Pembrolizumab and Sarcoma: A meta-analysis

Abstract Introduction: Pembrolizumab is a monoclonal antibody that promotes antitumor immunity. This study presents a systematic review and meta-analysis of the efficacy and safety profile of this treatment as monotherapy or in combination with other drugs for the treatment of sarcomas. Methods: A literature search was conducted across Google Scholar, PubMed/MEDLINE, and EMBASE from February 15th to April 15th. Eligible studies were clinical trials that reported efficacy or outcomes of pembrolizumab in sarcoma patients, either alone or in combination with other drugs. In contrast, those lacking sufficient data or not meeting trial criteria were excluded. Results: Ten clinical trials met the eligibility criteria, including 419 sarcoma patients (53.7% male; median age 55.4). Pembrolizumab was administered either as monotherapy in 23% of cases or in combination with other agents in 77% of cases. The progressive disease rate was 83% with monotherapy and 36% with combination therapy. Objective response rates varied, with the highest observed in the pembrolizumab plus talimogene laherparepvec combination (35%) and the lowest in pembrolizumab monotherapy (ranging from 0% to 11.2%). Median progression-free survival ranged from 1.4 (Pembrolizumab + Cyclophosphamide) to 7.8 months (Pembrolizumab + Lenvatinib in undifferentiated pleomorphic sarcoma). Combination therapy was associated with significantly better tumor response (<0.001). However, rates of endocrine, gastrointestinal, some hepatic, and dermatological adverse events were significantly associated with combination therapy compared to monotherapy (p < 0.05). Conclusion: Pembrolizumab-based combination therapies have the potential to enhance treatment efficacy in sarcoma, although they may be associated with an increased risk of adverse events. Introduction Sarcomas are rare tumors that develop from mesenchymal tissue and are known for their diverse histological subtypes. Although they are uncommon, they carry particular clinical significance due to their relatively higher incidence in adolescents and young adults. The primary treatment is surgical resection, often combined with chemotherapy or radiotherapy, either before (neoadjuvant) or after (adjuvant) surgery, depending on the specific subtype [1]. Immunotherapy has introduced a breakthrough in cancer treatment. Unlike traditional approaches such as chemotherapy and radiation, which can harm healthy cells and lead to significant side effects, immunotherapy takes a more targeted and refined approach. It helps the body’s immune system recognize and attack cancer cells, offering a potentially more effective and less toxic alternative [2]. Cancer immunotherapy includes a variety of treatment methods, such as immune checkpoint inhibitors, adoptive cell transfer, cytokine therapies, and cancer vaccines [3]. What sets immunotherapy apart is its ability to produce long-lasting effects, sometimes leading to extended remission or even complete disappearance of the disease in some patients [4]. In addition, immunotherapy is often better tolerated than traditional treatments, since it tends to focus more precisely on cancer cells while causing less harm to healthy tissues [2]. Pembrolizumab is a monoclonal antibody that targets the programmed cell death protein 1 (PD-1) receptor, blocking its interaction with the ligands PD-L1 and PD-L2, which are often expressed by tumor cells. By interrupting this pathway, pembrolizumab removes a key mechanism of immune suppression, allowing cytotoxic T cells to become more active and better able to attack cancer cells [5]. PD-1 is an immune checkpoint receptor found on activated T cells. When it binds to PD-L1 or PD-L2, it downregulates immune activity by inhibiting T-cell function and helping tumor cells avoid destruction. Research has shown that tumors often increase PD-L1 expression as a strategy to escape immune detection, weakening the body’s ability to fight cancer [6]. Despite significant research, sarcomas remain difficult to treat effectively. Soft tissue sarcomas, in particular, have a 5-year survival rate of only about 65%, highlighting the ongoing need for more effective therapeutic options [1]. Pembrolizumab has shown durable antitumor activity across several solid tumor types, along with a generally favorable safety and tolerability profile [7]. This systematic review and meta-analysis aims to assess the antitumor efficacy and safety of pembrolizumab, both as a standalone therapy and in combination with other agents, in treating different types of sarcomas through a systematic review and meta-analysis of clinical trials. Only data from peer-reviewed sources were included, ensuring the reliability of the data [8]. Methods Study design The study is a systematic review and meta-analysis encompassing clinical trials assessing the effectiveness of pembrolizumab