Ovarian cancer (OC) is the third most common and deadly malignancy of the female reproductive system. In 2022, the global burden of OC is estimated to be approximately 325,000 new cases and approximately 207,000 deaths, with a projected 47 percent increase in the incidence of OC and a 58 percent increase in deaths by 2045 (1). Northern Europe and North America have historically experienced the highest incidence rates of OC; however, recent trends indicate a shift in these regions, with a decline in incidence. Conversely, there has been an increase in the incidence of OC in certain regions of Eastern Europe and Asia, particularly among women under the age of 50 (2). OC typically manifests insidiously, with patients often exhibiting no specific symptoms in the early stage. However, approximately 70% of patients have already reached the advanced stage with distant metastases at the time of diagnosis (3). The prognosis for advanced OC is poor, with a 5-year survival rate of approximately 25 percent and a 10-year survival rate of approximately 15 percent (4). The standard first-line treatment options for OC include surgery or neoadjuvant chemotherapy followed by surgery (5), followed by platinum-containing chemotherapy. Approximately 75-80% of patients with OC respond to these initial treatments, but 70% of patients eventually experience recurrence, develop drug resistance, and die from their cancer (6, 7). These findings underscore the imperative for the development of novel therapeutic interventions for OC, with particular emphasis on novel therapeutic strategies for recurrent or advanced OC.

Immune checkpoint inhibitors (ICIs) are a category of pharmaceuticals that target immunological receptors on T cells, therefore augmenting anti-tumor immune responses (8). Unlike traditional treatment methods, ICI therapy has demonstrated the ability to rejuvenate immune system activity, allowing the body to fight cancer cells (9). In specific cases, these medicines have shown extended effectiveness and low toxicity (10). Following the approval of ipilimumab in the United States in 2011, ICIs have advanced considerably in cancer immunotherapy (11). The FDA-approved immune checkpoint inhibitors (ICIs) currently encompass several categories: anti-PD-1 inhibitors, anti-PD-L1 inhibitors, anti-CTLA-4 inhibitors, and anti-LAG-3 inhibitors. New immune checkpoint targets, including TIGIT, TIM-3, VISTA, and CD3L1, are presently undergoing clinical development (12). In the past decade, PD-1, PD-L1, and CTLA-4 antibodies have emerged as the predominant agents in immunotherapy (13, 14). Pembrolizumab, introduced in 2014 as the first PD-1 inhibitor, initiated a new era in cancer immunotherapy (15). Since that time, several inhibitors aimed at PD-1 and its ligand PD-L1, including nivolumab, atezolizumab, durvalumab, and avelumab, have received approval from the U.S. Food and Drug Administration (FDA) for the treatment of various malignant tumors (16, 17).

Pembrolizumab is a specific humanized IgG4 monoclonal antibody that effectively inhibits the interaction between the programmed cell death protein PD-1 on T cells and its ligand, consequently activating T cell-mediated antitumor immune responses (18, 19). Pembrolizumab has received approval from the FDA for the treatment of certain tumor types, including melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and renal cell carcinoma (20). Treatment options consist of pembrolizumab administered either as monotherapy or in conjunction with chemotherapy or radiotherapy. The KEYNOTE-716 trial demonstrated that postoperative adjuvant pembrolizumab monotherapy significantly enhanced survival rates in patients with stage IIB or IIC melanoma without distant metastasis, consistently decreased recurrence risk, and exhibited a predictable safety profile (21). The KEYNOTE-189 trial demonstrated that the combination of pembrolizumab and chemotherapy significantly extended overall survival and progression-free survival compared to chemotherapy alone in previously untreated metastatic non-squamous NSCLC lacking EGFR/ALK mutations (22). The KEYNOTE-040 trials indicate that pembrolizumab significantly extends overall survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who have progressed following platinum-based therapy, in comparison to standard treatments like methotrexate, docetaxel, or cetuximab, while also demonstrating superior safety (23). The KEYNOTE-564 trial indicated that pembrolizumab, when used as adjuvant therapy following nephrectomy in patients with renal cell carcinoma, significantly enhanced disease-free survival compared to placebo and exhibited a favorable safety profile (24). In addition to the use of common solid tumors, a single-arm, open-label phase II basket trial conducted by the MD Anderson Cancer Center in the United States employed pembrolizumab in patients diagnosed with advanced rare cancers (alveolar soft tissue sarcoma, testicular mesothelioma, intracranial meningioma, and neuroblastoma) who had demonstrated disease progression following standard treatment modalities. The results demonstrated that a subset of patients exhibited a certain degree of efficacy and were well tolerated (25).

