Trends in the prescription of immune checkpoint inhibitors for non-small cell lung cancer in the Netherlands from 2016 to 2020, a national cancer registry analysis

Introduction

Background

Lung cancer is the leading cause of cancer death worldwide, with a low survival rate of 10% to 20% after 5 years of diagnosis (1). In recent years, the introduction of immune checkpoint inhibitors (ICIs) has offered new treatment options for patients with lung cancer. ICIs have shown to increase the overall survival (OS) of patients with lung cancer, especially those patients with better performance status (PS) and higher programmed death-ligand 1 (PD-L1) tumoral expression (2-4).

In 2015, the European Medicines Agency (EMA) approved the use of the first programmed cell death protein 1 (PD-1) inhibiting monoclonal antibody for non-small cell lung cancer (NSCLC) patients, nivolumab (5). Since then, several new ICI drugs for treating lung cancer have continued to be tested and are approved. Immunotherapy alone or in combinations with chemotherapy, as first- and further-line treatments have been implemented. As a result of the innovations in the use of ICIs to treat patients with lung cancer, tumor characteristics, treatment regimens and clinical outcomes have changed over recent years.

Rationale and knowledge gap

Most data on ICI treatment effectiveness are obtained through randomized controlled trials (RCTs), being tested in selected patients with clinical characteristics such as favorable PS and mild symptomatology. RCTs usually provide good internal validity and control for bias. However, real-world observational studies are necessary to complement RCTs evidence, providing better external validity and information on the performance of ICIs in a wider range of patients with different clinical characteristics (6,7).

Insight in the evolution of ICI therapy and its outcomes for lung cancer in a real-world setting will be informative to various stakeholders including clinicians, patients, and policy makers. National level data allow for the analysis of effectiveness in large populations with diverse clinical characteristics.

Objective

The aim of this study is to provide a description of the trends in patient and disease characteristics, treatment patterns, and survival in NSCLC patients treated with ICIs in the Netherlands from 2016 to 2020, using a national registry and an in-depth local cohort. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-264/rc).

Methods

Netherlands Cancer Registry (NCR)

The NCR is a database containing national-level information about the characteristics and prevalence of cancer, and it is administered by the Netherlands Comprehensive Cancer Organisation (IKNL). This database gathers information cancer patient’s first-line treatment, including patients treated with ICIs inside and outside RCT settings. After being informed of the new diagnosis by either the patient’s healthcare provided or the Dutch Nationwide Pathology Databank (PALGA), patients’ clinical and treatment-related data is collected. Dutch law allows the medical centers to collect data from patients when this is used for scientific and statistical purposes, without the need of informed consent. This data was provided to us anonymized. Patients included from the NCR in this study were adults over the age of 18 diagnosed with NSCLC and treated with ICIs in the Netherlands, between January 2016 and December 2020. Data on the number of NSCLC patients that received anti-cancer systemic therapies in the form of chemotherapy or ICIs were received as well.

Oncological Life Study (OncoLifeS)

The OncoLifeS is a hospital-based data-biobank including patients referred to the University Medical Center Groningen (UMCG), a tertiary-level hospital offering healthcare services to the northern part of the Netherlands, for cancer treatment, which links clinical and socio-economic characteristics with a biological specimens’ repository (8). OncoLifeS is approved by the Medical Ethical Committee of UMCG, and all included patients gave written informed consent to join OncoLifeS. Data from OncoLifeS was used for a secondary analysis of ICIs as first- and further-line NSCLC treatment. For this sub-analysis, we included adults over 18 years of age diagnosed with NSCLC who received treatment with ICIs between January 2016 and December 2020.

Data collection

The national data for ICI treatment requested from NCR included sex, age, PS, institution of cancer diagnosis and ICI treatment, date of diagnosis, TNM stage, PD-L1 expression, ICI type, start and stop dates, and the date of death/last contact. This information was gathered by trained IKNL employees from clinical records. Date of death is collected by IKNL through the linkage with the municipal personal records database, insuring complete survival follow-up data.

Regarding the information gathered from OncoLifeS, data on patients’ age, sex, education, and smoking status was collected through the OncoLifeS questionnaires, filled in by the patients around the start of their immunotherapy treatment. Furthermore, data was retrieved from electronic medical records, providing information on PS, TNM stage, date of diagnosis, PD-L1 expression, treatment line, as well as chemotherapy and ICI type, start and stop dates, and date of death. Details on variable definition can be found in Table S1.

