Abstract
Purpose
The combination therapy of lenvatinib and immunotherapy as first-line treatment remains controversial in unresectable hepatocellular carcinoma (uHCC). This research aimed to compare the efficacy and safety of lenvatinib monotherapy (L) and combination therapy of lenvatinib and immune checkpoint inhibitor (LI) in lenvatinib-insensitive patients with uHCC.
Methods
Two hundred fifty-five uHCC patients were enrolled in this study. Patients were classified into two groups: (1) Lenvatinib monotherapy (L); (2) Combination therapy (LI). Patients who remained stable disease (SD) but did not achieve complete response (CR) or partial response (PR) or progression disease (PD) for at least 3 months after receiving lenvatinib monotherapy were defined as lenvatinib-insensitive. Overall survival (OS) and progression-free survival (PFS), baseline characteristics, and safety were compared between groups.
Results
The LI group had longer OS (15.9 months vs. 11.9 months, P = 0.001) and PFS (12.6 months vs. 7.3 months, P < 0.001) than the L group. ECOG PS was an independent prognostic factor affecting OS and Up-to-seven was an independent prognostic factor affecting PFS. The frequency of grade ≥ 3 treatment-related adverse events (TRAEs) was not significantly different.
Conclusions
Our study demonstrated that the combination therapy (LI) had longer OS and PFS than the lenvatinib monotherapy (L) in lenvatinib-insensitive patients with uHCC.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10637-024-01502-7.
Keywords: Unresectable hepatocellular carcinoma, Lenvatinib, Immune checkpoint inhibitor, Lenvatinib-insensitive
Introduction
Hepatocellular carcinoma (HCC) accounts for about 75–85% of all liver tumors, and its incidence ranks sixth among malignant tumors in the world [1]. Lenvatinib is a tyrosine kinase inhibitor (TKI) that has been approved as a first-line treatment for advanced HCC by the Barcelona Clinic Liver Cancer (BCLC) guidelines since 2018 [2]. Furthermore, lenvatinib has emerged as the predominant TKI utilized in the clinical management of HCC. In recent years, immune checkpoint inhibitors (ICI) have exhibited promising clinical benefits in unresectable hepatocellular carcinoma (uHCC) patients [3–5]. The combination of TKI and ICI has achieved great results in a lot of studies [6–9], and it has become the standard second-line treatment according to the guidelines [10]. There are also many retrospective studies suggesting the superiority of combination therapy compared with TKI monotherapy in first-line treatment [11, 6]. However, the failure of LEAP-002 has also caused a lot of controversies in the combination therapy. In this global, randomized, double-blind, phase 3 study, the efficacy of lenvatinib monotherapy was comparable to that of the combination of lenvatinib and ICI [12]. We are anxious to know which patients will benefit from the combination and which will not. Subgroup analyses from previous studies have provided some hints, but no studies have explored these patients who are not sensitive to lenvatinib monotherapy.
Given the potential efficacy of combination therapy, clinicians often prematurely administer immunotherapy to patients who are insensitive to lenvatinib. In clinical practice, patients who remained stable disease (SD) but did not achieve complete response (CR) or partial response (PR) or progression disease (PD) for at least 3 months after receiving lenvatinib monotherapy were defined as lenvatinib-insensitive [13]. However, the efficacy of combination therapy versus monotherapy in lenvatinib-insensitive patients remains unclear.
In this study, two groups were set up: the lenvatinib monotherapy (L), the lenvatinib and ICI combination therapy (LI). This research aimed to compare the efficacy and safety between the two groups in lenvatinib-insensitive patients with uHCC.
