Abstract
Purpose
Programmed death-1 (PD-1) inhibitor sintilimab plus bevacizumab has been approved as the first-line treatment for patients with advanced hepatocellular carcinoma (aHCC). However, the clinical benefits of sintilimab plus bevacizumab in a real-world setting in China is insufficiently defined to date. This study aims to evaluate the efficacy and cost-effectiveness of sintilimab plus bevacizumab biosimilar in a real-word cohort of patients with aHCC from China.
Methods
We reviewed the clinical data of 112 consecutive patients with aHCC who received sintilimab plus bevacizumab as a first-line treatment in Chongqing University Cancer hospital between July, 2021 and December, 2022. Overall survival, progression-free survival, overall response rate, and adverse event rates were assessed based on the RECIST 1.1. The survival curves were grafted by Kaplan–Meier method.
Results
Sixty-eight patients with aHCC were included our study. Efficacy evaluation results showed that 8 patients were partial remission, 51 patients were stable and 9 patients showed progression disease. Median overall survival and progression-free survival were 344.00 (168.77–419.23) days and 238.00 (174.56–301.44) days, respectively. Adverse events occurred in 35 patients (51.5%), including 9 patients with grade ≥ 3. The life-year (LY) and quality-adjusted LY (QALY) were 1.97 and 2.92, respectively, with a cost of $35,018.
Conclusion
Our data confirmed the promising efficacy, tolerable toxicity and cost-effectiveness in Chinese patients with aHCC who received sintilimab plus bevacizumab as the first-line therapy regimen in real-world practice.
Keywords: Survival, Cost-effectiveness, Sintilimab, Bevacizumab biosimilar, Hepatocellular carcinoma
Introduction
Hepatocellular carcinoma (HCC) represents the main type of primary liver cancers and the third highest mortality worldwide (Llovet et al. 2021). The multi-tyrosine kinase inhibitor (mTKI) sorafenib has been recommended as the first-line treatment for patients with advanced hepatocellular carcinoma (aHCC) since 2009 (Llovet et al. 2008). Abundant efforts to increase in effective and durable systemic treatment options have been made, in order to improve the prognosis of aHCC. Recently, many tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting angiogenesis and immune checkpoints exhibit the clinical value in phase III trials, especially the IMbrave 150 study (Finn et al. 2020; Ren et al. 2021; Kato et al. 2019; Xu et al. 2021).
In the IMbrave 150 study, the median overall survival (mOS) was 19.2 months (95% CI 17.0–23.7) with the combination of atezolizumab (an immune checkpoint inhibitor) and bevacizumab (an antiangiogenic agent) and 13.4 months (95% CI 11.4–16.9) with sorafenib (hazard ratio = 0.66; 95% CI 0.52–0.85; p < 0.001) (Finn et al. 2020). Based on the survival benefits and few adverse events in the IMbrave 150 trial, other combinations of immunotherapy with anti-angiogenesis in the treatment of patients with aHCC also displayed promising efficacy with improved OS and progression-free survival (PFS) (Kato et al. 2019; Ren et al. 2021; Xu et al. 2021).
The ORIENT-32 study was aimed to assess the therapeutic value of sintilimab (an anti-PD-1 antibody) plus a bevacizumab biosimilar compared with sorafenib in the first-line treatment for aHCC (Ren et al. 2021). The median PFS was significantly longer in the sintilimab-bevacizumab biosimilar group than that in the sorafenib group (4.6 months [95% CI 4.1–5.7] vs. 2.8 months [95% CI 2.7–3.2]; HR 0.56, 95% CI 0.46–0.70; p < 0.0001). As for the median OS, the sorafenib group was 10.4 months (8.5—not reached), and the combination treatment group was not reached (HR 0.57, 95% CI 0.43–0.75; p < 0.0001). ORIENT-32 is the first phase 3 study to show the encouraging efficacy of a PD-1 inhibitor (sintilimab) in combination with an anti-VEGF antibody in the first-line setting for patients with HCC. Due to the efficacy and safety from the ORIENT-32 study, the combinations of sintilimab and bevacizumab biosimilar have been approved by National Medical Products Administration (NMPA) and covered by medical insurance to HCC therapy. However, the data in the real world remain scarce.
Herein, a retrospective study was carried out to analyze the performance of sintilimab plus bevacizumab biosimilar in patients with aHCC in a real-world setting. In addition, we evaluated the cost-effectiveness of this combination as the first-line treatment of aHCC in actual clinical practice.