This study was carried out conformed to the provisions of the Declaration of Helsinki (as revised in 2013) (9). Regarding the data from the NCR provided by IKNL, according to the Central Committee on Research involving Human Subjects (CCMO), this type of observational study does not require approval from an ethics committee in the Netherlands. The Privacy Review Board of the NCR approved the use of anonymized data for this study. Furthermore, the OncoLifeS study has been approved by the medical ethics committee of the UMCG (no. 2010/109) and has been International Organization for Standardization (ISO) certified (9001:2008 Healthcare). It has been also registered in the Dutch Trial Register under the number: NL7839. All the participants in OncoLifeS have signed informed consent.

Statistical analysis

A complete case analysis was carried out. Descriptive statistics were used to present the national level data regarding the first-line treatment with ICI (source: NCR) and the any-line treatment (source: OncoLifeS). Frequency and percentages were used to present categorical variables. Means and standard deviations (SDs) were used to present continuous variables. These statistical analyses were performed using SPSS 25. Annual percentage change (APC) was calculated to present the changes in patient and tumor characteristics, as well as treatment regimens from 2016 to 2020. APC was calculated using Joinpoint 4.9.1.0 software.

Survival analysis was performed to observe changes in median OS over the years. The Kaplan-Meier method, with 95% confidence intervals (CIs), was used to calculate median OS. To ensure each individual had the opportunity for at least two years of follow-up, the censoring date was set at two years after the treatment initiation date of the last patient included in the study (December 31^st, 2022). Consequently, survival time was defined as the interval between the ICI treatment start date until either death or the censoring date. To account for individual and group differences in follow-up times, we calculated hazard ratios (HRs) using four Cox proportional hazards regression models. Model 1 was an univariable model, model 2 was adjusted for age and gender, model 3 included model 2 plus adjusting for stage and PS, and model 4 included model 3 plus adjustment for tumor PD-L1 expression. These analyses were carried out in Stata 14.

Results

Patients treated with first-line ICI

From January 2016 to December 2020, 22,665 NSCLC patients received anti-cancer systemic therapies in the form of chemo or immunotherapy in the Netherlands, of whom 6,816 (30.1%) were treated with ICI as first-line treatments. The mean age of the patients was 65 years (SD =9.2) and were mostly male (n=3,707, 54.4%). The majority of patients were treated with PD-1 inhibitors as monotherapy (63.2%). The most commonly prescribed ICI was pembrolizumab as monotherapy (43.9%), followed by pembrolizumab as a combination with two chemotherapeutic agents (34.7%). At the start of ICI treatment, 75% of the patients had stage IV NSCLC. Regarding the PS, the largest proportion of patients were classified as 0–1 (91.3%) (Table 1 and Table S2).

Patients treated with any-line ICI

In the years 2016 to 2020, a total of 449 NSCLC patients were treated with ICIs in the UMCG and signed informed consent to join OncoLifeS. These patients had a mean age of 64.7 years (SD =9.4) and were predominantly male (60.1%). From these patients, the majority were treated with ICIs as second-line treatment (n=253, 56.3%). The majority of patients received immunotherapy treatment for a stage IV NSCLC, especially as second and third lines (94.1% and 100% respectively). PD-1 inhibitors were the most commonly used drugs as first-, second- and third-lines of treatment (48.1%, 90.1% and 71.4% respectively). The most commonly prescribed ICI was nivolumab as monotherapy (53.2%), and pembrolizumab as monotherapy (20.3%).

Changes over the years in the prescription of ICI in the Netherlands as first-line treatment

The proportion of NSCLC patients treated with ICI as first-line treatment increased from 1.1% in 2016 to 54.9% in 2020 (APC =14.5%, P=0.002), compared to the chemotherapy-only treated patients (98.8% to 45.1%, APC =−14.5%, P=0.002) (NCR data, Figure 1). Patients with a stage III disease treated with ICI grew in proportion, from 11.9% to 25.6% (APC =3.5%, P=0.03), whilst the proportion of stage IV patients declined from 88.1% to 72.4% (APC =−3.9%, P=0.03, Table 2). The administration of ICIs to patients with a tumor PD-L1 expression of ≥50% decreased steady from 2016 to 2020 [APC of −13.82% (P=0.04)] (Table 2).

Figure 1 Proportion of non-small cell patients with lung cancer treated with immunotherapy and/or chemotherapy in the Netherlands 2016–2020. APC, annual percentage change.

Changes over the years in the prescription of ICI in the Netherlands as all-line treatment

In our secondary analysis using OncoLifeS data on ICIs prescribed as all-line ICI treatment, the age of the patients at the start of the treatment increased with an APC of 0.61% during this time period (P=0.02). Patients with a stage III NSCLC grew in proportion (APC =5.4%, P=0.04). The proportion of combination therapy increased with an APC of 12.4% (P=0.049), as well as use of ICI as first line treatments (APC of 17.1%, P<0.001) during the study period (Table S3).