in treating sarcomas. It encompasses trials where pembrolizumab is used alone as well as in combination with other treatments. The drug combinations were as follows: group A (Pembrolizumab + Doxorubicin), group B (Pembrolizumab + Axitinib), group C (Pembrolizumab + Eribulin), group D (Pembrolizumab + Talimogene Laherparepvec), group E (Pembrolizumab + Epacadostat), group F (Pembrolizumab + Olaratumab), group G (Pembrolizumab + Levatinib), and group H (Pembrolizumab + Cyclophosphamide). The search process was conducted from February 15th to April 15th 2025, in full compliance with the PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Data sources and search strategy A thorough search was performed using Google Scholar, PubMed/MEDLINE, and EMBASE. A set of keywords was utilized to retrieve pertinent studies, specifically: (anti-PD-1; PD-1 inhibitor; Keytruda; MK-3475; Lambrolizumab; Pembrolizumab; Sarcoma; Sarcomas; Spindle cell sarcoma; Spindle cell sarcomas). Eligibility criteria Eligible studies consisted of clinical trials evaluating the efficacy of pembrolizumab in treating sarcomas, either as a standalone therapy or in combination with other treatments. Studies were excluded if they were not clinical trials, did not investigate pembrolizumab for sarcoma treatment, or failed to provide adequate data on treatment efficacy or patient outcomes. Study selection process The study selection process was conducted independently by two researchers who carefully screened the titles and abstracts of all identified studies. Each study was assessed based on the predefined inclusion and exclusion criteria. In instances of disagreement regarding a study’s eligibility, a third researcher was consulted to resolve the conflict and reach a consensus. Data items Data extracted from the eligible studies encompassed a wide range of information, including the first author’s name, year of publication, trial phase, sarcoma subtype, number of enrolled patients, sex distribution, treatment regimen, median patient age, reported adverse events, and various clinical outcome measures, including progression-free survival, overall survival, complete response, partial response, stable disease and progressive disease. Data analysis and synthesis The extracted data were organized using Microsoft Excel (2019) and analyzed with SPSS version 25.0 (IBM Corp.). Descriptive statistics were reported as frequencies, percentages, medians, and ranges. Categorical variables were compared using the Chi-square or Fisher's exact test, as appropriate. Continuous variables, including overall survival and progression-free survival (PFS), were analyzed using the non-parametric Mann-Whitney U test. Results Study selection process and eligibility criteria A total of 103 records were initially identified through the search process. Among these, 42 were excluded because they were unretrievable, two were removed as duplicates, and one was excluded for not qualifying as a full research article. Then, the titles and abstracts of the remaining 58 studies were screened, resulting in the exclusion of 20 records that were deemed irrelevant. After that, 38 studies underwent full-text screening, of which 27 were excluded based on exclusion criteria. Subsequently, 11 studies were assessed for eligibility, and one was excluded because it did not provide complete data. In the end, 10 studies were included for final review and analysis (Figure 1) [7, 9-17]. Characteristics of included trials All the studies included were clinical trials, consisting of eight Phase II trials, one Phase I trial, and one study that encompassed both Phase I and II designs. The raw data, along with key characteristics of each study, are summarized in Tables 1, 2, and 3. Analysis of progressive disease rates in sarcoma patients treated with pembrolizumab monotherapy, based on two studies, revealed an overall rate of 83% (95% CI: 26%–100%). In contrast, a meta-analysis of patients receiving pembrolizumab in combination with other therapeutic agents showed a substantially lower progressive disease rate of 36% (95% CI: 23%–51%) (Figure 2). Table 1. Baseline characteristics of clinical trials evaluating pembrolizumab and combination therapies for sarcoma First Author /Year [reference] Trial Phase Type of sarcoma Therapy regimens No. of patients Sex Median Age Male Female Pollack et al,2020 [10] I/II Soft tissue sarcoma Pembrolizumab 200mg/q3w(IV) Doxorubicin 45-75mg 37 22 15 58.4 Wilky et al, 2019 [11] II Soft tissue sarcoma Pembrolizumab 200mg/q3w (IV) Axitinib 5mg (Orally) 33 18 15 44 Tawbi et al,2017 [9] II Soft tissue sarcoma + Osteosarcoma Pembrolizumab 200mg/q3w (IV) 84 53 31 53a/ 33b Haddox et al,2024 [17] II Soft tissue sarcoma Pembrolizumab 200mg/q3w(IV) Eribulin 1.4mg/m2 (iv) 57 24 33 60.4* Kelly et al,2020 [13] II Soft tissue sarcoma Pembrolizumab 200mg/q3w(IV) Talimogene Laherparepvec ≤4ml×102 (intratumourally) 20 12 8