Adjuvant alectinib versus crizotinib in completely resected ALK-positive non-small-cell lung cancer: a real-world retrospective cohort study

Introduction

Anaplastic lymphoma kinase (ALK) gene rearrangement is one of the major oncogenic drivers in lung cancer and is present in approximately 3–5% of patients with non-small-cell lung cancer (NSCLC) (1,2). Although targeted therapy has substantially improved outcomes in advanced ALK-positive NSCLC (3-8), postoperative recurrence remains an important clinical problem in patients undergoing curative resection (9,10).

Before the publication of the ALINA trial, adjuvant chemotherapy remained the standard treatment for resectable ALK-positive NSCLC, although its benefit in this molecular subgroup was still uncertain (9,10). In advanced disease, the first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib showed superior efficacy compared with conventional chemotherapy (4,5). However, its limited blood-brain barrier penetration and the absence of approval in the adjuvant setting raised concerns about its ability to prevent postoperative central nervous system (CNS) recurrence (11,12).

The global multicenter phase III ALINA trial subsequently showed that, compared with adjuvant chemotherapy, alectinib significantly reduced the risk of recurrence or death in completely resected ALK-positive NSCLC, corresponding to a 76% risk reduction, and also markedly lowered the incidence of CNS recurrence (13). This result marked an important shift toward targeted therapy in the adjuvant management of ALK-positive NSCLC. As a representative second-generation ALK-TKI, alectinib has stronger and more selective ALK inhibitory activity, better CNS penetration, and activity against some crizotinib-resistant mutations (14-16). These properties are consistent with its superior performance over crizotinib in the first-line treatment of advanced disease (6-8).

Against this background, recently reported results, available in abstract form, from the ECOG-ACRIN E4512 trial provided further evidence regarding the role of first-generation ALK inhibition in the postoperative setting (17). This phase III trial enrolled patients with R0 resected stage IIA–IIIB ALK-positive NSCLC and evaluated whether adjuvant crizotinib could improve disease-free survival (DFS). However, at a median follow-up of 58.3 months, crizotinib did not improve DFS compared with observation, with a median DFS of 72.8 versus 75.1 months and a hazard ratio (HR) of 1.06 [90% confidence interval (CI): 0.63–1.77; P=0.86]. In addition, the median duration of crizotinib treatment was 13.5 months, 22% of patients required dose reductions, and 25% discontinued treatment because of toxicity (17). By contrast, treatment adherence was better with alectinib in the ALINA trial, suggesting that tolerability may also influence the benefit of adjuvant therapy (13).

Taken together, the available evidence suggests that important differences exist among ALK-TKIs in the adjuvant setting. In the present study, we directly compared the efficacy and CNS protective effects of adjuvant alectinib and crizotinib in resectable ALK-positive NSCLC in a real-world cohort, with the aim of providing evidence to support clinical decision-making. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0766/rc).

Methods

Study design and patient population

This was an observational, retrospective analytical real-world cohort study conducted at Sun Yat-sen University Cancer Center. We retrospectively screened cases of patients who underwent curative lung resection (R0 resection) in the Department of Thoracic Surgery at Sun Yat-sen University Cancer Center between April 1, 2012, and October 10, 2023, and were pathologically confirmed as having ALK-positive NSCLC after surgery. Preoperatively, each patient routinely underwent contrast-enhanced chest and abdominal computed tomography (CT) and brain magnetic resonance imaging (MRI), or positron emission tomography-CT (PET-CT). Patients underwent sublobectomy, lobectomy or pneumonectomy with systematic lymph node dissection, depending on the feasibility of complete intraoperative resection of the pulmonary lesion. The inclusion criteria were as follows: age ≥18 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, postoperative pathological stage IA–IIIB according to the American Joint Committee on Cancer (AJCC) 8th edition (18), ALK gene rearrangement confirmed by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) (19), and treated with adjuvant alectinib or crizotinib after surgery. The exclusion criteria were as follows: presence of two or more distinct pulmonary lesions identified preoperatively or intraoperatively, suggesting multifocal disease or separate tumor nodules; palliative lung resection or failure to achieve R0 resection; receipt of neoadjuvant therapy before surgery; receipt of radiotherapy before or after surgery; a personal history of synchronous or metachronous malignancies; and radiologically or pathologically confirmed disease recurrence or distant metastasis before initiation of adjuvant therapy, including preoperative brain metastases.

