Abstract
Background/Aim: Cemiplimab in patients with non-small cell lung cancer (NSCLC) with PD-L1 (programmed death ligand type 1) expression ≥50% showed a significant improved overall survival (OS) with increasing expression of PD-L1. To our knowledge there exist no similar data published for pembrolizumab regarding the increased OS in relation to the PD-L1 expression. Therefore, the objective of our study was to determine whether improvement in OS reflects increased expression levels of PD-L1 (≥50%) in patients with NSCLC. Patients and Methods: Retrospective data from 9 Czech and 1 Polish comprehensive oncology Centers were used. All patients with stage IV NSCLC and PD-L1 expression ≥50% treated with pembrolizumab in daily practice were included. The groups of patients according to the expression of PD-L1 were determined as follows: PD-L1 50-59%, 60-69%, 70-79%, 80-89% and 90-100%. The log-rank test and the Cox regression model were used to compare survival between study groups. Results: A total of 617 patients were included in the study. We did not observe a statistically significant difference in OS between groups of patients with different levels of PD-L1 expression in the pooled comparison (p=0.445). Furthermore, we did not observe a statistically significant difference even when comparing OS in patients with PD-L1expression of 50-59% (reference) with the group of other patients according to the level of expression of PD-L1 in the Cox regression model including the effect covariates. Conclusion: PD-L1 expression showed no significant effect on OS in patients with NSCLC with PD-L1≥50% treated with pembrolizumab.
Pembrolizumab, cemiplimab and atezolizumab have been shown to prolong overall survival (OS) in patients with non-small cell lung cancer (NSCLC) with high PD-L1 (programmed death ligand type 1) expression (1-3). However, it appears that single-agent immunotherapy may result in early progression in some patients (4, 5). It is important to study in detail the possible predictive markers of immunotherapy in order to find out patients at risk for early progression. One of these parameters may be the level of expression of PD-L1. There is a trend towards increasing the effectiveness of immunotherapy based on higher expression of PD-L1 as shown by several studies (6-8).
The study with cemiplimab in NSCLC patients with PD-L1 expression ≥50% further supports this assumption, as it has proved that increasing PD-L1 expression is associated with the improvement of the objective response rate (ORR) to treatment, progression-free survival (PFS) and OS (2, 9). The authors confirmed this fact by formation of subgroups according to PD-L1 expression at levels of 50-59%, 60-89% and above 90% (2). However, to our knowledge, detailed data showing a similar relationship between pembrolizumab and gradually increasing PD-L1 expression levels are not known.
The aim of the study was to determine whether the improvement in OS reflects the increase in PD-L1 expression levels (≥50%) in patients with NSCLC treated with pembrolizumab monotherapy.
Patients and Methods
Study design and treatment. Retrospective data from 9 Czech and 1 Polish comprehensive oncology centers (University Hospital Pilsen, University Hospital Brno, Bulovka Hospital, Thamayer Hospital, University Hospital Hradec Kralove, Liberec Regional Hospital, Motol University Hospital, Pardubice Hospital and Maria Sklodowska-Curie National Research Institute of Cancer in Warsaw) were used. All patients with PD-L1 expression ≥50% with stage IV NSCLC treated with pembrolizumab in daily practice until July 2023 were included. All the patients were treated according to the current clinical guidelines using first line pembrolizumab in dose 200 mg q3w or 400 mg q6w intravenously. Clinical follow-up controls including physical examination, plain chest X-ray and routine laboratory tests were performed every 3 or 6 weeks. CT scans were performed every 3 to 4 months. The project is registered on ClinicalTrials.gov under the registration number NCT04228237. All participants were required to sign an informed consent form, which had been approved by the Ethics Committee, as a prerequisite to their participation in the registry.
Statistics. Standard frequency tables and descriptive statistics were used to characterize patient samples. For survival analysis, OS was defined as the date from the initiation of treatment to death from any cause. Living patients were censored on the last date on which they were known to be alive. Furthermore, few patients were censored on the date of loss for follow-up. Groups of patients according to the expression of PD-L1 were determined as follows: PD-L1 50-59%, 60-69%, 70-79%, 80-89%, and 90-100%. The log-rank test (Mantel-Cox) and the Cox regression model were used to compare survival between study groups. The influence of given variable on OS is then quantified using hazard ratios. The median follow-up was determined using the reverse Kaplan-Meier method. All reported p-values are two-sided, and the level of statistical significance was established at α=0.05. Statistical processing and testing were performed using IBM SPSS Statistics 29, and R software was utilized to plot the survival curves.
