Efficacy and safety of camrelizumab combined with chemotherapy in the first-line treatment of advanced gastric cancer: a single-arm, phase II study
Highlight box
Key findings
• Camrelizumab in combination with SOX (S-1 and oxaliplatin) exhibited encouraging efficacy and a tolerable safety profile as an initial treatment for advanced gastric cancer.
What is known and what is new?
• Four pivotal trials, CheckMate-649, Asian ATTRACTION-04, KEYNOTE-859, and ORIENT-16 demonstrated that immunotherapy combined with chemotherapy significantly prolonged overall survival (OS) compared to chemotherapy alone, but with a limited survival advantage.
• The first-line treatment of camrelizumab combined with SOX chemotherapy resulted in the median progression-free survival of 7.4 months and the median OS of 20.2 months for advanced gastric cancer.
What is the implication, and what should change now?
• This study provides the first evidence that combining camrelizumab and chemotherapy as first-line treatment for advanced gastric cancer resulted in favorable efficacy and tolerable safety. This innovative combination strategy represents a promising new therapeutic approach for advanced gastric cancer patients.
Introduction
According to GLOBOCAN 2020 estimates, gastric cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of cancer death, with 1,089,000 new cases and 769,000 deaths annually worldwide (1). In 2020, China had 478,508 new cases of gastric cancer, accounting for 43.9% of global new cases, and 373,789 deaths, accounting for 48.6% of global deaths (2). Approximately 50% of patients with gastric cancer are diagnosed with advanced disease and will receive systemic therapy. However, first-line therapy with chemotherapy provides limited clinical benefits, with an overall survival (OS) of around 1 year (3,4).
The phase III CheckMate-649 trial demonstrated that first-line nivolumab plus chemotherapy (CAPOX or FOLFOX) significantly improved OS compared with chemotherapy alone in advanced gastric cancer [median OS 13.8 vs. 11.6 months; hazard ratio (HR) 0.80; 99.3% confidence interval (CI): 0.68–0.94] (5). The KEYNOTE-859 trial showed that first-line pembrolizumab plus chemotherapy (PF or CAPOX) improved OS significantly more than placebo plus chemotherapy for advanced gastric cancer, but with a limited survival advantage (median OS 12.9 vs. 11.5 months; HR 0.78; 95% CI: 0.70–0.87) (6). Additionally, the phase III ORIENT-16 trial showed that sintilimab plus CAPOX significantly improved OS compared with placebo plus CAPOX in patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥5 (median OS 18.4 vs. 12.9 months; HR 0.66; 95% CI: 0.50–0.86) (7). However, S-1 is more commonly used in Asian patients as it is more tolerated in Asian patients than Caucasian patients due to pharmacogenomic differences in S-1 metabolism (3). Indeed, in the phase III ATTRACTION-4 trial, which recruited Asian patients, nivolumab plus SOX or CAPOX significantly improved PFS regardless of PD-L1 expression but not OS (median PFS 10.94 vs. 8.41 months; HR 0.70; 95% CI: 0.57–0.86; median OS 17.45 vs. 17.15 months; HR 0.90; 95% CI: 0.75–1.08) (8).
Camrelizumab is a humanized high-affinity immunoglobulin G4-kappa monoclonal antibody against programmed cell death protein 1 (PD-1). Camrelizumab combined with chemotherapy has been approved in China for the treatment of non-small cell lung cancer and esophageal squamous cell carcinoma based on the significantly improved survival benefit compared with chemotherapy. For advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, cohort one of a phase II trial evaluated camrelizumab plus CAPOX followed by camrelizumab plus apatinib (a VEGFR2 inhibitor) as the first-line treatment and exhibited promising antitumor activity and a manageable safety profile (9). Based on limited data on camrelizumab plus SOX as first-line treatment for HER2-negative unresectable advanced or recurrent gastric or GEJ adenocarcinoma, we conducted a single-arm phase II clinical study to evaluate the efficacy and safety of this regimen. We present this article in accordance with the TREND reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-336/rc).