Sex was defined as the biological sex recorded in the electronic medical record and was categorized as male or female. Gender identity was not available in this retrospective dataset.

Treatment regimens and assessment

A total of 48 patients with ALK-positive NSCLC who underwent curative surgery were included in this study and were divided into two groups: the alectinib group (n=26) and the crizotinib group (n=22). Adjuvant TKI therapy was initiated within 4–12 weeks after surgery, and the treatment decision was made by the attending physician after considering clinical guidelines, drug accessibility, medical insurance policies, and individual patient factors and preferences. Alectinib was administered orally at 600 mg twice daily (bid), and crizotinib was administered orally at 250 mg bid. No patient received perioperative chemotherapy; alectinib or crizotinib was the only adjuvant systemic anticancer treatment. Treatment was continued until completion of the planned treatment course, radiologically or pathologically confirmed disease recurrence, intolerable toxicity, or patient-initiated discontinuation.

Postoperative follow-up was scheduled as follows: during treatment, routine imaging evaluations (chest CT ± abdominal CT) were performed every 3–6 months, and brain MRI was performed every 6–12 months; if recurrence or metastasis was suspected, confirmation by histopathology or cytology was required; if biopsy was not feasible, assessment was made by two independent radiologists according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) (20), and consensus was reached. In this study, recurrence patterns were defined as follows: locoregional recurrence referred to recurrence within the ipsilateral lobe, ipsilateral hilar, mediastinal, or supraclavicular lymph nodes; distant metastasis referred to metastasis to the contralateral lung, contralateral lymph nodes, pleura, pericardium, or extrathoracic organs such as the brain, bone, liver, and adrenal glands. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (21). All follow-up data were collected through the hospital electronic medical record system. Follow-up duration was calculated from surgery to death or the last clinical assessment, with a data cutoff of October 31, 2025.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (approval No. SL-B2026-250-01; approval date: 14 April 2026). The requirement for informed consent for this retrospective analysis was waived because anonymized data were used. Because adjuvant treatment with crizotinib or alectinib had not yet been approved in China during the study period, all patients included in this study had signed informed consent forms for off-label drug use before receiving adjuvant ALK-TKI therapy.

Study endpoints

The primary endpoint was the 3-year DFS rate, defined as the proportion of patients who remained free from disease recurrence, metastasis, or death from any cause within 36 months after surgery.

Secondary endpoints included DFS, defined as the time from the date of surgery to the first occurrence of disease recurrence, metastasis, or death from any cause; the 2-year DFS rate; time to brain metastasis (TBM), defined as the time from the date of surgery to the first radiologically detected intracranial metastasis; the 3-year brain metastasis-free survival (BMFS) rate; and safety. BMFS was defined as the time from surgery to the first radiologically detected brain metastasis, with patients without brain metastasis censored at the last follow-up.

Statistical analysis

Age was the only continuous variable and was summarized as median [interquartile range (IQR)]; between-group comparison was performed using the Wilcoxon rank-sum test. Categorical variables were presented as n (%) and compared using Fisher’s exact test or the Fisher-Freeman-Halton exact test with Monte Carlo simulation, as appropriate. The 3-year DFS rate and 2-year DFS rate were estimated using the Kaplan-Meier method. Median DFS and TBM were likewise estimated using the Kaplan-Meier method, and survival curves were generated. Between-group comparisons of survival curves were performed using the log-rank test. Median follow-up was estimated using the reverse Kaplan-Meier method. Cox regression was used to calculate HRs and 95% CIs. Given the limited number of DFS events, an exploratory multivariable Cox model including treatment group and postoperative nodal status (N0 vs. N1–2) was fitted. A sensitivity analysis excluding patients with stage IA disease was performed using Kaplan-Meier estimates, the log-rank test, and univariable Cox regression. All tests were two-sided, and P<0.05 was considered statistically significant. Statistical analyses were performed using R software (version 4.5.1). No multiplicity adjustment was applied for multiple subgroup analyses; all subgroup findings should therefore be regarded as exploratory.