Results
Patient characteristics. In total, 625 patients with stage IV NSCLC with PD-L1 expression ≥50% treated with first-line pembrolizumab were enrolled in the study. Median age of patients was 69 years (38-88 years). Baseline patient characteristics are summarized in Table I.
Baseline characteristics of patients.
Overall survival of patients. The median OS reached 14.44 months (95% CI=12.5-16.84 months). The median follow-up time was 25.6 months (at the time of the evaluation of the results, 40% of the patients were censored). The Kaplan–Meier curve is shown in Figure 1.
Overall survival (OS) of all study population (patient with non-small cell lung cancer PD-L1≥50% treated with pembrolizumab). PD-L1: Programmed death ligand type 1.
Effect of PD-L1 expression on overall survival. In our group of patients, no significant effect of PD-L1 expression on OS was observed (p=0.445). The Kaplan–Meier curves are shown in Figure 2. We did not demonstrate the effect of PD-L1 expression on OS even when using the Cox regression model adjusted for relevant covariates (Figure 3).
Overall survival (OS) according to PD-L1 expression (patient with non-small cell lung cancer PD-L1≥50% treated with pembrolizumab). PD-L1: Programmed death ligand type 1.
Cox regression hazard model for overall survival (patient with non-small cell lung cancer PD-L1≥50% treated with pembrolizumab). NOS: Not otherwise specified; PD-L1: Programmed death ligand type 1.
Discussion
To our knowledge, we herein present a unique study on the detailed view of different levels of PD-L1 expression in relation to overall survival in patients with NSCLC with high PD-L1 expression treated with pembrolizumab. The finding that PD-L1 expression in these patients does not affect OS is clinically important. According to the guidelines, patients with NSCLC with PD-L1 ≥50% can be treated both with immunotherapy alone and with chemoimmunotherapy (10). If there was a significant difference in OS according to PD-L1 expression, then it would be worth considering whether patients with lower PD-L1 expression (e.g., PD-L1 50-60%) should not be treated with chemoimmunotherapy. However, our study did not demonstrate the relationship of PD-L1 to OS in NSCLC patients with PD-L ≥50%.
The first study that has drawn attention to the possible effect of PD-L1 expression in patients with NSCLC treated with pembrolizumab in monotherapy was the study by Aguiar et al. (7). In a group of 187 patients, they have shown better OS, PFS and ORR in patients with very high expression of PD-L1 (90-100%) compared to patients with expression of PD-L1 of 50-89%. It should be noted that this study has included considerably more patients with histologically verified adenocarcinomas compared to our group of patients, as well as different PD-L1 immunohistochemistry marker tests in some patients. On the contrary, Edahiro et al. have included 149 patients in their study, who have been divided into cohorts with PD-L1 50-89% and 90-100%, and have shown a non-significant trend in improved time to treatment to failure in patients with ultrahigh expression of PD-L1 (PD-L1 90-100%) (11). Similarly, Park et al. showed no effect on PFS or disease control rate (12). However, the pembrolizumab subgroup has included only 33 patients. Shah et al. have then demonstrated in their study with 166 patients a longer median OS in patients with ultra-high expression of PD-L1 compared to expression of 50-89% (13). However, this group has partially differed in its characteristics from our patients (including patients with Eastern Cooperative Oncology Group, ECOG, performance status 2, non-Caucasians). Shah et al. have then published an even more extensive study that includes 1,952 patients treated with pembrolizumab in monotherapy (14). In this study, they have confirmed a lower risk of death with ultra-high expression of PD-L1. Again, the characteristics of patients have slightly differed from those of our study. Moreover, all the studies mentioned above have not included European populations. Therefore, it can be suggested that the outcome of patients with regard to PD-L1 expression could differ according to geographical location, as no improvement in OS has been observed in our group of patients from Central Europe in patients with ultra-high expression of PD-L1 (90-100%) compared to patients with PD-L1 50-59%. In addition, slight differences between the groups in the individual studies could have played a role, when it cannot be excluded that the better results associated with ultrahigh expression of PD-L1 (90-100%) are only associated with certain characteristics of the patients. On the other hand, it has not been proven that the level of PD-L1 expression alone is associated with common patient characteristics (15). Therefore, further analysis would be required to clarify his issue. Another factor that could have played a role in the difference between the results is that PD-L1 expression has been determined in the studies mentioned above only from small biopsy samples, which may not fully capture the heterogeneity of the PD-L1 expression side of the tumor (16). The patients could have been thus assigned to a different group, although the average PD-L1 expression of the entire tumor could have been different. Another factor is possible human error in PD-L1 reading, however automatic machine reading currently achieves similar accuracy (17).
