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Comparative Effectiveness of Pembrolizumab Vs. Nivolumab In www.nature.com/scientificreports OPEN Comparative efectiveness of pembrolizumab vs. nivolumab in patients with recurrent or advanced NSCLC Pengfei Cui1,2,4, Ruixin Li2,4, Ziwei Huang3,2,4, Zhaozhen Wu3,2, Haitao Tao2, Sujie Zhang2 & Yi Hu1,2,3* The efcacies of pembrolizumab and nivolumab have never been directly compared in a real-world study. Therefore, we sought to retrospectively evaluate the objective response rate (ORR) and the progression-free survival (PFS) of patients with recurrent or advanced non-small cell lung cancer (NSCLC) in a real-world setting. This study included patients with recurrent or advanced NSCLC diagnosed between September 1, 2015 and August 31, 2019, who were treated with programmed cell death 1 (PD-1) inhibitors at the Cancer Center of the Chinese People’s Liberation Army. PFS was estimated for each treatment group using Kaplan–Meier curves and log-rank tests. The multivariate analysis of PFS was performed with Cox proportional hazards regression models. A total of 255 patients with advanced or recurrent NSCLC treated with PD-1 inhibitors were identifed. The ORR was signifcantly higher in the pembrolizumab group than in the nivolumab group, while PFS was not signifcantly diferent between the two groups. Subgroup analysis showed that the ORR was signifcantly higher for pembrolizumab than for nivolumab in patients in the frst-line therapy subgroup and in those in the combination therapy as frst-line therapy subgroup. Survival analysis of patients receiving combination therapy as second- or further-line therapy showed that nivolumab had better efcacy than pembrolizumab. However, the multivariate analysis revealed no signifcant diference in PFS between patients treated with pembrolizumab and those treated with nivolumab regardless of the subgroup. In our study, no signifcant diference in PFS was noted between patients treated with pembrolizumab and those treated with nivolumab in various clinical settings. This supports the current practice of choosing either pembrolizumab or nivolumab based on patient preferences. Immunotherapy is one of the most important breakthroughs in cancer treatment, and compared with standard therapies, immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) signifcantly prolong overall survival (OS) in patients with a wide range of tumor types1,2. Te checkpoint inhibitors nivolumab and pembroli- zumab (PD-1 inhibitors) are approved by the Food and Drug Administration (FDA) for use in non-small cell lung cancer (NSCLC); these agents show great efcacy in subsequent-line therapy for advanced NSCLC3,4. Although these antibodies are both IgG4 subtype antibodies that target the PD-1 receptor, they bind to diferent epitopes in the receptor and have diferent afnities 5. It is unknown whether the diferences in pharmacokinetics and dos- ing strategies between these two drugs afect the clinical outcomes of patients. In metastatic NSCLC, cross-trial comparisons suggest diferent efcacies for these two drugs. In a clinical trial, pembrolizumab as a single agent was superior to doublet chemotherapy in patients with high programmed death legend 1 (PD-L1) expression (≥ 50%)6. However, nivolumab failed to achieve a positive result in patients with > 1% PD-L1 expression in the following CheckMate 026 study7. Although the diferent outcomes in these two trials could be due to diferences in the second-line therapies that patients received in the chemotherapy arms, they do suggest a possible diference 1Department of Graduate Administration, Chinese PLA General Hospital, Beijing, China. 2Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Haidian, Beijing 100853, China. 3School of Medicine, Nankai University, Tianjin, China. 4These authors contributed equally: Pengfei Cui, Ruixin Li and Ziwei Huang. *email: [email protected] SCIENTIFIC REPORTS | (2020) 10:13160 | https://doi.org/10.1038/s41598-020-70207-7 1 Vol.:(0123456789) www.nature.com/scientificreports/ in efcacy between these two drugs. Recently, a retrospective real-world analysis of patients with advanced mela- noma showed no signifcant diference in OS between patients treated with frst-line pembrolizumab and those treated with frst-line nivolumab8. A meta-analysis that indirectly compared pembrolizumab and nivolumab as second-line therapy for the treatment of NSCLC also showed no signifcant diferences in OS or progression-free survival (PFS) between pembrolizumab and nivolumab9. However, there are currently no real-world studies that have compared the efcacies of these two medications in NSCLC either alone or combined with chemotherapy; therefore, we sought to retrospectively compare the efcacies of pembrolizumab and nivolumab in patients with recurrent or advanced NSCLC in