Survival analysis

The mean follow-up time for the national level was 13.8 months. The median OS for the NCR cohort was 17.4 months (95% CI: 16.4–18.1, Figure 2), the 1-year OS was of 59.0% (95% CI: 57.8–60.2%) and the 2-year survival was 25.9% (95% CI: 24.8–26.9%, Table 3). When analyzing the OS per year of ICI treatment start, the median OS for 2016 was 16.6 months (95% CI: 9.1–19.5) and peaked in 2018: 19.4 months (95% CI: 17.0–22.0) and slightly decreasing to reach 16.5 (95% CI: 15.3–17.9) in 2020 (Figure 2). Regarding the Cox regression model 1, the hazard ratio for death due to any cause was higher for patients who received treatment in a more recent year (HR =1.04; 95% CI: 1.00–1.07). However, after adjustment for tumor’s PD-L1 expression (model 4), this association became non-significant (HR =0.99; 95% CI: 0.95–1.03) (Figure 3).

Figure 2 Median overall survival for patients with NSCLC who were treated with immune checkpoint inhibitors as first-line treatment (data from the NCR)a; as well as approval dates of first-line treatments in the Netherlands*. a, includes data from the University Medical Center Groningen on patients with lung cancer treated with immune checkpoint inhibitors as first line of treatment; *, no missing data in date of death or loss of follow-up was found. OS, overall survival; NCR, Netherlands Cancer Registry; ICI, immune checkpoint inhibitor; RCT, randomized controlled trial; NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1; CI, confidence interval.

Figure 3 Factors associated with overall survival for patients with non-small cell lung cancer who were treated with immune checkpoint inhibitors as first-line treatment (data from the NCR); Cox regression models with HR and 95% CI*. ^a, model 2: adjusted by age and gender; ^b, model 3: adjusted by age, gender, stage, and performance status; ^c, model 4: adjusted by age, gender, stage, and performance status and PD-L1 expression; *, includes patients treated with immune checkpoint inhibitors as first-line in the University Medical Center Groningen. NCR, Netherlands Cancer Registry; HR, hazard ratio; CI, confidence interval; PD-L1, programmed death-ligand 1.

In our secondary analysis, using data from OncoLifeS in the UMCG including all lines of treatment, we found that the median OS is highly determined by treatment line, varying from 18.8 months (95% CI: 13.8–24.4) for first-line, 9.4 months (95% CI: 7.3–11.2) for second-line treated patients, and 7.5 months (95% CI: 6.0–9.3) third and further-line treatments.

Discussion

Key findings

Using real world data, we showed how ICIs, alone or combined with chemotherapy, were replacing therapeutic schemes based only on chemotherapy as first-line treatment of NSCLC in the Netherlands, from 2016 to 2020. Also, we found changes in the treatment schemes and patients’ profiles at national-level when ICIs were used as first-line treatments, such as the increasing use for stage III NSCLC and in patients with lower PD-L1 expression. Furthermore, on population-based level, we found a stable OS, with an increase in survival from the years 2016 to 2018, followed by a small non-significant decrease in in the years 2019 and 2020.

Strengths and limitations

Our study has strengths and limitations. We had access to a comprehensive national level data regarding the use of ICIs in the Netherlands. However, a limitation of this dataset is the collection of only first-line treatment in the NCR national-level data, which leads to the inclusion of only patients enrolled in RCTs in the early years of the immunotherapy (2016–2017), since these therapies as first-line treatments were not authorized for their use in routine clinical care. This did not allow us to observe the performance of ICI as second- and further-line treatments, which in return can lead to an overestimation of the median OS, as well as a lower survival in the years 2019–2020. This might be due to a higher selection of patients with better clinical profiles and higher survival expectations included in RCTs in the early years of ICI implementation (2016–2017). Nevertheless, incorporating data from patients treated in more recent years (2021–2022) could provide a more comprehensive assessment of real-world evidence. However, due to the annual update process of the survival data sourced from the NCR, accessing more recent survival data to ensure patients were followed for at least 2 years was not possible at the time of completing this work. Furthermore, in our secondary analysis using a local, center-specific dataset (OncoLifeS cohort) granted us access to patient information for all-lines of treatment, allowing us to observe how survival decreased in patients treated with ICIs as second and further lines of treatment. Moreover, we lacked information on variables known to be indicative of treatment efficacy, such as tumor mutation burden (TMB) and tumor-infiltrating lymphocytes (TILs). This limitation impeded our ability to account for these crucial tumor characteristics, thereby hampering our ability to limit confounding biases (10,11). Finally, we were unable to adjust the OS by deaths due to coronavirus disease 2019 (COVID-19), since the survival of patient being treated during 2020 might have been reduced, given that COVID-19 was particularly aggressive with patients with lung cancer and increased their mortality rate (12,13). In addition, we did not have access to updated survival data for patients with lung cancer who underwent chemotherapy-only treatments between 2019 and 2020. This limitation hampered our ability to test this hypothesis in patients treated with systemic therapies other than ICIs.