Material and methods
Study design and patients
The clinical data of uHCC patients at Jiangsu Cancer Hospital were reviewed from January 1, 2019, to March 1, 2024. All patients were clinically or pathologically diagnosed with HCC by the American Association for the Study of Liver Diseases (AASLD) guidelines and had not received systematic antitumor therapy before receiving lenvatinib. Lenvatinib-insensitive patients were defined as those who remained SD but did not achieve CR or PR or PD for 3 months after receiving lenvatinib monotherapy. All patients were diagnosed with uHCC by a multidisciplinary team. Case inclusion criteria are as follows: patients remained SD for at 3 months after receiving lenvatinib monotherapy; patients with unresectable HCC; lenvatinib-insensitive patients received lenvatinib monotherapy or lenvatinib plus ICI combination therapy sequentially; aged 18 to 75 years; complete data; patients were diagnosed with stage B (patients with diffuse, infiltrative, extensive HCC liver involvement) or C by BCLC guidelines. Case exclusion criteria are as follows: patients achieved CR or PR or PD during the first 3 months of lenvatinib monotherapy; received any other treatments during this treatment period, such as surgery, percutaneous ethanol injection, or radiotherapy; incomplete data; discontinued treatment due to serious adverse reactions; cancers other than HCC exist. The Ethics Committee of Jiangsu Cancer Hospital has approved this research.
Treatment procedure
In both L and LI groups, patients received lenvatinib (Eisai, Lenvatinib, Shanghai, China) monotherapy for 3 months and remained SD but did not achieve CR or PR or PD. In the L group, lenvatinib-insensitive patients (received lenvatinib monotherapy and remained SD but did not achieve CR or PR or PD for 3 months) subsequently received lenvatinib monotherapy continued. In the LI group, lenvatinib-insensitive patients subsequently received lenvatinib plus ICI combination therapy.
Six ICIs available including pembrolizumab (MERCK SHARP & Dohme, Pembrolizumab, Shanghai, China), camrelizumab (SUNCADIA, Camrelizumab, Suzhou, China), tislelizumab (BeiGene Biopharmaceutical Co, Tislelizumab, Guangzhou, China), nivolumab (Bristol-Myers Squibb, Nivolumab, New Jersey, America), toripalimab (Shanghai Junshi Biosciences Co, Toripalimab, Shanghai, China), and sintilimab (Innovent Biopharmaceuticals Co, Sintilimab, Suzhou, China) were prescribed intravenously. The patients received a fixed dose of 0.2 g of tislelizumab, pembrolizumab or camrelizumab, sintilimab every 21 days, a fixed dose of 3.0 mg/kg of nivolumab every 14 days, a fixed dose of 0.24 g of toripalimab every 21 days.
Patients were treated with lenvatinib at a dose of 8 mg or 12 mg (body weight < 60 kg, body weight ≥ 60 kg) once daily. The dose of lenvatinib could be reduced to 8 mg or 4 mg once daily or to 4 mg every other day if it was essential to control adverse events and toxicity. Treatment was stopped when tumor progression, intolerable adverse events, a decline in liver function, or death during the course of treatment. The biochemical indexes, routine blood, urine routine, thyroid function, tumor markers and other related laboratory tests were examined every month. All patients receive contrast-enhanced MRI and CT examinations every 1–2 months to evaluate tumor response.
Endpoints and assessments
The therapeutic effect was evaluated by the mRECIST standard. The primary endpoints were overall survival (OS) and progression-free survival (PFS). OS (L group) was calculated from the day of 3 months after receiving lenvatinib treatment to the day of death from any cause, or the last day of follow-up (March 1, 2024). OS (LI group) was calculated from the day of receiving lenvatinib plus ICI (3 months after receiving lenvatinib treatment) to the day of death from any cause, or the last day of follow-up (March 1, 2024). PFS (L group) was defined as the interval from the date of 3 months after receiving lenvatinib treatment to the day of tumor progression or the day of death from any cause, the last day of follow-up (March 1, 2024). PFS (LI group) was defined as the interval from the date of receiving lenvatinib plus ICI (3 months after receiving lenvatinib treatment) to the day of tumor progression or the day of death from any cause, the last day of follow-up (March 1, 2024). The secondary outcome was overall response rate (ORR). Using National Cancer Institute General toxicity criteria (NCI-CTC 5.0) to evaluate adverse drug reactions.
Statistical analysis
Propensity score matching (PSM) was conducted for the following variables: Barcelona Clinic Liver Cancer (BCLC) stage, gender, age, Child–Pugh Score, HBV, ECOG PS, Cirrhosis, Tumor thrombus, AFP. The chi-square test was performed for categorical variables in the two groups. Analysis of variance was applied to continuous variables in the two groups. The Kaplan–Meier method was applied to calculate OS and PFS, and the log-rank test was performed. P < 0.05 was considered statistically significant. The survival curve was obtained by SPSS 26.0 and R. SPSS 26.0 and R were used to analyze all statistical data. Hazard ratios (HRs) were estimated using the Cox proportional hazard model. If univariate Cox analysis showed that the difference was statistically significant (P < 0.05), the multivariate Cox proportional hazards regression model was further included to determine the independent influencing factors of OS and PFS.
