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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