Camrelizumab combined with sorafenib versus sorafenib alone in patients with advanced hepatocellular carcinoma: a retrospective study

Background: Few studies have evaluated the ecacy and safety of immunotherapy and targeted therapy in combination. The present study aimed to compare camrelizumab plus sorafenib versus sorafenib alone in patients with advanced hepatocellular carcinoma using a propensity score analysis. Patients and methods: Between January 2019 and January 2021, a total of 100 patients with advanced HCC in the Second Aliated Hospital of Army Medical University were retrospectively analyzed. Of the patients involved, 35 patients received combined camrelizumab plus sorafenib treatment, and 65 patients received sorafenib monotherapy. After 1:1 propensity score matching (PSM), 34 patients were included in each group. The progression-free survival (PFS), overall survival (OS), treatment response and the relevant adverse effects (AEs) were evaluated. Results: The combined-therapy group showed signicantly improved overall response rate (ORR) than the sorafenib-only group (before PSM, P=0.037; after PSM, P=0.010), but no difference was noted in disease control rate (DCR) (before PSM, P=0.695; after PSM, P=1.000). The median PFS was signicantly longer in the combined-therapy group than the sorafenib-only group (before PSM, P=0.041; after PSM, P=0.043). However, the two groups exhibited comparable median OS (before PSM, P=0.135; after PSM, P=0.105). Although The incidence of thrombocytopenia after PSM was signicantly higher in the combined-therapy group than in the sorafenib-only group, most of the AEs could be easily controlled after treatment. Conclusion: The combination treatment of camrelizumab with sorafenib showed promising ecacy with acceptable safety for the management of advanced HCC.


Introduction
Hepatocellular carcinoma (HCC), one of the most lethal malignant tumors globally, is the second-ranked cause of cancer death worldwide [1]. HCC is often detected at a late stage due to the insidious and asymptomatic progression, which is not amenable to the curative interventions including liver resection, liver transplantation and radiofrequency ablation [2,3]. Despite tremendous progress in HCC diagnosis and treatment, the clinical outcomes of advanced HCC remain disappointing with the current available therapeutic modalities [4]. Therefore, it is of paramount importance to investigate more effective treatment strategies against advanced HCC.
Multitarget tyrosine kinase inhibitors (TKIs) play a vital role in the clinical management of patients with various kinds of solid tumors [5]. TKIs suppress tumor proliferation and angiogenesis by targeting the vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), broblast growth factor receptors (FGFRs), stem cell factor receptor (KIT) and glial cell-derived neurotrophic factor receptor (RET) [6][7][8]. Of these, sorafenib is the rst-line targeted agent for advanced HCC patients,which achieved a median overall survival (OS) of 6.5-10.7 months and median time to progression of 2.8-5.5 months [9,10]. However, sorafenib is associated with a low response rate of 30% and a high risk of acquired drug resistance and disease progression, thus limiting its long-term clinical bene ts [11]. Although other molecular targeted drugs have been developed, the targeted therapy e cacy in advanced HCC remains a serious concern.
Immune checkpoint inhibitors (ICIs), which target cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death protein1 (PD-1) and programmed cell death protein ligand 1 (PD-L1), show a promising prospect in cancer therapeutics [12]. The anti-PD-1 antibodies nivolumab and pembrolizumab have gained the U.S. Food and Drug Administration (FDA) approval as second-line agents for the treatment of advanced HCC [13,14]. Despite the positive role of ICIs for HCC, the subsequent phase 3 CheckMate459 [15] and  trials demonstrated that nivolumab (versus placebo) and pembrolizumab (versus sorafenib) failed to show signi cant survival superiority, indicating the necessity to explore more appropriate systemic treatment strategies to enhance the immunotherapy e cacy. The angiogenesis inhibitors can impair immunosuppression in the tumor microenvironment, thus facilitating antitumor e cacy of immune checkpoint inhibitors through in uence on T cell activation, which provides a strong rationale for combination trials [17]. Recently, the combination of atezolizumab plus bevacizumab was approved by FDA as rst-line therapy for unresectable HCC [18], which encourages further investigation for other potential promising combination treatment.
Hence, the present study aimed to evaluate the safety and therapeutic e cacy of Camrelizumab plus sorafenib in comparison with sorafenib monotherapy for patients with advanced HCC.