Results
Patient characteristics
Between January 2019 and March 2024, 255 patients with unresectable HCC at Jiangsu Cancer Hospital were enrolled in the research; 83 patients received L therapy and 172 patients received LI therapy. However, 80 patients were excluded by the exclusion criteria. Sixty-one patients in each group were matched after PSM.
The baseline characteristics of matched patients are shown in Supplemental Table 1. There was no significant difference in BCLC stage, gender, age, Child–Pugh Score, HBV, ECOG PS, cirrhosis, distant metastases, tumor thrombus, AFP, number of intrahepatic tumors, size of the largest tumor (cm) and Up-to-seven between the two groups (The flowchart is shown in Supplemental Fig. 1 and Supplemental Fig. 2).
Tumor response and survival in all patients
Table 1 summarizes the tumor responses of the two groups. There were 0, 2, 44, and 15 patients who achieved CR, PR, SD, and PD in the L group, respectively. There were 2, 16, 41, and 2 patients who had CR, PR, SD, and PD in the LI group, respectively. The ORR of LI group was significantly higher than that of the L group (29.51% vs. 3.28%, P < 0.01).
Table 1.
Best anti-tumor response according to the mRECIST
| Best response | L,n (%) N = 61 | LI,n (%) N = 61 | P |
|---|---|---|---|
| CR | 0 (0%) | 2 (3.28%) | 0.154 |
| PR | 2 (3.28%) | 16 (26.23%) | 0.000 |
| SD | 44 (72.13%) | 41 (67.21%) | 0.555 |
| PD | 15 (24.59%) | 2 (3.28%) | 0.001 |
| ORR | 2 (3.28%) | 18 (29.51%) | 0.000 |
Responses were evaluated according to modified Response Evaluation Criteria in Solid Tumors by investigators
*Bold values indicate P < 0.05
The median OS of the LI group was significantly longer than that of the L group (15.9 months vs. 11.9 months, P = 0.001). The LI group exhibited significantly prolonged median PFS compared to the L group (12.6 months vs. 7.3 months, P < 0.001) (Fig. 1).
Fig. 1.
Kaplan–Meier curves for OS and PFS of lenvatinib-insensitive patients with uHCC who received L and LI. Abbreviations: uHCC unresectable hepatocellular carcinoma, L Lenvatinib monotherapy group, LI Lenvatinib combined with ICI group, ICI immune checkpoint inhibitor, OS overall survival, PFS progression-free survival
Prognostic factors associated with good OS and PFS
In the univariate analysis, BCLC stage, ECOG PS, cirrhosis, distant metastases, tumor thrombus, Up-to-seven were significantly associated with the OS. ECOG PS = 0 (hazards ratio [HR], 2.131; 95% confidence interval [CI], 1.142–3.975; P = 0.017) was significantly associated with longer OS in the multivariate analysis (Table 2). In the univariate analysis, BCLC stage, ECOG PS, distant metastases, Up-to-seven were significantly associated with the PFS. Up-to-seven ≤ 7 was significantly associated with longer PFS in the multivariate analysis of all 122 patients (Table 2).
Table 2.