Patients and methods
Patients
This was a single-arm retrospective study conducted at Chongqing University Cancer Hospital (CUCH). The trial was performed in accordance with the Declaration of Helsinki (7th) and also got the approval of the ethics committee of CUCH. The need for informed consent was waived because of the retrospective nature.
Between July 2021 and September 2022, a total of 112 aHCC patients treated with sintilimab and bevacizumab biosimilar were reviewed initially. Patients with aHCC who received this treatment were retrospectively enrolled and analyzed. These patients, who were diagnosed with histologically or clinically confirmed advanced HCC (aHCC) according to the latest international guidelines, should meet the following inclusion and exclusion criteria: (1) an estimated life expectancy more than 3 months; (2) an Eastern Co-operative Oncology Group performance status score (ECOG PS) of 0–2; (3) at least one measurable target lesion. Patients complicated with other primary malignancies or other organ dysfunction, such as heart failure, malignant hypertension, acute myocardial infarction were excluded. A flow chat of patient enrollment is demonstrated in Fig. 1. Based on the inclusion and exclusion criteria above, 68 patients with aHCC were ultimately included in our study for further analysis. Baseline characteristics including but not limited to age, gender, PS, body weight, hepatic function indicators, hepatitis B virus marker, HBV DNA, white blood cell, platelet counts and previous treatments were collected and evaluated retrospectively.
Fig. 1.
Flow diagram of hepatocellular carcinoma patients’ enrollment
Systemic treatment and follow-up
All the enrolled patients were received sintilimab plus bevacizumab biosimilar combination treatment, and assessed treatment response and safety every 6–12 weeks. Patients were followed up until death or cutoff data (January 10, 2023). Sintilimab was intravenously administered at the standard dose of 200 mg every 3 weeks. In addition, bevacizumab biosimilar was prescribed based on the body weight (15 mg/kg, every 3 weeks). Contrast-enhanced computer tomography of the chest and abdomen or abdominal magnetic resonance imaging was performed every 6–8 weeks during treatment and, therefore, radiological response was recorded.
Radiological response of the target lesions in the liver was assessed according to the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST 1.1), including complete response (CR), partial remission (PR), stable disease (SD) and progression disease (PD) (Chiou and Burotto 2015). Disease control rate (DCR) was referred as CR, PR, and SD. Objective response rate (ORR) was defined as CR and PR. The OS was calculated from the date of initial therapy to the death or last follow-up. PFS referred to the time from the first treatment to PD confirmed by imaging or death from any cause. Safety evaluation was done by adverse events according to the Common Terminology Criteria Adverse Events version 5.0 (CTCAE 5.0) (Freites-Martinez et al. 2021).
Cost-effectiveness analysis
A Markov model with three mutual health states (PFS, PD and death) was constructed to evaluate the economic outcome of sintilimab plus bevacizumab biosimilar in aHCC (Fig. 2). The model cycle was 21 days, and the simulation time horizon was a lifetime. The output parameters of the model included total cost, life-year (LY), quality-adjusted LY (QALY), and incremental cost-effectiveness ratio (ICER). All costs were adjusted to be expressed in US dollars (1 US dollar = 6.48 China yuan, July 2021). Future costs and health outcomes were adjusted by a discount rate of 5% annually based on the Chinese pharmacoeconomic evaluation guidelines (Yue et al. 2021). The willingness-to-pay (WTP) threshold was proposed to be three times the gross domestic product (GDP) per capita in 2021 ($37,547) (Yue et al. 2021). The utility values of PD and PFS states were assumed to be 0.68 and 0.76, respectively, according to other researches (Shlomai et al. 2018).
Fig. 2.
Partitioned survival model structure. Ellipses and arrows represent the three health states and possible transitions mutually, respectively
Statistical analysis
All data, including categorical and continuous variables, were calculated and expressed as mean ± standard deviation (SD) or median (interquartile range, IQR) or number (percentage, %) as appropriate. PFS and OS curves were generated by the Kaplan–Meier method. All statistical analyses were conducted using the SPSS, version 26.0 (IBM Corp.), GraphPad Prism 9.0 (GraphPad Software, Inc.) and TreeAge Pro (TreeAge Software, Williamstown, MA).