Treatment Protocol
The sorafenib-only group was administered sorafenib 400 mg orally twice daily. The combined-therapy group received camrelizumab 200 mg intravenously every 2 weeks in combination with sorafenib 400 mg orally once daily. When the patients experienced grade 3/4 treatment-related adverse events (AEs), the dose of sorafenib was reduced to 200 mg/day or discontinued until the AEs severity decreased to grade ≤ 2. Patients were treated until death, disease progression, unacceptable toxicity, consent withdrawn from the study.

Endpoints And Assessments
Demographic and clinical data were recorded and included age, gender, hepatitis B virus (HBV) carrier, Liver cirrhosis, ECOG performance score, and Child-Pugh score, Barcelona Clinic Liver Cancer (BCLC) stage, alpha-fetoprotein (AFP), total bilirubin (TBIL), albumin (ALB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count (PLT), white blood cell (WBC), prothrombin time (PT), tumor size, tumor number, macrovascular invasion, extrahepatic metastasis, and previous local regional therapy. The patients received CT or MRI evaluation at baseline and every 2 cycles of treatment (8 weeks) thereafter. Tumor responses were assessed according to the mRECIST and classi ed as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD).
The primary endpoint was progression-free survival (PFS). Secondary endpoints included over survival (OS), objective response rate (ORR), disease control rate (DCR) and AEs.
PFS was calculated as the time from the start of treatment to the date of disease progression or death due to any cause. OS was de ned as the time from the start of treatment to the date of death due to any cause or the last follow-up. DCR was de ned as the proportion of patients with CR, PR, and SD. ORR was de ned as the proportion of patients with CR or PR. AEs were assessed and graded based on the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0).

Statistical Analysis
We performed Propensity score matching (PSM) analysis based on the following variables: age, sex, HBV carrier, liver cirrhosis, ECOG performance score, Child-Pugh stage, BCLC stage, AFP, tumor size, tumor number, macrovascular invasion, extrahepatic metastasis and previous local regional therapy. The continuous data were expressed as mean ± standard deviation or median with interquartile range and compared using t test or Mann-Whitney-Wilcoxon test. The categorical data were presented as frequency with proportion and analysed using Chi-square test or Fisher exact test. OS and PFS were estimated by the Kaplan-Meier method and log-rank test. P values < 0.05 were considered statistically signi cant. Statistical analyses and PSM were conducted using SPSS version 25.0 (IBM SPSS, Inc, Chicago, IL).

Baseline
Between January 2019 and January 2021, a total of 100 patients with advanced HCC in our hospital were enrolled in the present study, of which 35 patients received combined therapy and 65 patients received sorafenib monotherapy. 34 pairs were matched after PSM. The patient characteristics at baseline are shown in Table 1. No signi cant differences were found between the two groups in age, sex, HBV carrier, liver cirrhosis, ECOG performance score, Child-Pugh stage, BCLC stage, AFP, TB, ALB, AST, ALT, PLT, WBC, PT, tumor size, tumor number, macrovascular invasion, extrahepatic metastasis and previous local regional therapy both before and after PSM.

Treatment E cacy
No CR was observed in either group (Table 2). Before PSM, the ORR was signi cantly higher in the combined-therapy group than in the sorafenib-only group (17.1% vs. 3.1%, P = 0.037). The DCR was 68.6% in the combined-therapy group and 72.3% in the sorafenib-only group, respectively (P = 0.695). There was no signi cant difference in OS between the two groups, with median OS of 14.1 months (6.8-21.4 months) in the combined-therapy group and 9.6 months (6.7-12.5 months) in the sorafenib-only group (P = 0.135). However, the combined-therapy group exhibited statistically signi cant prolonged PFS compared to the sorafenib-only group (10.2 months; 95% CI 4.5-19.0 vs. 6.1 months; 95% CI 2.5-9.7; P = 0.041) (Fig. 1).

Adverse Events
All recorded treatment-related AEs are listed in Table 3. The most common AEs were hand and foot syndrome, thrombocytopenia and hyperbilirubinaemia in the combined-therapy group and hand and foot syndrome in the sorafenib-only group. Elevated transaminase was the most frequent grade 3/4 AEs observed in both groups (before and after PSM). The incidence of thrombocytopenia (p = 0.005) and anemia (p = 0.040) before PSM and thrombocytopenia (p = 0.011) after PSM was signi cantly higher in the combined-therapy group than the sorafenib-only group. However, most of these AEs were grade 1 or 2, which can be easily alleviated after dose adjustment and supportive treatment. Dose modi cations or treatment interruptions due to AEs were similar in the combinedtherapy group and the sorafenib-only group (42.9% vs. 41.5%, P = 0.899 before PSM; 42.9% vs. 41.2%, P = 0.806 after PSM,). No treatment-associated deaths occurred in this study.