Comparison with similar research

Previous evidence provided by RCTs has shown beneficial effects in the clinical outcomes of patients with lung cancer treated with ICIs, such as increased OS and more favorable treatment response (14-16). The main survival results from our study are, depending on the specific ICI prescribed, comparable to the ones provided by previous relevant RCTs evaluating the use of ICIs as first-line for NSCLC treatment; finding a median OS of 17.4 months in the NCR, compared to a range between 17.1–23.2 months in RCTs. Regarding the 1-year survival rate, in our study we found a survival rate of 59% vs. 53.1–73% from RCTs, and a lower 2-year survival rate (25.9% vs. 34–45.5% from RCTs) (17-21). Furthermore, similar with the findings presented in our study, Griesinger et al. conducted an observational study that assessed the nationwide utilization of ICIs in Germany and France. Their work yielded results comparable to our own, showing generally similar median OS and 1- and 2-year survival rates (22). Details on this comparison can be found in Table S4.

Explanations of findings

In our study we observed an initial increase in OS during the early years of monotherapy adoption as a first-line treatment for NSCLC, followed by a subsequent small decrease in recent years (2019–2020); this can be explained by factors such as the approval of ICIs as first-line treatments by the Dutch authorities at the end of 2018, which led to the availability of these therapies to patients outside RCT settings with broader clinical characteristics. Additionally, the inclusion in 2019 in Dutch national guidelines of combined chemo-immunotherapy treatment schemes administered to patients with <50% PD-L1, which has been shown to be a predictor of survival (23), further contributed to these trends. Furthermore, in our secondary analysis evaluating any-line treatment with ICIs in the UMCG from 2016 to 2020 that, median OS was determined by treatment line, being highest in first-line treatments, and decreasing in second and third treatment-lines. However, when comparing this data to the one from RCTs, we can observe a lower survival, explained by the inclusion of a majority patients treated with ICIs as second-line, with lower OS expectations. Similar real-world data analysis on melanoma patients have found an increase in median OS following the introduction of ICIs, especially after the incorporation of combined chemo-immunotherapy treatments (24). These changes in patients’ outcome can be a result of the use of ICI-based therapies in patients that, in the past, would have received chemo-radiotherapy treatments available at the time, only to be left with no further treatment options after these failed.

Implications and actions needed

Currently, new immunotherapy-based treatments continue to be developed and approved for the treatment of lung cancer with a view on reducing the burden of the disease in the world. Real-world data will continue having an important role in complementing RCT evidence on the effectiveness of these therapies in real clinical settings. Future research is needed in the evaluation of the clinical outcomes of ICI-based therapies as they are becoming a standard for treatment in early stages of lung cancer, as adjuvant and neo-adjuvant therapies, as well as first-line treatment combinations with chemotherapy in late-stage lung cancer.

Conclusions

With this analysis until 2020, we found that ICI-based therapies have substituted chemotherapy-only schemes as first-line treatment in NSCLC patients in the Netherlands since their introduction. OS increased in patients until 2018 followed by a small decrease from 2019, likely due to the decrease in the proportion in recent years of individuals with ≥50% PD-L1 expressions included in treatment regimens. New evaluations using real-world data will have to be carried out to document the changes consequence of the introduction of ICIs as first-line treatments in the national guidelines, as they become the standard of care for lung cancer in all stages.

Acknowledgments

The authors thank the registration team of the Netherlands Comprehensive Cancer Organisation (IKNL) for the collection of data for the Netherlands Cancer Registry.

Funding: This work was supported by Mexico’s National Council of Science and Technology (CONACYT) (grant No. 1074186); and European Union’s Horizon 2020 research and innovation program (grant No. 875171).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-264/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-264/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-264/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-264/coif). T.J.N.H. reports grants from Roche, BMS, Astra Zeneca; expert testimony BMS all paid to Institution (UMCG). 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 carried out conformed to the provisions of the Declaration of Helsinki (as revised in 2013). Regarding the data from the NCR provided by IKNL, according to the Central Committee on Research involving Human Subjects (CCMO), this type of observational study does not require approval from an ethics committee in the Netherlands. The Privacy Review Board of the Netherlands Cancer Registry approved the use of anonymized data for this study. Furthermore, the OncoLifeS study has been approved by the medical ethics committee of the UMCG (no. 2010/109) and has been ISO certified (9001:2008 Healthcare). It has been also registered in the Dutch Trial Register under the number: NL7839. All the participants in OncoLifeS have signed informed consent.

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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