Among the 48 patients included in the final analysis, no missing data were identified for the baseline variables, treatment group, DFS outcomes, BMFS outcomes, follow-up time, treatment exposure variables, or safety variables used in the reported analyses; therefore, no imputation was performed.

Results

Baseline patient characteristics

A total of 48 patients were included, with 26 patients in the alectinib group and 22 in the crizotinib group. The clinicopathological characteristics of the cohort are summarized in Table 1. The median age was 50.0 years (IQR, 42.8–59.5 years), and adenocarcinoma was the predominant histologic type (93.8%). Postoperative N2 disease was present in 26 patients (54.2%), including 13 in each group.

Nine patients with stage IA disease were also included. Among them, postoperative pathology showed a solid component ≥20% in four cases, a micropapillary component ≥20% in five cases, spread through air spaces in two cases, and subpleural invasion without pleural involvement in one case. On the basis of multidisciplinary discussion, these patients were recommended to undergo genetic testing and receive adjuvant targeted therapy.

Efficacy

As of October 31, 2025, median follow-up estimated using the reverse Kaplan-Meier method was 84.6 months (95% CI: 56.8–108.3) overall, 51.9 months (95% CI: 46.1–73.1) in the alectinib group, and 121.9 months (95% CI: 95.3–154.3) in the crizotinib group. A total of 27 DFS events (56.3%) were observed, including 7 events (26.9%) in the alectinib group and 20 events (90.9%) in the crizotinib group. Three deaths (6.3%) occurred, including one in the alectinib group (3.8%) and two in the crizotinib group (9.1%).

The DFS curves for the two treatment groups are shown in Figure 1. Median DFS was not reached in the alectinib group (95% CI: 44.1 months to not reached) and was 28.23 months in the crizotinib group (95% CI: 19.31–37.16), with a significant between-group difference (P<0.001). The unadjusted HR for recurrence or death was 0.20 (95% CI: 0.08–0.47). In an exploratory multivariable Cox model adjusting for postoperative nodal status (N0 vs. N1–2), the adjusted HR was 0.20 (95% CI: 0.08–0.47; P<0.001).

Figure 1 DFS according to adjuvant treatment group. Kaplan-Meier curves showing DFS in patients who received adjuvant alectinib or crizotinib after complete resection. CI, confidence interval; DFS, disease-free survival; HR, hazard ratio.

The difference was evident at the 2-year landmark and remained at 3 years. The 2-year DFS rate was 100.0% (95% CI: 86.8–100.0%) in the alectinib group and 59.6% (95% CI: 34.8–76.8%) in the crizotinib group. At 3 years, the corresponding rates were 91.4% (95% CI: 69.1–97.6%) and 41.4% (95% CI: 23.6–60.4%), respectively.

Brain metastasis outcomes are presented in Figure 2. Postoperative recurrent brain metastasis occurred in 3 patients (11.5%) in the alectinib group and 13 patients (59.1%) in the crizotinib group. The HR was 0.16 (95% CI: 0.05–0.56; P=0.001). Median TBM was not reached in the alectinib group and was 50.53 months in the crizotinib group (95% CI: 44.32–56.74). The 3-year BMFS rate was 95.2% (95% CI: 70.8–99.3%) in the alectinib group and 74.8% (95% CI: 48.2–89.3%) in the crizotinib group.

Figure 2 BMFS according to adjuvant treatment group. Kaplan-Meier curves showing BMFS in the alectinib and crizotinib groups. BMFS, brain metastasis-free survival; CI, confidence interval; HR, hazard ratio.