Cox regression analyses of the associated factors for OS and PFS
| Univariable analysis for OS | Multivariable analysis for OS | Univariable analysis for PFS | Multivariable analysis for PFS | |||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |
| BCLC | ||||||||
| B/ C | 48.874 (9.010–265.116) | 0.000 | 0.959 (0.268–3.432) | 0.949 | 0.472 (0.258–0.862) | 0.015 | 1.525 (0.688–3.384) | 0.299 |
| Gender | ||||||||
| Male/ Female | 0.784 (0.4436–1.410) | 0.417 | 0.934 (0.593–1.469) | 0.766 | ||||
| Age, years | ||||||||
| < 60/ ≥ 60 | 0.888 (0.516–1.527) | 0.667 | 1.008 (0.662–1.535) | 0.971 | ||||
| Child–Pugh Score | ||||||||
| 5/ > 5 | 1.079 (0.610–1.907) | 0.794 | 1.240 (0.801–1.918) | 0.334 | ||||
| HBV | ||||||||
| − / + | 1.284 (0.718–2.298) | 0.400 | 0.859 (0.556–1.328) | 0.494 | ||||
| ECOG PS | ||||||||
| 0/ > 0 | 2.863 (1.455–5.632) | 0.002 | 2.131 (1.142–3.975) | 0.017 | 0.657 (0.423–1.020) | 0.061 | 1.263 (0.785–2.031) | 0.337 |
| Cirrhosis | ||||||||
| No/ Yes | 1.609 (0.930–2.783) | 0.089 | 0.633 (0.359–1.116) | 0.144 | 1.285 (0.843–1.958) | 0.244 | ||
| Tumor thrombus | ||||||||
| No/ Yes | 4.508 (2.424–8.383) | 0.000 | 0.718 (0.363–1.421) | 0.341 | 0.735 (0.473–1.140) | 0.169 | ||
| Distant metastases | ||||||||
| No/ Yes | 13.078 (5.290–32.333) | 0.000 | 1.962 (0.795–4.839) | 0.144 | 0.638 (0.403–1.008) | 0.054 | 1.282 (0.717–2.292) | 0.402 |
| AFP (ng/mL) | ||||||||
| < 400/ ≥ 400 | 1.358 (0.802–2.302) | 0.255 | 0.711 (0.464–1.087) | 0.116 | ||||
| Up-to-seven | ||||||||
| ≤ 7 / > 7 | 0.297 (0.168–0.522) | 0.000 | 0.666 (0.389–1.142) | 0.140 | 0.335 (0.215–0.522) | 0.000 | 0.612 (0.403–0.929) | 0.021 |
*Bold values indicate P < 0.05
PFS progression-free survival, HR hazard ratio, CI confidence interval, BCLC Barcelona Clinic Liver Cancer, HBV chronic hepatitis B virus, ECOG PS Eastern Cooperative Oncology performance status, AFP alpha-fetoprotein
Survival in subgroups of patients
The risk of death and progression between the L and LI groups in subgroup is compared. Figure 2 shows that the LI group had a lower risk of death than the L group in almost all subgroups (except BCLC B stage, male, ECOG PS > 0 and without distant metastases). The LI group had a lower risk of progression than the L group in almost all subgroups (except males, without HBV and ECOG PS > 0). The LI group reduced the risk of death significantly compared with the L group in patients with Child–Pugh Score > 5 (HR = 0.21; 95% CI, 0.06–0.78). The LI group reduced the risk of progression significantly compared with L group in patients with BCLC B stage (HR = 0.28; 95% CI, 0.09–0.84) and HBV (HR = 0.28; 95% CI, 0.16–0.47).
Fig. 2.
Subgroup analyses according to different variables for comparing OS and PFS between L and LI groups in lenvatinib-insensitive patients with uHCC. Abbreviations: uHCC unresectable hepatocellular carcinoma, L Lenvatinib monotherapy group, LI Lenvatinib combined with ICI group, ICI immune checkpoint inhibitor, OS overall survival, PFS progression-free survival
Safety
Table 3 summarizes the frequency of adverse events after treatment initiation for all 122 patients. The most common adverse events in the groups were fatigue (n = 86), decreased appetite (n = 97). However, one patient required discontinuation in LI group on account of severe gastrointestinal bleeding. There was no significant difference in the number of patients excluded due to serious complications between the groups. Overall, the frequency of grade ≥ 3 adverse events demonstrated no significant difference. No treatment-associated death occurred in this study.
Table 3.