Methods
Study design and participants
This single-arm phase II clinical trial was conducted at the Affiliated Hospital of Xuzhou Medical University in Xuzhou, China. This study was registered on 09/02/2020, with the Chinese Clinical Trial Registry (ChiCTR2000029691) and conducted in accordance with the Declaration of Helsinki (as revised in 2013). The protocol was approved by the China Ethics Committee of Registering Clinical Trials (No. ChiECRCT20200024). Informed consent was provided by all patients involved in the study.
Patients were eligible for inclusion if they were aged 18 years or older with previously untreated locally advanced unresectable or metastatic HER2-negative adenocarcinoma of the stomach or GEJ diagnosed by histology or cytology. Other key inclusion criteria were that the patient must have a Easter Cooperative Oncology Group performance score of 0–1, at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (10), adequate organ function, and a life expectancy of 3 months or more. The exclusion criteria included disease progression within 6 months after the completion of neoadjuvant chemotherapy, adjuvant chemotherapy, or radiotherapy; allergy or hypersensitivity to therapeutic agents, or autoimmune disease; use of steroids for more than 50 days, or the need for long-term steroid use.
Treatment procedures
Patients received camrelizumab combined with SOX chemotherapy. Camrelizumab was administered at a dosage of 200 mg by intravenous infusion for 30–60 minutes every 3 weeks. In the SOX regimen, S-1 was given 40 mg/m2 orally twice daily on days 1–14, and oxaliplatin was given 130 mg/m2 intravenously for 2–6 hours, on day 1, every 3 weeks. The treatment continued until disease progression, death, or intolerable toxicity. Patients with disease progression could continue the study treatment at the investigator’s discretion and were re-evaluated after 4 weeks. Camrelizumab was prescribed for up to a year.
Clinical analysis
Tumor imaging was performed by investigators per RECIST version 1.1 using computed tomography (CT) or magnetic resonance imaging (MRI) every 6 weeks. Safety was monitored throughout the study and for 30 days after the last dose of the study drug, including abnormal clinical symptoms, vital signs, and laboratory tests. Adverse events (AEs) were graded per the Common Terminology Criteria for Adverse Events version 5. Survival follow-up was performed after patients completed treatment. Survival (date of death and cause of death) and post-study treatment information (including treatment received) were collected every 3 months until death or loss to follow-up.
PD-L1 expression assessment
PD-L1 expression was evaluated using the PD-L1 immunohistochemistry 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, USA). The level of PD-L1 expression was reported as a CPS, which is calculated by dividing the number of PD-L1-positive cells (including tumor cells, lymphocytes, and macrophages) by the total number of tumor cells and multiplying by 100.
Outcomes
The primary endpoint was PFS, and the secondary endpoints were OS, disease control rate (DCR), and objective response rate (ORR). PFS was defined as the time from treatment initiation to first documented disease progression per RECIST version 1.1 or death from any cause; OS was defined as the time from treatment initiation to death from any cause; ORR was defined as the proportion of patients with the best overall response of confirmed complete or partial response assessed by investigators according to RECIST version 1.1; DCR was defined as the proportion of patients with confirmed complete or partial response or stable disease (≥6 weeks) assessed by investigators according to RECIST version 1.1. Efficacy was evaluated in the patients who received at least 1 dose of the study drug. Safety was evaluated in patients who received the study drug and had at least 1 post-baseline safety record.
Statistical analysis
This was a single-arm exploratory study with no prespecified hypotheses therefore no formal sample size calculation was performed. Patient characteristics were summarized using frequency count (percentage) for categorical variables and median [interquartile range (IQR)] for continuous variables. The proportion of patients achieving an objective response was generated using the binomial distribution. Kaplan-Meier estimates of PFS and OS were compared between subgroups per PD-L1 CPS using a log-rank test. The HR and 95% CI were analyzed using the Cox proportional hazard model. Analyses were performed using MedCalc version 18.2.1 (MedCalc, Ostend, Belgium) and R statistical software version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria). P<0.05 was considered statistically significant.