A plethora of clinical trials have been conducted to ascertain the efficacy and safety of pembrolizumab in the treatment of OC. However, the majority of these clinical trials are single-arm, thus lacking high-quality randomized controlled trials (RCTs). In this paper, all eligible studies will be included to comprehensively analyze the efficacy and safety of pembrolizumab in the treatment of advanced or recurrent OC, in anticipation of providing clinicians with more accurate data and guidance when choosing treatment options.

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) (26) guidelines and has been registered with PROSPERO (NO: CRD42024620116).

Our systematic review and meta-analysis provides a comprehensive evaluation of pembrolizumab for advanced or recurrent OC, synthesizing evidence from multiple single-arm studies. By incorporating data from 9 studies involving 625 patients, our aggregated analysis demonstrates that pembrolizumab exhibits clinically meaningful efficacy, with an ORR of 24% and a DCR of 63%, alongside manageable safety. Specifically, the ORR signifies a notable antitumor response, while the DCR reflects disease stabilization in a substantial proportion of patients, suggesting therapeutic benefit. As for survival outcomes, the pooled mPFS was 4.82 months, and mOS reached 13.54 months, highlighting pembrolizumab potential to extend survival in this challenging population. The incidence of any grade AEs was 81%, with grade ≥3 AEs at 32%, supporting an acceptable safety profile consistent with prior reports of immune checkpoint inhibitors. This study offers pivotal evidence-based guidance for integrating pembrolizumab into treatment strategies for advanced or recurrent OC.

OC represents the most lethal gynecological malignancy, distinguished by its high malignancy, significant invasiveness, and elevated recurrence rate (39). Advanced and recurrent OC is associated with a poor prognosis, posing substantial treatment challenges and serving as a focal point for clinical research. The identification of effective treatment methods is a global common goal. Treatment options for OC currently encompass surgery, chemotherapy, and emerging modalities, including targeted therapy and immunotherapy. The category of targeted therapy drugs primarily encompasses anti-angiogenic agents, PARP inhibitors, and additional classes of drugs (40). Bevacizumab, an anti-angiogenic drug, was the inaugural pharmaceutical agent approved by the U.S. FDA and the European Medicines Agency (EMA) for first-line maintenance therapy in OC. The findings from GOG-0218 and ICON7 indicated substantial improvements in progression-free survival (41, 42). As research continues to advance, bevacizumab treatment for patients with platinum-resistant and platinum-sensitive recurrent OC has shown not only PFS benefits but also significant improvements in ORR (43, 44). The results of the PRIMA trial suggest that niraparib (a PARP inhibitor) can significantly prolong PFS in patients with advanced OC (45).

Immunotherapy has become an important treatment option after surgery, radiotherapy, chemotherapy, and targeted therapy, offering new strategies for managing advanced, recurrent, or metastatic malignant tumors (46). Pembrolizumab, the inaugural PD-1 inhibitor approved in the United States, has ushered in a novel phase of tumor immunotherapy. KEYNOTE-028 represented the inaugural clinical trial utilizing pembrolizumab monotherapy for the treatment of patients with PD-L1-positive advanced OC. Twenty-six patients underwent treatment, resulting in an ORR of 11.5%, a DCR of 62%, a mPFS of 1.9 months, and a mOS of 13.8 months (47). A clinical trial testing pembrolizumab with niraparib for patients with recurrent platinum-resistant OC (KEYNOTE-162) found that, out of 60 patients who could be evaluated, the ORR was 18%, and the DCR was 65%, with three patients having complete responses. The mPFS was 3.4 months, while the mOS was not reached (31). A study examining the combination of pembrolizumab and carboplatin for recurrent platinum-resistant OC indicated that out of 29 patients, the ORR was 10.3%, the DCR was 62%, the mPFS was 4.63 months, and the mOS was 11.3 months (35). A separate study assessing the efficacy of pembrolizumab in conjunction with bevacizumab and oral cyclophosphamide for recurrent OC indicated an ORR of 47.5%, a DCR of 95%, a mPFS of 3.5 months, and a mOS of 85 months (48). Based on the data presented, it can be found that pembrolizumab is effective in the treatment of advanced or recurrent OC, with its efficacy further improved when used in conjunction with other treatment regimens. The findings of this meta-analysis substantiate the effectiveness of pembrolizumab in the treatment of advanced or recurrent OC.

