClinicalTrials.gov Identifier	Phase	Treatment Arm	Results
NCT03033446	II	Nivolumab + Y90 – radioembolization	ORR: 31% DCR: 58.3% median PFS: 4.6 months (95% CI 2.3–4.8) median OS: 15.1 months (95% CI 7.8–NR)
NCT03939975	II	Pembrolizumab or Nivolumab + thermal ablation	median PFS: 5 months (95% CI, 2.9–7.1) median OS: 16.9 months (95% CI, 7.7–26.1)
NCT01853618	I/II	Tremelimumab + RFA or TACE	PR: 26.3% 6 months PFS: 57.1% median OS: 12.3 months (95% CI: 9.3–15.4)

Abbreviations: DCR: disease control rate; NR: not reached; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; PR: partial response; RFA: radiofrequency ablation; TACE: transarterial chemoembolization.

A phase I/II trial published by Duffy and colleagues investigated the role of the combination of the CTLA-4 inhibitor tremelimumab plus TACE or RFA in Barcelona Clinic Liver Cancer (BCLC) Stage B and C HCC patients [8]. According to the results of this study, partial response (PR) was observed in 26.3% of cases, with 6-month PFS of 57.1% and median OS of 12.3 months (95% CI, 9.3–15.4). An interesting finding of this study concerns the HCV-positive population, with 12 of 14 HCC patients experiencing a notable reduction in viral load and a dramatical increase in CD8 + T cells reported in tumor biopsies after 6 weeks [8]. In another phase II trial conducted by Zhao and colleagues, the authors evaluated the role of thermal ablation plus a PD-1 inhibitor (pembrolizumab or nivolumab or JS001) in 50 HCC patients [9]. Median PFS, median Time to Progression (TTP), and median OS were 5 months (95% CI, 2.9–7.1), 6.1 months (95% CI, 2.6–11.2), and 16.9 months (95% CI, 7.7–26.1), respectively [9].

Another strategy under assessment is based on the combination of TACE plus immunotherapy. With efficacy data still pending, the preliminary results of the PETAL phase I/II study on conventional TACE followed by the PD-1 inhibitor pembrolizumab reported an acceptable safety profile for this combination [10]. Similarly, the IMMUTACE phase II trial is investigating the efficacy and tolerability of TACE plus nivolumab in intermediate-stage HCC patients (NCT03572582), and other trials are evaluating double checkpoint blockade with durvalumab plus tremelimumab combined with RFA, TACE or cryoablation (NCT02821754) or following TACE (NCT03638141) in HCC patients with advanced disease.

As witnessed by the presentation of the SORAMIC and SARAH trials on SIRT alone or combined with sorafenib, SIRT is under assessment in combination with immunotherapy [11,12]. A single-center, nonrandomized phase II trial conducted by Tai and colleagues evaluated the role of Y90-radioembolization plus nivolumab in Asian HCC patients with advanced disease (NCT03033446) [13]; interestingly, the ORR and disease control rate (DCR) were 31% and 58.3%, respectively, with median PFS of 4.6 months and median OS of 15.1 months [13]. Similarly, several ongoing studies are investigating SIRT plus pembrolizumab (NCT03099564) or nivolumab (NCT02837029). Another promising combination of immunotherapy plus locoregional therapies concerns the use of SBRT, including a phase II trial evaluating pembrolizumab – SBRT following disease progression during first-line sorafenib (NCT03316872).

Despite therapeutic combinations of immune checkpoint inhibitors and locoregional treatments appear promising, some considerations come to mind. First, locoregional approaches have been suggested to increase hypoxia and to release several cytokines (including, among the others, TGFbeta, VEGF-1, VEGF-2), which in turn are able to impair the efficacy of antitumor immune response [14]. Based on these premises, and similar to what observed in recent trials (e.g. IMbrave150, KEYNOTE-524, etc.), studies exploring combinations of locoregional therapies with immunotherapy and antiangiogenic agents should be prioritized and supported in the near future [15–18]. For example, the results of the LEAP-012 phase III trial exploring TACE plus pembrolizumab – lenvatinib in advanced HCC patients are awaited (NCT04246177), as well as those of several ongoing studies in this setting (NCT04191889, NCT03778957). In addition, an important number of unmet needs has to be faced, including the timely transitioning from locoregional to systemic therapies in advanced HCC and the lack of data on sequencing of ICIs with locoregional therapies in hepatocellular carcinoma. Furthermore, another problem needing to be addressed remains how to optimize the schedule and dose of immunotherapy with locoregional approaches.

Certainly, combining immunotherapy with locoregional therapies represents a timely and interesting research avenue in HCC management, given the synergistic effect produced by these treatment strategies, hesitating in increased antitumor immunity. At the same time, the identification of predictive biomarkers of response remains a priority in this setting, especially considering that the number of indications for immunotherapy is supposed to further increase in the near future. In our view, the question whether predictors such as PD-L1 expression, TMB, MSI, and gut microbiota could be applied to select the right patients to receive locoregional therapies plus immunotherapy and to provide useful information for disease-monitoring and treatment-decision making remains critical.

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