Results
Patient characteristics and treatment
Between January 2020 and July 2021, 25 patients were included and received at least 1 dose of study drug. Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 [22 (88.0%)], poor differentiation [19 (76.0%)], and lymph node metastases [23 (92%)]. A total of 17 patients (68.0%) had their primary tumor in the stomach, whereas 8 patients (32.0%) had their primary tumor in the GEJ. In terms of PD-L1 CPS, 7 patients (28%) had PD-L1 CPS <1; 18 patients (72%) had PD-L1 CPS ≥1, of which 15 had PD-L1 CPS ≥5 (60.0%). All patients had microsatellite stability (MSS) status (Table 1).
Table 1
Characteristic | Patients (n=25) |
---|---|
Age (years) | |
Median [IQR] | 60 [50−66] |
Range | 26−74 |
Gender, n (%) | |
Male | 22 (88.0) |
Female | 3 (12.0) |
ECOG performance status, n (%) | |
0 | 3 (12.0) |
1 | 22 (88.0) |
Histologic subtype, n (%) | |
Diffuse | 15 (60.0) |
Intestinal | 6 (24.0) |
Other | 4 (16.0) |
Differentiation, n (%) | |
Well differentiated | 2 (8.0) |
Moderately differentiated | 4 (16.0) |
Poorly differentiated | 19 (76.0) |
Primary site, n (%) | |
Gastric | 17 (68.0) |
Gastro-esophageal junction | 8 (32.0) |
Number of metastatic sites, n (%) | |
One | 17 (68.0) |
Two or more | 8 (32.0) |
Metastatic sites, n (%) | |
Lung | 3 (12.0) |
Liver | 6 (24.0) |
Lymph node | 23 (92.0) |
Other | 5 (20.0) |
Prior surgery, n (%) | |
No | 24 (96.0) |
Yes | 1 (4.0) |
MSI status, n (%) | |
MSS | 25 (100.0) |
PD-L1 expression, n (%) | |
CPS <1 | 7 (28.0) |
CPS ≥1 | 18 (72.0) |
CPS ≥5 | 15 (60.0) |
IQR, interquartile range; ECOG, Eastern Cooperative Oncology Group; CPS, combined positive score; MSI, microsatellite instability; MSS, microsatellite stability; PD-L1, programmed cell death ligand 1.
At the data cutoff of June 2022, 2 had completed camrelizumab therapy according to protocol, and 23 had discontinued treatment. Among 23 patients who discontinued treatment, 12 withdrew consent, 3 had experienced intolerable toxicity, 4 had disease progression, and 4 had died (Figure 1). A total of 16 (64%) patients completed at least 6 cycles of camrelizumab (range, 2–17 cycles), and 15 (60%) patients completed at least 6 cycles of SOX chemotherapy (range, 2–8 cycles, Tables S1,S2).
Clinical outcomes
After a median follow-up of 15.2 months (95% CI: 8.3–18.4), 8 of 25 patients reported disease progression or death, and the median PFS was 7.4 months (95% CI: 5.6–16.4) (Figure 2A). A total of 12 patients died and the median OS was 20.2 months (95% CI: 10.5–29.9) (Figure 2B). A total of 9 patients had a partial response with an ORR of 36% (95% CI: 18.0–57.5%). The DCR was 92% (95% CI: 74.0–99.0%), including 9 partial responses and 14 stable diseases (Table 2, Figure 3).
![Click on image to zoom](http://cdn.amegroups.cn/journals/pbpc/files/journals/1/articles/89793/public/89793-PB8-4212-R1.jpg/w300)
Table 2
Best overall response, n (%) | Total (n=25) | PD-L1 CPS ≥5 (n=15) | PD-L1 CPS ≥1 (n=18) | PD-L1 CPS <1 (n=7) |
---|---|---|---|---|
Complete response | 0 | 0 | 0 | 0 |
Partial response | 9 (36.0) | 7 (46.7) | 9 (50.0) | 0 |
Stable disease | 14 (56.0) | 8 (53.3) | 8 (44.4) | 6 (85.7) |
Progressive disease | 2 (8.0) | 0 | 1 (5.6) | 1 (14.3) |
Objective response rate | 9 (36.0) | 7 (46.7) | 9 (50.0) | 0 |
Disease control rate | 23 (92.0) | 15 (100.0) | 17 (94.4) | 6 (85.7) |
CPS, combined positive score; PD-L1, programmed cell death ligand 1.