This study performed subgroup analysis only based on varying PD-L1 statuses and doses, owing to the absence of standardized subgroup classification criteria across studies. The findings indicated that of the 9 studies incorporated in this analysis, 1 study did not assess patients for PD-L1 status (49), 2 studies evaluated a total of 42 patients for PD-L1 status without conducting subgroup analysis based on this status (33, 34), while 6 studies identified 390 PD-L1-positive patients and 199 PD-L1-negative patients, performing subgroup analyses based on PD-L1 status. The ORR in the PD-L1-positive group was 24%, which was marginally higher than the 18% observed in the PD-L1-negative group. However, this difference was not statistically significant (p=0.07>0.05). A systematic meta-analysis examining the efficacy of PD-1 or PD-L1 inhibitors in cancer treatment in relation to PD-L1 expression status demonstrated that treatment outcomes in the PD-L1-positive group were superior to those in the PD-L1-negative group, with the difference being statistically significant (47). This study did not find any significant differences in efficacy between the two groups. The reason for this may be that the data related to PD-L1 status in this study was systematically missing, leading to inconsistent results with other studies. It may also be due to the single-arm clinical trial or the limited number of patients enrolled. Similarly, just as 7T fMRI with T2prep BOLD sequences can detect subtle functional changes in the olfactory bulb and piriform cortex in Parkinson’s disease patients (50), OC research could use more sensitive detection methods to quantify PD-L1 expression. And just as EEG can reveal neurobiological differences between different symptom subtypes of ADHD (51), OC studies could explore multimodal biomarkers to optimize patient stratification. Nevertheless, the implementation of these methods is currently challenging. Furthermore, the implementation of additional high-quality randomized controlled trials is recommended to verify the difference in efficacy between the two groups.

Subgroup analysis results based on different dosing regimens showed that the subgroup receiving 200 mg q3w demonstrated significantly superior outcomes in terms of ORR and mPFS compared to the subgroup receiving 10 mg/kg q2w (p < 0.05). However, no statistically significant difference was observed between the two groups in terms of DCR and mOS (p > 0.05). With regard to the safety assessment, no statistically significant differences were observed in the probability of any grade AEs occurring between the two groups (p > 0.05). However, the probability of occurrence of ≥3-grade AEs was significantly lower in the subgroup receiving a dose of 10 mg/kg q2w compared to the subgroup receiving a dose of 200 mg q3w. The findings indicate that, regarding short-term efficacy, the group administered a dose of 200 mg q3s may outperform the group receiving a dose of 10 mg/kg q2w. In terms of long-term efficacy, no significant difference was observed between the two groups. In the context of severe AEs, individualized dosing may be more advantageous than standardized dosing. Further high-quality RCTs are necessary to validate these findings.

During the course of immunotherapy, ICIs exert their antitumor immunotherapeutic effects by regulating T cell activity. In addition to their direct action against tumor cells, these agents have the potential to induce systemic immune-related adverse events (irAEs) (52). Conventional chemotherapy or radiotherapy has been shown to cause tissue damage that is related to the site of action. The resulting AEs are both fixed and predictable. Conversely, the AEs associated with immunotherapy are distinct, with irAEs being both widespread and unpredictable (53). irAEs can potentially affect all organs and systems in the human body. AEs involving the skin, gastrointestinal tract, endocrine system, respiratory system, and musculoskeletal system are relatively common, as is thyroid dysfunction. However, AEs involving the cardiovascular and pulmonary systems are relatively less common (54). irAEs have been observed to occur within a time frame ranging from a few weeks to several months following the initiation of therapy, with the potential for occurrence after the cessation of treatment also being documented (54). irAEs vary from asymptomatic to severe or life-threatening and are categorized into five grades, from grade 1 to grade 5. Certain immune-related AEs, such as hypothyroidism, may be managed with hormone replacement therapy, eliminating the necessity for corticosteroids (55). Grade 1–2 irAEs are typically addressed through symptomatic treatment, which may involve the use of topical or oral corticosteroids. IrAEs that impact the heart, lungs, liver, or nervous system are more severe and necessitate high-dose intravenous corticosteroids as the initial treatment approach. Grade 3–4 irAEs frequently necessitate hospitalization and are predominantly managed with systemic corticosteroids, either orally or intravenously (56).

The study revealed that the incidence rate of AEs of any grade was 81% in the combined treatment group, which is higher than the 73% observed in the pembrolizumab monotherapy group (47). The high number of AEs is mainly because most studies used combination therapy that included pembrolizumab, like treatments with carboplatin, cyclophosphamide, and bevacizumab. The AEs induced by these drugs during treatment are challenging to differentiate from the irAEs caused by pembrolizumab. Consequently, the incidence of common AEs in the entire study population was relatively high, including fatigue, nausea, vomiting, fever, and hypertension. But pembrolizumab may not be the main cause of these AEs, implying its safety profile may be better than this study’s. The most prevalent irAEs observed in this study were grade 1–2 hypothyroidism and grade 1–2 hyperthyroidism, with incidence rates of 17% and 7%, respectively. The probability of grade ≥3 hypothyroidism and hyperthyroidism was found to be significantly reduced. In the KEYNOTE-100 study, two patient deaths were attributed to AEs related to pembrolizumab treatment, including one case of Stevens-Johnson syndrome and one case of hypoaldosteronism (31). In the LEAP-005 study, one patient died due to treatment-related AEs, specifically hypovolemic shock. We outline the sequence of events that transpired below: Initially, the patient exhibited gastrointestinal symptoms, including nausea and emesis, which were reminiscent of coffee grounds. These symptoms progressed to renal failure, accompanied by lactic acidosis, ultimately resulting in death due to multi-organ failure. After a detailed review by the investigation team, it was found that this death was linked to the use of lenvatinib along with pembrolizumab (36).