Results
Baseline characteristics
A total of 112 aHCC patients were screened initially and were enrolled for efficacy analysis after exclusion. The baseline characteristics of final patients are expressed in Table 1. Most patients were male (59, 86.8%) and middle-aged (55 ± 11.4 years), with a mean body mass index of 24.7. Across all the participants, the proportion of patients with hepatitis B and hepatitis C was 85.3% (n = 58) and 4.4% (n = 3), respectively. The median serum AFP level was 159 ng/mL (IQR 12–2698), and the median serum PIVKA-II level was 934 mAU/mL (IQR, 58–10,218). Forty-five (66.2%) patients received loco-regional treatment concurrent with the administration of first-line systemic treatment. The mean diameter of each patients’ largest tumor nodule was 8.21 ± 5.85 cm at baseline.
Table 1.
Baseline characteristics of patients with advanced hepatocellular carcinoma
| Variables | Value |
|---|---|
| Age, mean years ± standard deviation (SD) | 55 ± 11.4 |
| Body mass index (kg/m2) | 22.6 ± 3.8 |
| Gender (male: female) | 59: 9 |
| BCLC stage (B:C) | 38: 30 |
| ECOG PS score, n (%) | |
| 0–2 | 65 (95.6%) |
| 3 | 3 (4.4%) |
| Child–Pugh score (A), n (%) | 66 (97.1%) |
| Diameter of largest target lesion (mean centimeter ± SD) | 8.08 ± 4.3 cm |
| Macrovascular invasion, n (%) | 39 (57.4%) |
| Baseline AFP (ng/mL)(≥ 400: < 400) | 28: 40 |
| Metastasis, n (%) | |
| None | 11 (16.2%) |
| Intrahepatic metastasis | 36 (52.9%) |
| Extrahepatic metastasis | 21 (30.9%) |
| Number of liver tumors | |
| Single | 14 (20.6%) |
| Multiple | 54 (79.4%) |
| Smoking history, n (%) | |
| Never | 26 (38.2%) |
| Ever | 34 (50.0%) |
| Current | 8 (11.8%) |
| Drinking status, n (%) | |
| Never | 52 (76.5%) |
| Ever | 9 (13.2%) |
| Current | 7 (10.3%) |
| Hepatitis B virus history, n (%) | 58 (85.3%) |
| Hepatitis C virus history, n (%) | 3 (4.4%) |
| History of hypertension, n (%) | 8 (11.8%) |
| History of diabetes, n (%) | 11 (16.2%) |
| Loco-regional therapies, n (%) | |
| None | 19 (27.9%) |
| Interventional therapy | 45 (66.2%) |
| Others | 4 (5.9%) |
Treatment response
The initial doses of sintilimab and bevacizumab biosimilar were 200 mg and 15 mg/kg, respectively.
At the time of their best response status, no patients attained CR in accordance with the RECIST 1.1 criteria. PR was observed in 8 patients, SD was observed in 51 patients (seen in Table 2). The remaining 9 patients were progressed. According to the above results, the overall response rate (ORR) and disease control rate (DCR) were 11.8% and 86.8%, respectively. The vast majority of best response to therapy among the study period was found after the initial two courses of treatment.
Table 2.
Clinical response of sintilimab plus bevacizumab
| Response | Values |
|---|---|
| Complete response, n (%) | 0 |
| Partial response, n (%) | 8/68 (11.8%) |
| Stable disease, n (%) | 51/68 (75.0%) |
| Progressive disease, n (%) | 9/68 (13.2%) |
| Objective response rate | 8/68 (11.8%) |
| Disease control rate | 60/68 (86.8%) |
From the survival curves in Fig. 3, median OS and PFS were 344.00 (168.77–419.23) days and 238.00 (174.56–301.44) days, respectively.
Fig. 3.
Progression-free survival (A) and overall survival (B) of advanced hepatocellular carcinoma patients treated with sintilimab and bevacizumab biosimilar
Safety
Treatment-related adverse events (AEs) are summarized in Table 3. AEs of any grade and grade ≥ 3 were reported by 35 patients (51.5%) and 9 patients (13.2%), respectively. The most common AEs in the group of sintilimab–bevacizumab biosimilar were the elevation of γ-glutamyltransferase (33, 48.5%), alanine aminotransferase (32, 47.1%), aspartate aminotransferase (31, 45.6%), and decreased lymphocytes (26, 38.2%). Serious AEs leading to treatment discontinuation were hypertension (1, 1.5%) and interstitial pneumonia (1, 1.5%).
Table 3.