The median OS in our study has been 14.44 months, which is less than what was announced in the registration study (1). However, these results are similar or only slightly lower than in other studies of real-world evidence (RWE) (14, 18-22). The lower efficacy results in RWE studies are a general fact, due to the different characteristics of the patients in a strictly selected sample in a clinical study vs. real clinical practice (14). Among other factors, patients treated in routine practice have more comorbidities, worse average performance status, etc.
A limitation of our study is its retrospective design, which is associated with certain imbalances between individual groups of patients according to the level of expression of PD-L1. On the contrary, a strength of our study is the large number of patients, which should partially substitute for limit this deficiency. Another limitation is the lack of follow-up treatment data, which could have influenced the OS of individual patients, which has also been suggested by the study by Cortellini et al. (23). On the other hand, we consider OS to be the gold standard for assessing the effectiveness of treatment (especially for immunotherapy), which is why we have decided to use this parameter.
Conclusion
According to our data, the PD-L1 expression levels have no significant effect on OS in patients with NSCLC treated with pembrolizumab in monotherapy with PD-L1 ≥50%. Therefore, our data do not confirm PD-L1 expression in this group of patients as a predictive marker for mono-immunotherapy.
Acknowledgements
The Authors would like to thank all patients voluntarily taking part in the study.
Footnotes
Authors’ Contributions
MS and MK-W designed the study; PD performed statistical analyses; MS, MK-W, ST, OV, JK, MD, MH, DH, AB, OF and MV collected and interpreted the data; MS, MK-W, PD wrote the manuscript with support from ST, OV, JK, MD, MH, DH, AB, OF and MV. MK supervised the project.
Conflicts of Interest
MS received honoraria from BMS, MSD, Roche, Astra Zeneca, Pfizer, Amgen, Merck for their contributions. Consultations and lectures not related to this project: MK-W received honoraria from BMS, MSD, Roche, AstraZeneca, Pfizer, Janssen, Sanofi, Amgen, and Takeda for the above. Consultations and lectures unrelated to this project: ST received honoraria from BMS, MSD, Roche, Astra Zeneca, Pfizer, and Takeda for consultations and lectures unrelated to this project. PD declares that there is no conflict of interest. OV declares no conflict of interest. JK declares no conflict of interest. MD received honoraria from Amgen, Astra Zeneca, BMS, MSD, Pfizer, Roche, Sanofi, and Jansen for consultations and lectures unrelated to this project. MH received honoraria from MSD, Astra Zeneca, Roche for consultations and lectures unrelated to this project. DH declares no conflict of interest. AB received educational support from Astra Zeneca unrelated to this project. OF received honoraria from Roche, AstraZeneca, Amgen, Mirati, BMS, Pfizer, and MSD for consultations and lectures unrelated to this project. MV declares that there is no conflict of interest. MK received honoraria from Merck, Astra Zeneca, Takeda, Roche, and Amgen for consultations and lectures unrelated to this project.
Funding
This study was supported by a Grant from the Ministry of Health of the Czech Republic – Conceptual Development of Research Organisation (Faculty Hospital in Pilsen – FNPl, 00669806) and by the Cooperatio Programme, research area SURG, by UNCE/MED/006 Charles University – Centre of Clinical and Experimental Liver Surgery).
- Received May 7, 2024.
- Revision received June 10, 2024.
- Accepted July 1, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