The subgroup analysis of 3-year DFS according to disease stage and node (N) stage is shown in Figure 3. In stage II disease, the 3-year DFS rate was 80.0% (95% CI: 51.6–100.0%) in the alectinib group and 16.7% (95% CI: 2.8–99.7%) in the crizotinib group, with an HR of 0.098 (95% CI: 0.011–0.831; P=0.03). Given the small sample size of this subgroup (n=11), these findings should be interpreted cautiously. In stage III disease, the 3-year DFS rate was 100.0% (95% CI: 63.2–100.0%) in the alectinib group and 46.2% (95% CI: 25.7–83.0%) in the crizotinib group, with an HR of 0.20 (95% CI: 0.056–0.708; P=0.01).

Figure 3 Subgroup analysis of 3-year DFS. Forest plot showing HRs for 3-year DFS according to disease stage and N stage. HRs and 95% CIs are displayed on a logarithmic scale. HR <1 favors alectinib. Ale, alectinib; CI, confidence interval; Cri, crizotinib; DFS, disease-free survival; HR, hazard ratio; N, node.

Nine patients with stage IA disease and high-risk pathological features were included, comprising six patients in the alectinib group and three in the crizotinib group. Because of the marked imbalance between groups, this subgroup was evaluated descriptively only. Recurrence or death occurred in 4 patients (44.4%), including two in the alectinib group and two in the crizotinib group. The 3-year DFS rate was 77.8% (95% CI: 54.9–100.0%) in the overall stage IA subgroup and 83.3% (95% CI: 58.3–100.0%) in the alectinib-treated stage IA subgroup and median DFS was not reached in that subgroup. In a sensitivity analysis excluding the nine patients with stage IA disease (n=39), the 3-year DFS rates were 94.7% (95% CI: 68.1–99.2%) with alectinib and 36.8% (95% CI: 16.5–57.5%) with crizotinib (unadjusted HR 0.15; 95% CI: 0.06–0.42; log-rank P<0.001).

DFS outcomes were also assessed according to postoperative nodal status. Among N0 patients (n=15), the 3-year DFS rate was 88.9% (95% CI: 41.6–98.2%) in the alectinib group and 33.3% (95% CI: 4.8–72.3%) in the crizotinib group, with an HR of 0.25 (95% CI: 0.06–1.09) and a borderline log-rank P value of 0.048. Among patients with N1–2 disease, the 3-year DFS rate was 93.9% (95% CI: 62.9–99.2%) in the alectinib group and 43.8% (95% CI: 22.1–68.5%) in the crizotinib group, with an HR of 0.17 (95% CI: 0.06–0.52; P<0.001). The P value in the N0 subgroup was borderline, and no multiplicity correction was applied to subgroup analyses; these findings should therefore be interpreted cautiously.

Thirteen patients with N2 disease were included in the alectinib group, including four with skip N2 metastasis and nine with non-skip N2 metastasis. At the 36-month landmark, the 3-year recurrence rate was 0% (0/4) in patients with skip N2 disease and 33.3% (3/9) in non-skip N2 disease. The difference did not reach statistical significance (P=0.34, Fisher’s exact test), possibly due to the small sample size.

Treatment exposure and safety

The median treatment duration was 24.3 months (IQR, 24.2–24.7 months) in the alectinib group and 20.6 months (IQR, 13.6–24.2 months) in the crizotinib group. Dose reductions occurred in 6/26 (23.1%) and 6/22 (27.3%) patients, respectively, and temporary treatment interruptions were documented in 2/26 (7.7%) and 5/22 (22.7%), respectively. In the alectinib group, 24/26 patients (92.3%) completed the planned treatment course, one (3.8%) discontinued prematurely because of recurrence, and one (3.8%) remained on treatment at the data cutoff; in the crizotinib group, 11/22 (50.0%) completed the planned course and 11/22 (50.0%) discontinued prematurely because of adverse events (n=5), recurrence (n=4), or patient preference (n=2).