The age range of patients included in this meta-analysis was broad (25–89 years), with the median age in each study concentrated between 55 and 65 years. The lack of detailed data from each study precluded subgroup analyses by age, thereby limiting our ability to assess the influence of age on the efficacy and safety of immunotherapy for OC. As the age of the people increases, factors such as chronic viral stimulation, the senescence-associated secretory pattern (SASP) of aging cells, and abnormal immune training collectively mediate inflammatory aging, which is a key risk factor for morbidity and mortality in the elderly (57). The impact of age on the efficacy and safety of tumor immunotherapy is a complex and multifaceted area of research. As demonstrated in extant literature and evidenced by existing research, the impact of age on the efficacy and safety of immunotherapy remains a contentious and complex issue. The two studies included in this meta-analysis with the greatest discrepancy in median age, i.e., Christine’s study (median age 55 years) (34)and John B Liao’s study (median age 65 years) (35), demonstrated no significant difference in mOS results, which is consistent with the results of the EMPOWER-Lung 3 trial (58). However, Jaclyn Sceney’s study yielded contrary results, suggesting that advancing age may reduce the efficacy of immunotherapy (59). Current research findings indicate variability in the impact of age on the safety of immunotherapy. A cohort study conducted by Nebhan CA et al. on monotherapy with immune checkpoint inhibitors in patients aged 80 years and older found no significant difference in the incidence of irAEs among the three groups: patients aged less than 85 years, those aged 85–89 years, and individuals aged 90 years and older (60). Research indicates that the occurrence of severe irAEs in patients aged 80 years and older does not show a significant increase; however, the associated mortality risk from these adverse reactions warrants careful consideration (61).

This meta-analysis, based entirely on single-arm studies, significantly increased the levels of heterogeneity and publication bias in this research. A single-arm trial constitutes a clinical trial design in which a single experimental group is established, devoid of a parallel control group. The study primarily compares results with external controls, such as historical data or target values, and does not adhere to the principles of randomization and blinding (62). Single-arm trials are predominantly utilized in the initial phases of drug development, especially during the exploratory stage of efficacy evaluation for cancer and rare diseases. Recently, there has been a rise in the application of single-arm trials in clinical settings, with several high-quality results being integrated into clinical guidelines or utilized as evidence for drug approval (62, 63). Single-arm clinical trials possess specific limitations. The lack of a control group limits the interpretation of results to the intervention measures, consequently diminishing the reliability of the evidence. Comparing with external historical data is the sole option due to the absence of parallel controls. The variations among these studies complicate evaluation and may introduce bias, thereby impacting the accuracy of efficacy and safety assessments (64). Thus, there are certain restrictions on this meta-analysis, which is based on single-arm clinical studies. Moreover, the study predominantly comprised patients from middle- and high-income countries, including the United States, China, and France. However, data from regions such as Africa and Latin America are lacking, which has a consequential effect on the representativeness of the global landscape of patients with advanced/recurrent OC. The present study documented a mOS of 13.54 months. However, it should be noted that only five studies furnished complete mOS data, and the longest follow-up duration did not surpass 21.3 months. However, there is a paucity of long-term survival data, with a maximum follow-up period of two years. Moreover, pivotal clinical concerns, such as the mechanisms of resistance to pembrolizumab and the modifications to treatment protocols following such resistance, remained unaddressed, impeding the provision of guidance for long-term treatment strategies. It is evident that further clinical trials and fundamental research are required in a range of regions in order to investigate the efficacy and safety of pembrolizumab in the treatment of OC.

Due to the limitations of this study, future large-scale prospective RCTs are necessary to validate the efficacy and safety of pembrolizumab for treating advanced or recurrent OC. The differences in efficacy among various combination therapy regimens and subgroups categorized by distinct criteria warrant further exploration. The drug’s mechanism of action and the factors contributing to AEs necessitate further investigation to improve the efficacy and safety of pembrolizumab in treating advanced or recurrent OC.

In summary, this meta-analysis demonstrates that treatment with pembrolizumab for advanced or recurrent OC significantly improves objective ORR and DCR and prolongs survival. Despite the occurrence of treatment-related AEs in a proportion of patients, these events are generally manageable. However, due to the limited clinical data available, the need for large-scale, multicenter, prospective RCTs in the future is evident, with the objective of validating the efficacy and safety of the treatment.