Efficacy and Safety of PD-1/PD-L1 Inhibitor as Single-Agent Immunotherapy in Endometrial Cancer: A Systematic Review and Meta-Analysis

Abstract

The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway plays a crucial role in the immune escape mechanism and growth of cancer cells in endometrial cancer (EC). Clinical trials investigating PD-1/PD-L1 inhibitor have shown promising results in other cancers, but their efficacy in EC still remains uncertain. Therefore, this meta-analysis aims to provide an updated and robust analysis of the effectiveness and safety of PD-1/PDL1 inhibitor as single-agent immunotherapy in EC, focusing on the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). This meta-analysis utilized STATA version 17 and RevMan version 5.4 software to pool the results of relevant studies. Five studies conducted between 2017 and 2022, comprising a total of 480 EC patients enrolled for PD-1/PD-L1 inhibitor immunotherapy met the inclusion criteria. The pooled proportion of EC patients who achieved ORR through PD-1/PD-L1 inhibitor treatment was 26.0% (95% CI: 16.0–36.0%; p < 0.05). Subgroup analysis based on mismatch repair (MMR) status showed an ORR of 44.0% (95% CI: 38.0–50.0%; p = 0.32) for the deficient mismatch repair (dMMR) group and 8.0% (95% CI: 0.0–16.0%; p = 0.07) for the proficient mismatch repair (pMMR) group. Pooled proportion analysis by DCR demonstrated an odds ratio (OR) of 41.0% (95% CI: 36.0–46.0%, p = 0.83) for patients undergoing PD-1/PD-L1 inhibitor treatment. Subgroup analysis based on MMR status revealed DCR of 54.0% (95% CI: 47.0–62.0%; p = 0.83) for the dMMR group, and 31.0% (95% CI: 25.0–39.0%; p = 0.14) for the pMMR group. The efficacy of PD-1/PD-L1 inhibitors was significantly higher in the dMMR group compared to the pMMR group, in terms of both ORR (OR = 6.30; 95% CI = 3.60–11.03; p < 0.05) and DCR (OR = 2.57; 95% CI = 1.66–3.99; p < 0.05). In terms of safety issues, the pooled proportion of patients experiencing at least one adverse event was 69.0% (95% CI: 65.0–73.0%; p > 0.05), with grade three or higher AEs occurring in 16.0% of cases (95% CI: 12.0–19.0%; p > 0.05). Based on the subgroup analysis of MMR status, PD-1/PD-L1 inhibitor immunotherapy showed significantly better efficacy among dMMR patients. These findings suggest that patients with dMMR status may be more suitable for this treatment approach. However, further research on PD-1/PD-L1 inhibitor immunotherapy strategies is needed to fully explore their potential and improve treatment outcomes in EC.

DNA mismatch repair system regulates the expression of PD-L1 through DNMTs in cervical cancer

“…Higher PD-L1 expression in dMMR endometrial tumors supports the clinical efficacy of PD-L1 inhibitors in the treatment of solid tumors, with significantly better objective response rates and disease control rates [ 40 ]. Moreover, PD-L1 expression elevated with an increase in TIL abundance within the endometrial tumor microenvironment, suggesting that PD-1 inhibitors could trigger a potent anti-tumor immune response due to the high PD-L1 expression [ 41 , 42 ]. We also found that the expression of PD-L1 in TCs was closely related to the expression of DNMTs.…”

Expression of PD-1 and PD-L1 in Endometrial Cancer: Molecular and Clinical Significance

“…The detection of this mutation places the patient in the POLE ultra-mutated category. Finally, for patients not falling under dMMR or POLE EDM categories, the patient's p53 status is assessed using immunohistochemistry IHC to determine whether they exhibit wild-type or null/missense mutations [22][23][24].…”

“…Hence, this prevents cancer cells from escaping the immune system by reactivating the T-cell-mediated process of eliminating tumour cells (Figure 2). Recent investigations have unveiled that anti-PD-1/PD-L1 first line therapy yields response rates varying between 20% and 65% in PD-L1-positive tumours in various cancers, including EC [24,[80][81][82]. Conversely, tumours lacking PD-L1 expression exhibit response rates ranging from 0% to 17% across diverse tumour types [79].…”

Efficacy and Safety of Atezolizumab as a PD-L1 Inhibitor in the Treatment of Cervical Cancer: A Systematic Review

“…PD-1 and PD-L1 inhibitors have shown efficacy in several solid tumors, leading to improved survival outcomes [ 15 ]. For example, pembrolizumab has been approved for PD-L1-positive cervical cancer based on improved overall survival and progression-free survival rates compared to chemotherapy in clinical trials like KEYNOTE-158 [ 16 ].…”