Treatment was generally well tolerated in both groups. In the alectinib group (n=26), all adverse events were grade 1–2, most commonly nausea/vomiting (4/26, 15.4%), rash (4/26, 15.4%), alanine aminotransferase/aspartate aminotransferase elevation (3/26, 11.5%), and weight increase (3/26, 11.5%). No grade ≥3 adverse events were observed.

In the crizotinib group (n=22), grade 1–2 adverse events were more frequent, mainly nausea/vomiting (9/22, 40.9%), diarrhea (8/22, 36.4%), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (4/22, 18.2%), and peripheral edema (4/22, 18.2%). Six patients (27.3%) experienced grade ≥3 adverse events, including ALT/AST elevation (n=2), lymphopenia (n=1), neutropenia (n=1), nausea/vomiting (n=1), and diarrhea (n=1). No treatment-related deaths were reported in either group. Treatment-related adverse events are summarized in Table 2.

Discussion

In this real-world retrospective study, adjuvant alectinib was associated with longer DFS than crizotinib, with an unadjusted HR of 0.20 for recurrence or death. A similar association was observed after exploratory adjustment for postoperative nodal status. The early separation of DFS outcomes and the higher 2- and 3-year DFS rates in the alectinib group suggest more durable postoperative disease control with alectinib during the key postoperative window, which is clinically relevant for both disease control and recovery after surgery. The finding was consistent with that reported in the phase III ALINA trial (13,22), further supporting the role of alectinib in the adjuvant setting and extending the comparison to two generations of ALK-TKIs. Together with the limited performance observed with adjuvant crizotinib in ECOG-ACRIN E4512 (17), these findings suggest that different ALK-TKIs may not be equally effective as adjuvant therapy.

CNS recurrence remains an important pattern of treatment failure in ALK-positive NSCLC after resection. The higher 3-year BMFS rate observed with alectinib (95.2% vs. 74.8%) is biologically plausible, given the stronger CNS penetration of alectinib and the limited cerebrospinal fluid (CSF) exposure reported for crizotinib (11,12,16,23). This finding is also consistent with the CNS benefit of alectinib observed in the first-line advanced-disease setting (23), extending the observation to the adjuvant setting.

In the stage II and III subgroups, alectinib was associated with DFS benefit in both subgroups, with higher 3-year DFS rates observed. The direction of effect was generally consistent with the overall population. Still, given the limited number of patients, especially in stage II disease, these subgroup findings should be interpreted as exploratory.

At present, randomized phase III evidence supporting adjuvant ALK-targeted therapy includes the ALINA and ELEVATE trials, neither of which included patients with stage IA disease (13,24). However, stage IA lung adenocarcinoma is not uniformly low risk (25-28). In our study, all nine stage IA patients had pathological high-risk features, including solid or micropapillary components ≥20% and spread through air spaces, and were recommended to undergo genetic testing and receive adjuvant targeted therapy after multidisciplinary discussion. Pathologically, solid and micropapillary adenocarcinoma subtypes are classified as high-grade patterns in the World Health Organization classification and the International Association for the Study of Lung Cancer grading system (29,30). These patterns are associated with invasive features and a higher risk of postoperative recurrence (27,28). Taken together, these observations suggest that tumor-node-metastasis (TNM) stage alone may underestimate the recurrence risk of stage IA ALK-positive NSCLC (31).

In our stage IA subgroup, the 3-year DFS rate was 83.3% in the six patients treated with alectinib, and median DFS was not reached. Although this finding is preliminary, it raises the possibility that stage IA patients with high-risk pathological features may derive benefit from adjuvant alectinib. This hypothesis is consistent with the broader development of adjuvant targeted therapy in oncogene-driven early-stage NSCLC, including ADAURA in stage IB–IIIA EGFR-mutated disease and the ongoing ADAURA2 study in stage IA2–IA3 disease (32,33). Given the very small sample size and between-group imbalance, these data should be considered hypothesis-generating. The sensitivity analysis excluding patients with stage IA disease yielded a similar treatment association, suggesting that their inclusion and unequal distribution did not drive the overall DFS finding.