Treatment-related adverse events in patients with advanced hepatocellular carcinoma, n (%)
| Adverse events | Any grade | Grade 3–4 |
|---|---|---|
| Any adverse event | 35 (51.5%) | 9 (13.2%) |
| Increased γ-glutamyltransferase | 33 (48.5%) | 2 (2.9%) |
| Increased alanine aminotransferase | 32 (47.1%) | 3 (4.4%) |
| Increased aspartate aminotransferase | 31 (45.6%) | 3 (4.4%) |
| Decreased lymphocyte count | 26 (38.2%) | 0 |
| Decreased appetite | 25 (36.8%) | 1 (1.5%) |
| Asthenia | 22 (32.4%) | 2 (2.9%) |
| Abdominal distension | 20 (29.4%) | 0 |
| Decreased weight | 20 (29.4%) | 0 |
| Decreased neutrophil count | 19 (27.9%) | 0 |
| Decreased white blood cell count | 18 (26.5%) | 0 |
| Increased total blood bilirubin | 11 (16.2%) | 2 (2.9%) |
| Elevated blood pressure | 8 (11.8%) | 0 |
| Abdominal pain | 6 (8.8%) | 1 (1.5%) |
| Diarrhea | 4 (4.9%) | 1 (1.5%) |
| Fever | 3 (4.4%) | 1 (1.5%) |
| Upper gastrointestinal hemorrhage | 2 (2.9%) | 0 |
| Pulmonary embolism | 2 (2.9%) | 0 |
| Hypertension | 2 (2.9%) | 1 (1.5%) |
| Interstitial pneumonia | 1 (1.5%) | 1 (1.5%) |
| Rash | 1 (1.5%) | 0 |
Cost-effectiveness
Base-case results of cost-effectiveness analysis exhibited that a total of 1.97 QALYs and 2.92 overall LYs yielded in patients treated with sintilimab plus bevacizumab biosimilar, with an accompanying cost of $35,018.
Discussion
ORIENT-32 is the first largest-scale, multi-center, open-label, randomized controlled trial in an attempt to evaluate the clinical benefit and safety of PD-1 inhibitor plus anti-VEGF therapies in patients with aHCC. Sintilimab–bevacizumab biosimilar displayed great superiority over sorafenib in Chinese patients with HBV-associated hepatocellular carcinoma, and therefore, combinations of sintilimab and bevacizumab biosimilar have been approved for routine clinical practice in HCC. Of note, ORIENT-32 was done during the COVID-19 pandemic and results might be affected by delays in drug administration and tumor evaluation. The purpose of our study was to confirm that whether sintilimab plus bevacizumab biosimilar would be an encouraging and economical treatment choice in a cohort of Chinese patients with aHCC under real-world conditions.
In our study, PFS of sintilimab and bevacizumab biosimilar combination was 7.9 months (238.0 days), longer than that of 4.6 months in ORIENT-32 trial. Moreover, the ORR and DCR in our study were different from that in ORIENT-32 (11.8% vs. 24% and 86.8% vs. 73%, respectively). Perhaps this disparity can be partly explained by the existence of most patients combined with local–regional therapies, including hepatic artery infusion chemotherapy (HAIC, n = 39), percutaneous ethanol injection (PEI, n = 3), and high-intensity focused ultrasound (HIFU, n = 3). Imaging evaluation of the response of liver cancer following local–regional therapy was inadequate by comparing the size of tumor before and after treatment based on RECIST 1.1 (Corona-Villalobos et al. 2014). The changes of enhancement components after therapy should also be considered. Following local–regional therapy, lack of enhancement is a surrogate for tumor death, and has been found to correlate well with pathological necrosis, although the diameter of tumors did not decrease (Young et al. 2018). This may explain why the DCR was higher and PFS was longer, while ORR was lower in our study.