Treatment-related adverse events
| Adverse events | L,n (%) N = 61 | LI,n (%) N = 61 | ||
|---|---|---|---|---|
| All grades | Grade 3/4 |
All grades | Grade 3/4 |
|
| Hand foot skin rash | 8 (13.1%) | 0 (0.0%) | 9 (14.8%) | 0 (0.0%) |
| Hypertension | 18 (29.5%) | 3 (4.9%) | 19 (31.1%) | 1 (1.6%) |
| Proteinuria | 7 (11.5%) | 0 (0.0%) | 10 (16.4%) | 0 (0.0%) |
| Abdominal pain | 11 (18.0%) | 1 (1.6%) | 22 (36.1%) | 0 (0.0%) |
| Diarrhea | 11 (18.0%) | 2 (3.3%) | 11 (18.0%) | 3 (4.9%) |
| Nausea | 13 (21.3%) | 2 (3.3%) | 24 (39.3%) | 0 (0.0%) |
| Hypothyroidism | 14 (23.0%) | 5 (8.2%) | 22 (36.1%) | 0 (0.0%) |
| Gastrointestinal bleeding | 5 (8.2%) | 0 (0.0%) | 5 (8.2%) | 2 (3.3%) |
| Fatigue | 38 (62.3%) | 2 (3.3%) | 44 (72.1%) | 2 (3.3%) |
| Decreased appetite | 52 (85.2%) | 1 (1.6%) | 42 (68.9%) | 2 (3.3%) |
| Aspartate aminotransferase increased | 26 (42.6%) | 4 (6.6%) | 24 (39.3%) | 2 (3.3%) |
| Alanine aminotransferase increased | 22 (36.1%) | 0 (0.0%) | 24 (39.3%) | 2 (3.3%) |
| Decreased platelet count | 11 (18.0%) | 2 (3.3%) | 13 (21.3%) | 4 (6.6%) |
| Decreased white blood cell | 8 (13.1%) | 0 (0.0%) | 10 (16.4%) | 0 (0.0%) |
| Decreased red blood cell | 7 (11.5%) | 0 (0.0%) | 8 (13.1%) | 0 (0.0%) |
| Total bilirubin increased | 7 (11.5%) | 0 (2.8%) | 6 (9.8%) | 2 (3.3%) |
| Albumin decreased | 5 (8.2%) | 0 (0.0%) | 4 (6.6%) | 2 (3.3%) |
TRAEs adverse events
Discussion
Lenvatinib-based systemic treatments were more widely used compared to atezolizumab plus bevacizumab as first-line treatment for uHCC in the Asia–Pacific region on account of the noninferior efficacy, safety, and lower price [14]. Although many studies have shown the superiority of the combination therapy of lenvatinib plus ICI. However, the failure of LEAP-002 research has left clinicians controversial about the combination therapy. Clinicians are eager to identify which patients are likely to benefit from the combination therapy and which are not.
Lenvatinib is a highly effective TKI and multiple guidelines recommend the use of lenvatinib monotherapy in first-line tretment. However, 76% of patients were still insensitive to lenvatinib monotherapy [15]. For these patients who are not sensitive to lenvatinib, there are still no studies to explore the appropriate treatments. But in clinical practice, doctors have empirically judged whether a patient is insensitive to lenvatinib and try to give lenvatinib-insensitive patients more aggressive treatment (LI). In clinical practice, lenvatinib insensitivity was defined as patients who received lenvatinib monotherapy and remained SD, but did not achieve CR or PR or SD for at least 3 months. A similar definition has been adopted in other studies [13]. This study retrospectively collected the data of these patients, hoping to find the optimal treatment for these patients who were insensitive to lenvatinib.
This retrospective cohort study showed that compared to lenvatinib monotherapy, the combination of lenvatinib and ICI led to longer OS and PFS in uHCC patients. Many studies have shown that the synergistic effect plays an important role in enhancing therapeutic efficacy of this combination [16–18]. Preclinical studies have suggested that lenvatinib can increase the infiltration of CD8 + T cells in the tumor microenvironment by blocking VEGF to temporarily normalize the tumor vessels, thereby amplifying the value of ICIs and increasing tumor sensitivity to this combination therapy [19–23]. Numerous cohort studies have reported the superiority of the combinations of lenvatinib plus ICI compared with lenvatinib monotherapy [24–29], which is consistent with these findings of this study. However, compared to Phase III LEAP-002 research, the lenvatinib monotherapy median OS (11.9 months vs.19.0 months) in this study was shorter. The possible reasons for this result were considered follows: (1) lenvatinib-insensitive patients in this study had a 3-month period that was not included in the calculation of OS and PFS; (2) the follow-up treatment for some patients after first-line treatment was not standardized; (3) more patients with BCLC stage of C, Child–Pugh Score > 5 and ECOG PS > 0 were included in this study [7].