Alectinib also showed numerically higher 3-year DFS rates across postoperative nodal subgroups. Although N0 disease is generally regarded as having a more favorable prognosis, the recurrence rate remained substantial in the crizotinib-treated N0 subgroup in our cohort. These findings suggest that postoperative nodal status alone may not fully identify patients at low recurrence risk, but the N0 subgroup result remains exploratory.

Skip N2 metastasis refers to the pattern in which mediastinal lymph nodes are positive whereas hilar lymph nodes remain negative. Previous studies have consistently shown that patients with non-skip N2 disease have worse outcomes than those with skip N2 disease (34-36). Among patients with N2 disease treated with alectinib in our cohort, non-skip N2 disease showed a numerically higher 3-year recurrence rate than skip N2 disease but the difference was not statistically significant. The data suggest that alectinib may still offer protection in patients with unfavorable nodal patterns. This observation remains exploratory and requires confirmation in larger cohorts.

Safety is particularly important in the adjuvant setting. In this cohort, no grade ≥3 adverse events or treatment-related deaths were observed with alectinib, whereas grade ≥3 adverse events occurred in the crizotinib group. This finding is consistent with the favorable tolerability profile of alectinib reported in previous studies (6-8,13), and further supports alectinib as adjuvant treatment. Treatment duration was shorter and temporary treatment interruptions and premature discontinuations were more frequent with crizotinib. However, recurrence itself prompted treatment discontinuation in four crizotinib-treated patients, limiting interpretation of the relationship between treatment exposure and DFS.

This study has several limitations. First, the single-center retrospective design cannot fully exclude selection bias or residual confounding, despite exploratory adjustment for nodal status. Second, subgroup analyses were based on small sample sizes and no multiplicity adjustment was applied. Third, follow-up was substantially shorter in the alectinib group than in the crizotinib group. Although median follow-up exceeded 36 months in both groups, the imbalance may reduce the precision of the 3-year DFS estimate and limits interpretation of later survival estimates. Finally, treatment choice was linked to calendar time. Although the planned postoperative surveillance schedule was broadly similar, changes over the study period in imaging sensitivity and interpretation, surveillance practices, perioperative management, pathological assessment and staging, and access to subsequent ALK-targeted therapies may have influenced event ascertainment or post-recurrence outcomes. Subsequent therapies would not affect the timing of the first DFS event but could affect outcomes after recurrence. The small number of deaths also limited assessment of overall survival (OS).

Conclusions

In patients with completely resected ALK-positive NSCLC, adjuvant alectinib was associated with longer DFS, better CNS control, and a more favorable safety profile than crizotinib. These findings may support considering alectinib as a preferred adjuvant option over crizotinib in postoperative adjuvant treatment decision-making. Further multicenter prospective studies are needed to validate these results in broader populations and to clarify resistance mechanisms and optimal treatment strategies after adjuvant therapy.

Acknowledgments

The authors thank all members involved in data collection and clinical follow-up. Preliminary results of this study were presented as a poster at the ESMO Congress 2025 (Berlin, Germany, October 17–21, 2025; Abstract 1829P).

During manuscript preparation, the authors used ChatGPT (OpenAI; last accessed 11 June 2026) for language editing, formatting assistance and preparation of submission-related text. No artificial intelligence (AI) tool was used for data collection, statistical analysis, interpretation of results, or generation of figures. The authors reviewed and edited all AI-assisted content and take full responsibility for the final manuscript.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0766/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0766/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0766/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0766/coif). The 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (approval No. SL-B2026-250-01; approval date: 14 April 2026). The requirement for informed consent for this retrospective analysis was waived because anonymized data were used. Because adjuvant treatment with crizotinib or alectinib had not yet been approved in China during the study period, all patients included in this study had signed informed consent forms for off-label drug use before receiving adjuvant ALK-TKI therapy.

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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