![Click on image to zoom](http://cdn.amegroups.cn/journals/pbpc/files/journals/1/articles/89793/public/89793-PB9-2362-R1.jpg/w300)
Subgroup analyses showed the median PFS was 3.6 months (95% CI: 0.5–6.7) in 7 patients with PD-L1 CPS <1, 16.4 months [95% CI: 5.6–not reached (NR)] in 18 patients with PD-L1 CPS ≥1, and 16.4 months (95% CI: 5.6–NR) in 15 patients with PD-L1 CPS ≥5 (Figure S1A). The median OS was 20.2 months (95% CI: 13.3–27.1) in patients with PD-L1 CPS ≥5, 20.2 months (95% CI: 16.4–NR) in those with CPS ≥1, and 3.6 months (95% CI: 3.3–4.1) in those with CPS <1 (Figure S1B). Among patients with PD-L1 CPS <1, no patients responded and 6 (85.7%) achieved stable disease. In contrast, for patients with PD-L1 CPS ≥1, 9 achieved a partial response, and 8 achieved stable disease with an ORR of 50% and a DCR of 94.4%. Additionally, all patients with PD-L1 CPS ≥5 had disease control, consisting of 7 partial responses and 8 stable diseases (Table 2).
Safety
Among 25 patients who received treatment and had at least 1 post-baseline safety record, 22 (88%) patients experienced any-grade AEs, and 7 (28%) patients experienced grade 3 or worse AEs. The most commonly reported AEs of any grade were reactive cutaneous capillary endothelial proliferation (RCCEP) [18 (72%)], neutropenia [8 (32%)], and leukopenia [6 (24%)]. Neutropenia [3 (12%)], RCCEP [2 (8%)], and thrombocytopenia [2 (8%)] were the most frequently occurring grade 3 or worse AEs. Twelve patients (48%) experienced grade 1 RCCEP, four patients (16%) experienced grade 2 RCCEP, and two patients (8%) experienced grade 3 RCCEP. Hypothyroidism and myocarditis are considered related to immunotherapy beyond RCCEP. Hypothyroidism was experienced by 2 patients (8%) (grade 1, n=1; and grade 2, n=1), and 1 patient developed grade 2 myocarditis (Table 3). Three patients discontinued the study treatment due to unacceptable toxicity: one patient experienced grade 3 RCCEP and grade 3 decreased neutrophil count; another patient had grade 3 RCCEP, grade 3 decreased white blood cell count, and grade 4 decreased neutrophil count; and the third patient experienced grade 3 decreased platelet count. No patients died due to AEs.