a real-world population to address this gap. Results Patient characteristics. We included 255 patients with advanced or recurrent NSCLC who were treated with PD-1 inhibitors in our study (consisting of 163 non-squamous NSCLC patients and 92 squamous carci- noma patients). Of the 255 patients, 191 (74.90%) were men, and 64 (25.10%) were women. Teir ages ranged from 29 to 86 years, with a median age of 61 years. Patients treated with pembrolizumab were more likely to receive frst-line therapy and combination therapy than those treated with nivolumab. Tere were no diferences in age, sex, ECOG performance status, smoking history, disease stage, CNS or intrathoracic metastasis status, histology, mutational status for EGFR or ALK, PD-L1 positivity, treatment cycles or follow-up time between those treated with pembrolizumab and those treated with nivolumab (Table 1). PFS of patients with recurrent or advanced NSCLC treated with pembrolizumab vs. nivolumab. With a median follow-up time of 249 days, the median PFS time for all treated patients was 22.14 weeks [95% confdence interval (CI) 3.83–116.77]. Te median PFS time for patients treated with pem- brolizumab was 23 weeks (95% CI 4.66–91.30), while the median PFS time for those treated with nivolumab was 20.86 weeks (95% CI 3.25–135.72) (Fig. 1). Te survival analysis showed that the ORR was signifcantly higher in the patients treated with pembrolizumab than in those treated with nivolumab (62 of 146 patients [42.47%] vs 25 of 109 patients [22.94%]; p = 0.001). However, there was no signifcant diference in PFS between the patients treated with pembrolizumab and those treated with nivolumab (p = 0.4031) (Fig. 1). When adjusted for age, sex, number of treatment lines, PD-L1 expression, CNS metastasis status, histology, pretreatment ECOG perfor- mance status, disease stage, treatment cycles, and therapeutic strategy (combined with chemotherapy or not), which may afect the efcacy of the PD-1 inhibitors, the multivariate analysis revealed no signifcant diference in PFS between the patients treated with pembrolizumab and those treated with nivolumab (HR 0.917; 95% CI 0.663–1.267; p = 0.598) (Table 2, Supplementary Table 7). Subgroup analyses of PFS between pembrolizumab- and nivolumab-treated patients. Ten, subgroup analyses of PFS were conducted on patients treated with frst-line therapy, patients receiving PD-1 inhibitor monotherapy as their frst-line therapy, patients receiving combination therapy as their frst-line ther- apy, patients treated with second-line therapy, patients receiving PD-1 inhibitor monotherapy as second- or further-line therapy, and patients receiving combination therapy as second- or further-line therapy (Supple- mentary Tables S1–S6). Te survival analysis showed that the ORR was signifcantly higher in patients treated with pembrolizumab than in those treated with nivolumab among patients in the frst-line therapy subgroup and among patients in the receiving combination therapy as their frst-line therapy subgroup (39 of 59 patients [66.10%] vs 8 of 26 patients [30.77%], p = 0.004; 33 of 44 patients [75.00%] vs 2 of 11 patients [18.18%], p = 0.001;, respectively) (Supplementary Tables S1 and S3). However, there was no signifcant diference in PFS between the patients treated with pembrolizumab and those treated with nivolumab regardless of the subgroup, except for the subgroup of patients receiving combination therapy as second- or further-line therapy, in which nivolumab demonstrated better efcacy than pembrolizumab (p = 0.04) (Figs. 2, 3, 4, 5 and Supplementary Figs. S1 and S2). When adjusted for age, sex, PD-L1 expression, CNS metastasis status, histology, pretreatment ECOG perfor- mance status, disease stage, treatment cycles, and combination status (combined with single-agent chemother- apy or double-agent chemotherapy), the multivariate analysis revealed no signifcant diference in PFS between patients treated with pembrolizumab and those treated with nivolumab regardless of the subgroup (Table 2, Supplementary Tables S8–S13). Discussion Pembrolizumab and nivolumab are both PD-1 receptor inhibitors whose efcacies have been demonstrated in several clinical trials10–13. Both have been approved for the treatment of NSCLC and melanoma by the FDA. Because there is no head-to-head randomized controlled trial (RCT) on the diferences between pembrolizumab and nivolumab to aid in therapeutic choices, this study compared the efcacies of these two inhibitors. First, we compared pembrolizumab to nivolumab in patients with recurrent or advanced NSCLC. Te survival analysis showed that pembrolizumab had a better ORR than nivolumab, but no signifcant diference in PFS was found between pembrolizumab and nivolumab. As the treatment lines and combination status were signifcantly
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