Discussion

At the time of preparing this manuscript, there are no reports available analyzing the efficacy and safety of toripalimab and sintilimab in treating HCC patients. A phase II/III trial (NCT03794440) of sintilimab combined with an anti-VEGF mAb Bevacizumab (IBI305) in HCC is still at its recruitment stage. In a randomized, multicenter phase 2/3 trial (NCT02989922) of camrelizumab (SHR-1210) in 217 patients with advanced HCC, the objective response rate (ORR) was 13.8% , six-month overall survival was 74.7%, and the median time to progression (TTP) and progression-free survival (PFS) was 2.6 and 2.1 months respectively [28]. In this retrospective observational study of 75 HBV-associated HCC patients, we have demonstrated the encouraging efficacy of toripalimab, camrelizumab and sintilimab (ORR 15.4%, 12.1% and 31.3%, respectively; overall ORR 17.3%), in a real world treatment setting, with well tolerated TRAE (overall 38.7% adverse event rate). Our findings are comparable to the results of the NCT02989922 camrelizumab trial, other PD-1 inhibitor therapy trials (KEYNOTE-224 and CheckMate-040) and real world observational data in advanced HCC patients [24]–[26].
Immune evasion through up-regulation of the PD-1 pathway is a pivotal mechanism in the progression of HCC. The efficacy of PD-1 checkpoint inhibitor therapy can be affected by the expression of PD-L on tumor cells, the number of different tumor specific neoantigens that the host immune cell can recognize, and the overall tumor micro environment (TME) [18], [30]. Using immunohistochemistry to characterize PD-L1 expression in selected tumor types has been suggested to be associated with the responsiveness of PD-1 treatment. However the role of such test has not been established in HCC [35]. Higher tumor mutational burden (TMB), results in a broadened display of tumor neoantigens, promoting a polyclonal, efficacious T cell effector response. PD-1 inhibitors generally have good responses in squamous cell carcinoma, cutaneous melanoma and lung cancers, whose TMB are above 10 mutations/megabase, with reported ORR ranges from 40% up to more than 70% in various clinical trial results [36]–[38]. In contrast uveal melanoma (UM) is a rare form of ocular tumor, which is believed to have one of the lowest TMB amongst all cancers [39]. Algazi et al. performed a meta-analysis focusing on UM patients receiving PD-1 inhibitor therapy, and reported only a 3.6% ORR and a median PFS of as short as 2.6 months [40]. HCC typically demonstrates a moderate TMB roughly of 2 mutations/megabase, underscoring the antigenic potential of HCC and perhaps also highlighting one of the reasons for the typical 15% - 20% ORR in PD-1 therapy in HCC, considerably lower than that of the cancer types with high TMB. In murine models of HCC, the result of dual therapy combining PD-1 blockade with other angiogenesis inhibitor has shown to be promising [41]. In order to understand and attempt increase the efficacy of PD-1 efficacy in combined therapy for advanced HCC patients, a number of clinical trials have been set up: NCT03794440, sintilimab with bevacizumab (VEGF inhibitor); NCT03713593, pembrolizumab plus lenvatinib (VEGR inihibtor); NCT03764293, camrelizumab and tyrosine kinase inhibitor apatinib; and a number of PD-L1 inhibitor trials (NCT03298451, NCT03847428, NCT03434379). Liver has a critical role in maintaining a state of immune balance, due to its anatomical position and function as a ‘filter’ of blood clearing potential pathogens while maintaining nonresponsiveness to non-pathogenic antigens. Under normal biological conditions, the presence of a predominantly immunosuppressive microenvironment in liver might affect disease control in patients with HCC [42]. In China, about 80% of the HCC patients also have HBV infection [31]. HBV core antigen has been shown to stimulate interleukin-10 (IL-10) secretion [32]. In HBV associated HCC patients, the presence of active HBV infection may further tip the immune balance towards more tolerance in the liver and also the whole body via potent immunosuppressive cytokines such as IL-10. In our cohort, all 75 patients have active HBV infections; nevertheless, the efficacy of PD-1 therapy is not significantly lower but similar to the published trials and observational studies where both HBV positive and negative patients were included. One of the possible drive to a potentially higher than usual ORR is that in our study, 14/75 (18.7%) of the patients are staged as BCLC B, while in most of these trials only patients who had progressed on or were intolerant to prior systemic treatments were included.
Besides the inherent biases in real world observational studies, there are several limitations. First, the mean duration of follow-up was short (22.7 ± 12.6 weeks). Second, this study was retrospectively designed, though objective endpoints (especially imaging data for tumor responses assessment) were elaborately and integrally recorded. Third, 76 of 151 patients were excluded from the final study, which might reduce the power of statistical analysis. But we believe the above data provide important experience on subgroups of patients frequently found in our everyday clinical practice and multi-disciplinary team (MDT) consultation. And despite all that, the strength of our study is the provision of unique real-life data on the safety and efficacy of PD-1-targeted immunotherapy with toripalimab, camrelizumab or sintilimab for HBV associated HCC patients, which might be the first study to evaluate PD-1 blockers in Mainland China.
In conclusion, our findings in this study support further applications of these drugs in HCC patients. Of course as non-randomized retrospective observational data, this study can only provide limited evidence to show that these drugs are efficacious and safe. It shall not be viewed as non-biased data and utilized in clinical decision making without further evidence base. What our study suggests is that toripalimab, camrelizumab and sintilimab, the three monoclonal PD-1 checkpoint blockers developed in China, appeared to have promising outcome in advanced HCC treatment with tolerable and manageable side effects, comparable to alternatives that are much more expensive, hence less assessable to Chinese patients; a multicenter, larger in scale, randomized controlled prospective study is needed to further understand the efficacy and safety of these drugs with or without other treatment modalities combined.

CONFLICT OF INTEREST/STUDY SUPPORT:

Specific author contributions: GS Y, XY H, M C and JZ C were involved in conception and design the study and interpretation of data. GS Y wrote the first draft of the article and did the statistical analysis. XY H, Q L, WC D, X C, YB G and JZ C made treatment decisions and manage the patients. PF Y and WX Y collected and recorded the data. All authors were responsible for re-drafting of the article and approved the final version.
Guarantor of the article: JZ C is the guarantor
Financial support: This study was partly supported by the grants from Natural Science Foundation of Guangdong Province (2017A030313645). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Potential competing interests: None
Statement of ethics: Approval for this retrospective study was obtained from the institutional ethics committee (NFEC-201903-Y1-01), and written informed consent was obtained from each patient before the procedure.
Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

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