Table 3
Adverse event | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade ≥3 | Any grade |
---|---|---|---|---|---|---|
RCCEP | 12 (48.0) | 4 (16.0) | 2 (8.0) | 0 | 2 (8.0) | 18 (72.0) |
Decreased neutrophil count | 3 (12.0) | 2 (8.0) | 2 (8.0) | 1 (4.0) | 3 (12.0) | 8 (32.0) |
Decreased white blood cell count | 3 (12.0) | 2 (8.0) | 1 (4.0) | 0 | 1 (4.0) | 6 (24.0) |
Decreased platelet count | 2 (8.0) | 1 (4.0) | 2 (8.0) | 0 | 2 (8.0) | 5 (20.0) |
Anemia | 3 (12.0) | 1 (4.0) | 1 (4.0) | 0 | 1 (4.0) | 5 (20.0) |
Abdominal distention | 4 (16.0) | 0 | 0 | 0 | 0 | 4 (16.0) |
Abdominal pain | 4 (16.0) | 0 | 0 | 0 | 0 | 4 (16.0) |
Decreased appetite | 1 (4.0) | 2 (8.0) | 0 | 0 | 0 | 3 (12.0) |
Diarrhea | 1 (4.0) | 1 (4.0) | 0 | 0 | 0 | 2 (8.0) |
Nausea | 2 (8.0) | 0 | 0 | 0 | 0 | 2 (8.0) |
Hypothyroidism | 1 (4.0) | 1 (4.0) | 0 | 0 | 0 | 2 (8.0) |
Gastrointestinal bleeding | 1 (4.0) | 1 (4.0) | 0 | 0 | 0 | 2 (8.0) |
Hyperglycemia | 2 (8.0) | 0 | 0 | 0 | 0 | 2 (8.0) |
Asthma | 0 | 1 (4.0) | 0 | 0 | 0 | 1 (4.0) |
Myocarditis | 0 | 1 (4.0) | 0 | 0 | 0 | 1 (4.0) |
Ascites | 0 | 0 | 1 (4.0) | 0 | 1 (4.0) | 1 (4.0) |
γ-glutamyltransferase increased | 1 (4.0) | 0 | 0 | 0 | 0 | 1 (4.0) |
Alkaline phosphatase increased | 1 (4.0) | 0 | 0 | 0 | 0 | 1 (4.0) |
Hyperbilirubinemia | 0 | 1 (4.0) | 0 | 0 | 0 | 1 (4.0) |
Data are presented as n (%). RCCEP, reactive cutaneous capillary endothelial proliferation.
Discussion
The first-line treatment of camrelizumab combined with SOX chemotherapy resulted in the median PFS of 7.4 months and the median OS of 20.2 months for HER2-negative, unresectable locally advanced or recurrent gastric cancer. The toxicity was acceptable and manageable. These results showed clinically meaningful benefits from camrelizumab combined with SOX chemotherapy.
The CheckMate-649, ATTRACTION-4, ORIENT-16, and this trial all investigate first-line anti-PD-1 antibody plus chemotherapy versus chemotherapy in advanced gastric cancer, with similar patient inclusion criteria. However, the geographic diversity of the patient populations varies across these trials. The CheckMate-649 trial included the global patients with advanced gastric cancer, consisting of approximately 25% Asian patients and 75% non-Asian patients. For patients who received nivolumab plus chemotherapy or chemotherapy, the median OS was 16.4 vs. 12.5 months (HR 0.73; 95% CI: 0.57–0.93) in Asian patients, and 13.1 vs. 11.2 months in White patients (HR 0.79; 95% CI: 0.69–0.91) (5). The ATTRACTION-4 trial included Asian patients only, with a median OS of 17.45 (95% CI: 15.67–20.83) versus 17.15 months (95% CI: 15.18–19.65) (HR 0.90; 95% CI: 0.75–1.08) for nivolumab plus chemotherapy versus chemotherapy (8). The majority of patients enrolled in the ATTRACTION-4 trial were from Japan and Korea, whereas patients from China accounted for approximately 5% of the total trial population (8). In contrast, the ORIENT-16 trial included Chinese patients with advanced gastric or GEJ adenocarcinoma. The median OS was 15.2 months in the combination group versus 12.3 months in the chemotherapy group (HR 0.77; 95% CI: 0.63–0.94) (7). One cohort of the phase II trial of camrelizumab plus CAPOX followed by a maintenance treatment of camrelizumab plus apatinib conducted in China reported a median PFS of 6.8 months (95% CI: 5.6–9.5) and median OS of 14.9 months (95% CI: 13.0–18.6) (9). This phase II study enrolled all patients from China and showed a numerically longer OS benefit than other studies (5,7,8). However, the promising efficacy signal of camrelizumab combined with SOX and maintenance apatinib requires confirmation in a phase III trial.
Management of PD-1 antibodies varies across studies. Nivolumab was used until disease progression, unacceptable toxicity, or withdrawal of consent in the ATTRACTION-4 and for a maximum of 2 years in CheckMate-649 trials (5,8). Pembrolizumab was administered for no more than 2 years in the KEYNOTE-859 trial (6). Since we observed many patients using PD-1 antibodies in clinical practice for less than a year, this exploratory study was designed to take camrelizumab for up to 1 year. Indeed, approximately 60% of patients were at least administered 6 cycles of camrelizumab in this study, consistent with the two phase III trials described above (5,8).