This study also revealed that the ECOG PS = 0 was an independent prognostic factor for OS. This may suggest that better physical condition can enable patients to have better tolerance to drugs and have the opportunity to receive more subsequent therapies. In the study’s multivariable analysis, a tumor burden exceeding the Up-to-seven criteria (> 7) emerged as an adverse factor for PFS, suggesting that an elevated tumor burden may indeed predict a poorer prognosis. This conclusion is also consistent with previous research findings [30, 31]. Patients with BCLC stage C could increase all-cause mortality risk compared to patients with BCLC stage B. However, the BCLC stage was not the independent factor affecting OS and PFS in the multivariate analysis in this study, although P < 0.05 in the univariate analysis. This may be on account of the patients with BCLC stage B in this research with diffuse, infiltrative, extensive HCC liver involvement but not these patients with well-defined nodules. In subgroup analysis, the risk of death was significantly lower in the LI group than in the L group in patients with Child–Pugh Score > 5. In the BCLC B and HBV subgroup, the LI group reduced the risk of progression significantly compared with the L group. This may suggest that patients with a lower tumor burden and higher body reserve could potentially derive greater benefits from the LI combination therapy.
This study still has some limitations. First, it was a retrospective study; therefore, selection bias was unavoidable. Second, we defined these patients who received lenvatinib monotherapy and remained SD for at least 3 months as lenvatinib-insensitive patients according to a statistical analysis of a small sample from our hospital. What is more, this definition has not been confirmed by multicenter randomized control studies. In the future, we should design better predictive models to recognize these patients who are insensitive to lenvatinib. Finally, we excluded patients in the groups who developed CR, PR, and PD within 3 months; therefore, the comparison of tumor response among the groups has some deviations.
Conclusions
In conclusion, this real-world study retrospectively collected the data of lenvatinib-insensitive patients (received lenvatinib monotherapy and remained SD but did not achieve CR or PR or PD for 3 months). By comparing the subsequent treatments they received, the study demonstrated that the combination therapy of lenvatinib plus ICI (LI) is more effective than lenvatinib monotherapy (L) in lenvatinib-insensitive patients with uHCC.
Supplementary Information
Below is the link to the electronic supplementary material.
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Acknowledgements
The authors thank all participating patients, their families, and physicians for collaborating in data collection.
Abbreviations
- uHCC
Unresectable hepatocellular carcinoma
- ICI
Immune checkpoint inhibitor
- L
Lenvatinib monotherapy group
- LI
Lenvatinib plus ICIs group
- OS
Overall survival
- PFS
Progression-free survival
- TKI
Tyrosine kinase inhibitor
- BCLC
Barcelona Clinic Liver Cancer
- PR
Partial response
- CR
Complete response
- PD
Progressive disease
- SD
Maintained stable disease
- ORR
Overall response rate
- PSM
Propensity score matching
- HBV
Chronic hepatitis B virus
- ECOG PS
Eastern Cooperative Oncology performance status
- AFP
Alpha-fetoprotein
- TRAEs
Treatment-related adverse events
Author contribution
All authors contributed to the study conception and design. [Qinyu Xu], [Guowen Yin] are the corresponding authors of this study. Data curation performed by [Zeyu Yu], [Bin Leng], [Ran You], [Chengdong Wang], [Lingfeng Diao]. The original draft written by [Zeyu Yu]. And all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by The project of Natural Science Foundation of Jiangsu Cancer Hospital (ZJ202215).
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The Ethics Committee of Jiangsu Cancer Hospital has approved this research.
Consent to participate
Informed consent was obtained from all individual participants included in the study.
Consent for publication
The authors affirm that human research participants provided informed consent for publication of the research.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Qingyu Xu and Guowen Yin contributed equally to this work.
Contributor Information
Qingyu Xu, Email: xqy1984king@njmu.edu.cn.
Guowen Yin, Email: jsnjygw@njmu.edu.cn.
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Associated Data
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Supplementary Materials
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Data Availability Statement
No datasets were generated or analysed during the current study.