Discussion
The continuous emergence of new agents for systemic treatment options represented a major breakthrough in the management of advanced HCC. Although the multikinase inhibitor sorafenib has been was approved as the rst-line systemic treatment against advanced HCC for a decade, its survival bene t is limited and response rate is low [9]. Recently, the combined molecular targeted therapy with immunotherapy attracted tremendous interests due to the potential improved therapeutic e cacy compared with monotherapy [21,22]. Our study is the rst, to our knowledge, to analyze the e cacy and safety of camrelizumab and sorafenib in patients with advanced HCC. The result demonstrated that the combined therapy showed superiority over sorafenib monotherapy in terms of PFS and ORR, though the OS bene t was not observed.
Different combined treatment modalities have been discussed in the advanced HCC due to the limited clinical bene ts of monotherapy [23]. The recent introduction of immunotherapy demonstrated promising e cacy in solid tumor treatment and various clinical trials involving immunotherapy are currently ongoing to explore the potential survival bene t in HCC patients [24,25]. However, the optimal combined regimens remain unde ned in spite of the remarkable progress in systemic therapy of advanced HCC. So far, there is little knowledge of the potential synergic effects on the combination of camrelizumab and sorafenib in patients with advanced HCC. Despite the great promise of molecular targeted agents, their clinical bene ts are limited regarding tumoral heterogeneity and acquired resistance [28,29], emphasizing the necessity of exploring combination therapies to improve the therapeutic e cacy. Our ndings showed the addition of camrelizumab to sorafenib was associated with prolonged PFS and higher ORR, which indicated that the combination of immunotherapy and targeted therapy was associated with enhanced antitumor bene t. Preclinical studies demonstrated that antiangiogenic agents targeting VEGF/VEGFR could inhibit tumor growth and metastasis [29,30]. In addition, angiogenesis inhibitors possessed immunomodulatory effects including increasing T-cell activity and promoting T-cell in ltration [31]. On the other hand, vasculature normalization via inhibition of angiogenesis could reduce tumor hypoxia and improve drug delivery, and facilitates immune cell in ltration [32]. Therefore, the targeted therapy could reprogram the immunosuppressive tumor microenvironment into an immunostimulatory environment, thereby contributing to enhancing antitumor immunity. 17 Moreover, more studies are encouraged to investigate the underlying mechanism of enhanced antitumor effects and identify patients who will bene t most from the combination.
The most common sorafenib-related AEs were in accordance with those observed in the previous reports. Here, any-grade AEs of thrombocytopenia occurred more frequently in the combined-therapy group compared with the sorafenib-only group, which were related to utilization of camrelizumab. Given the increased hematologic toxicities in the combination therapy, the incidence of grade 3/4 toxicities was comparable between the two treatment groups. Moreover, most of the AEs in both groups were mild to moderate in severity and no signi cant difference in the incidence of dose adjustments or treatment interruptions was observed between the two groups. The current study showed that the side effects of combined therapy are generally controllable and tolerable.
Several limitations in this study need to be addressed. First, the retrospective design of the retrospective study may have introduced potential biases, though PSM was introduced to reduce potential selection bias. Second, the study was based on a single-center experience with a relatively small number of patients.
Third, the follow-up period was short. Furthermore, the heterogeneous individual therapeutic response highlights the need to understand who will respond better to the treatment.

Conclusion
In conclusion, camrelizumab combined with sorafenib appears to be a promising therapeutic strategy in the management of advanced HCC, with prolonged PFS, higher ORR and well-tolerated AEs. The results offer our preliminary experience in combination strategies for advanced HCC, which are informative for clinical decision making. Nevertheless, further prospective randomized controlled studies with larger sample size and longer follow-up time are warranted to support these preliminary ndings of the study.

Declarations Ethnics declarations
Ethics approval and consent to participate The study was approved by the Ethics Committee of the Second A liated Hospital of Army Medical University. Written consent was obtained from patients for the collection of clinical data for research purposes.

Consent for publication
Not applicable.
Availability of data and materials The data and material are available for reasonable requests.

Competing interests
The authors declare that they have no con icts of interest.