Furthermore, the CheckMate-649 trial showed that prolonged OS was associated with high PD-L1 expression (5). A study used a graphical reconstructive algorithm to estimate time-to-event outcomes from Kaplan-Meier plots. By applying KMSubtraction, the study analyzed data from the PD-L1 CPS 1–4 subgroups in the CheckMate-649 trial and found no significant differences in survival between nivolumab plus chemotherapy and chemotherapy alone (11). Therefore, this combination therapy is strongly recommended for patients with CPS ≥5 (12-14). This study assessed the PD-L1 expression and found that 72% of patients had PD-L1 CPS ≥1. This study showed similar results: ORR, DCR, PFS, and OS were all improved in patients with PD-L1 CPS ≥1 in contrast to patients with PD-L1 CPS <1. Additionally, the ORR, DCR, PFS, and OS in patients with a PD-L1 CPS ≥5 were similar to those in patients with a PD-L1 CPS ≥1, which may be attributed to the small sample size in these two subgroups.
In this study, 88% of patients reported AEs, 28% of patients reported grade 3 or worse AEs, and no patients died due to AEs. The overall safety profile of camrelizumab in combination with chemotherapy was in line with the known toxicity of the combination treatment in advanced esophageal squamous cell carcinoma, advanced non-squamous non-small-cell lung cancer, and recurrent or metastatic nasopharyngeal carcinoma (15-18). RCCEP is the most common AE associated with camrelizumab. It predominantly affects the skin surface, particularly on the head, face, and trunk. RCCEP lesions can be categorized into five morphological types: “red-nevus-like”, “pearl-like”, “mulberry-like”, “patch-like”, and “tumor-like”, with the most common types being “red-nevus-like” and “pearl-like”. Most RCCEP cases are mild and do not require specific treatment. In this study, the majority of RCCEP cases were grade 1–2, with only 2 patients experiencing grade 3, consistent with findings from a multicenter phase II trial involving patients with advanced hepatocellular carcinoma treated with camrelizumab. Out of 145 patients (66.8%) in that study who developed RCCEP, all cases were grade 1 or 2. For most patients, RCCEP resolved spontaneously within 1.6 months after discontinuing camrelizumab (19). Furthermore, 2 patients developed grade 1 and 2 gastrointestinal bleeding, respectively. In summary, adding camrelizumab to SOX had an acceptable and manageable safety profile in patients with previously untreated HER2-negative, unresectable, locally advanced, or recurrent gastric cancer.
This study had some limitations. This was a single-center, single-arm, phase II study with a small sample size. The small sample size and lack of a control group required caution in the interpretation of the results. Additionally, the lack of formal sample size calculations in this study could affect the statistical power of the study and the results may not be conclusive.
Conclusions
This study reported promising clinical outcomes of camrelizumab in combination with SOX as the first-line treatment for previously untreated HER2-negative, unresectable locally advanced or recurrent gastric cancer, with an acceptable safety profile. This combination treatment suggests a new potential treatment approach and should be investigated to confirm our findings in a phase III trial.
Acknowledgments
The authors would like to express their gratitude to Junhui You and Yongting Li for their valuable scientific support.
Funding: This work was supported by
Footnote
Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-336/rc
Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-336/dss
Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-336/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-336/coif). D.A.B. receives consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, BeiGene, Guardant Health, Takeda, Janssen, and gets payments for lectures from Merck, AstraZeneca, Bristol-Myers Squibb, Bayer, Roche. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was registered on 09/02/2020, with the Chinese Clinical Trial Registry (ChiCTR2000029691) and conducted in accordance with the Declaration of Helsinki (as revised in 2013). The protocol was approved by the China Ethics Committee of Registering Clinical Trials (No. ChiECRCT20200024). Informed consent was provided by all patients involved in the study.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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