Immune checkpoint PD-1 and its ligand PD-L1, co-inhibitory factors of the immune response, play an important role in cancer immune escape and tumorigenesis, through preventing the proliferation of effector T cells, activating apoptosis of antigen-specific T cells and inhibiting apoptosis of regulatory T cells (Alsaab et al. 2017; Yi et al. 2022). Immunotherapy targeting PD-1/PD-L1 axis can effectively block immunologic tolerance and enhance anti-tumor activity of T cells. Sintilimab selectively bind to PD-L1 and block PD-1/PD-L1 signaling pathway (Wang et al. 2019). Signaling through VEGF pathway has been reported to confer a more immunosuppressive tumor microenvironment (Morse et al. 2019). Clinically, PD-1/PD-L1 and VEGF antibody individually showed limited clinical responses in aHCC (Donisi et al. 2020). Nevertheless, different combination patterns of immunotherapy plus antiangiogenic agents could achieve better therapeutic effect than either used alone, including gastric cancer, carcinoma of urethral epithelium renal cell carcinoma, endometrial cancer, breast cancer, and metastatic non-small-cell lung cancer (Song et al. 2020). As for the underlying mechanisms, antiangiogenic agents could promote tumor induced vessels normalization and reduction, and also convert tumor environment from immunosuppression to immune supportive status (Gao and Yang 2020). In normalized tumor vascular network, myeloid-derived suppressor cells and regulatory T cells declined; T cell infiltration increased and polarization of tumor-associated macrophages polarized to M2-like phenotype. In addition, inhibitory signals of dendritic cells differentiation and mature were blocked by anti-VEGF agents (Yi et al. 2019). Superior curative effect of anti-PD-1 plus VEGFR2 inhibitor in preclinical mouse models of HCC was related to the elevated level of infiltrating effector T cells, as well as increased M1 and decreased M2 tumor-associated macrophages (Sangro et al. 2021).
HCC causes large social and economic burden to patients and government in China. Immunotherapy combined with antiangiogenic therapy makes a landmark breakthrough in HCC therapeutic strategy with superiority over sorafenib (Jin et al. 2022). The price of immunotherapy and antiangiogenic therapy drugs has declined recently. The combination of sintilimab and bevacizumab biosimilar for the treatment of aHCC was covered by national medical insurance from March 2023. The present analysis initially came to the conclusion that sintilimab plus bevacizumab biosimilar was cost-effective as a first-line therapy for aHCC, especially in the implementation of diagnosis related groups (DRGs) payment. In addition, these drugs were affordable and available from the Chinese payer perspective with WTP.
Nonetheless, this study has several limitations. First, this was a retrospective and observational study. Second, sintilimab plus bevacizumab biosimilar has been approved for the treatment of aHCC in China recently. Therefore, the follow-up duration was short and the sample size was relatively limited, which may result in selection bias. Third, only the direct medical costs was analyzed, and accommodation cost, traffic and board expense were not included. Last, we did not compare sintilimab–bevacizumab biosimilar with other first-line strategies, sorafenib or lenvatinib, owing to a lack of robust head-to-head trial data.
In conclusion, the combination of sintilimab and bevacizumab biosimilar highlighted the favorable clinical benefit and tolerability in a real clinical setting of 68 patients with aHCC. Our study suggests that sintilimab plus bevacizumab biosimilar regimen to be cost-effective with reduced overall costs. This combination regimen provides a novel and attractive alternative treatment choice for these aHCC patients.
Acknowledgements
The authors greatly appreciate all the patients and their families for participating in this trial. We also express our gratitude to the staffs from medical-record department of Chongqing University Cancer Hospital for their selfless dedication. This work was supported by the Scientific research project of Chongqing Medical Biotechnology Association (No. cmba2022kyym-skxmG006) and Decision Consultation Management Innovation Project of Shapingba District (No. Jcd202278).
Author contributions
We are so glad to submit our paper to "Journal of Cancer Research and Clinical Oncology". In this research, Wchen and YLi conceived and designed the study. YJia, and Hchen collected the data and were responsible for patients' follow-up (figures 1-2). XZeng, GLiang and HZhao analyzed the data (Table 1-3 and figures 2-3). XZeng and YLi drafted the manuscript. All authors reviewed the manuscript, provided feedback, and approved the manuscript in its final form.
Funding
This work was supported by the Major International (Regional) Joint Research Program of the National Natural Science Foundation of China (No. 81920108027), Chongqing Outstanding Youth Science Fundation (No. cstc2020jcyj-jqX0030), Chongqing Science and Technology Innovation Leading Talent Support Program (No. cstc2021ycjh-bgzxm0073), and Chongqing University Innovation Research Group.
Data availability
The data used or analyzed in our study can be obtained from the corresponding authors on reasonable request.
Declarations
Conflict of interest
The authors declared that they had no financial interests.
Footnotes
Publisher's Note
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Contributor Information
Wen Chen, Email: 836049985@qq.com.
Yongsheng Li, Email: lys@cqu.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data used or analyzed in our study can be obtained from the corresponding authors on reasonable request.