Malignant pleural mesothelioma is an infrequent and aggressive type of cancer that is difficult to treat, and standard therapies have shown limited effectiveness. There have been recent advances in the development of targeted therapies for malignant pleural mesothelioma, including immunotherapy with pembrolizumab. This is a systematic review of the current role of pembrolizumab in the treatment of this disease. A systematic search was conducted through the databases and search engines. The eligible studies to be included were those that primarily focused on the outcomes of treating this disease with pembrolizumab, regardless of study design, line of therapy, mode of therapy, and ECOG performance status. After the initial and full-text screenings, 15 studies were reviewed. The number of cases was 454 with a mean age of 68.13 years, of which males (79.7%) were the predominant gender. Most of the cases were affected by epithelioid mesothelioma (76.7%). Pembrolizumab had been used as the first line of treatment in 62 (13.7%) cases. In 92.73% of cases, the therapy mode was pembrolizumab monotherapy. A total of 68 different adverse events were recorded. The most commonly associated adverse events were fatigue (14.8%), pruritis/rash (13.7%), and diarrhea (9.7%). Two patients died due to adverse events. The overall objective response was 17.8%, stable disease was 35.7%, progression-free survival was about 47.6% with a mean of 4.73 months, and 117 cases (25.8%) could reach treatment-related survival. Pembrolizumab can serve as a viable alternative in the management of malignant pleural mesothelioma, offering satisfactory outcomes and acceptable safety profiles
Pembrolizumab, malignant mesothelioma, pleural cancer, pulmonary cancer immunotherapy, PD-1 inhibitor, PD-L1 inhibitor.
Pembrolizumab is a monoclonal antibody that targets the programmed death-1 (PD-1) receptor on T cells and is used in the treatment of various types of cancer . PD-1 is a key immune checkpoint that plays a critical role in regulating the immune response and preventing autoimmunity. However, cancer cells can hijack this pathway and use it to evade the immune system. Pembrolizumab blocks the PD-1 receptor, enabling T cells to recognize and attack cancer cells [1,2]. Pembrolizumab has been approved for use in several types of cancer, including melanoma, head, and neck squamous cell carcinoma, urothelial carcinoma, classical Hodgkin's lymphoma, non-small cell lung cancer, and gastric cancer. It has also shown promising results in clinical trials for the treatment of other cancer types, such as hepatocellular carcinoma and renal cell carcinoma [3-10]. Malignant pleural mesothelioma (MPM) is an infrequent and aggressive type of cancer that emerges in the lining of the lungs (pleura) and is primarily caused by exposure to asbestos . Symptoms of MPM can include chest pain, shortness of breath, persistent coughing, and fatigue, but these can often be mistaken for other respiratory illnesses. The MPM is often not diagnosed until it has reached an advanced stage. Unfortunately, MPM is notoriously difficult to treat, and standard therapies such as surgery, radiation, and chemotherapy have shown limited effectiveness [1,12-14]. Despite these challenges, there have been recent advances in the development of targeted therapies for MPM, including immunotherapy with pembrolizumab [1,2].
The aim of this study is to review the current role of pembrolizumab in the treatment of MPM.
2.1 Study design
This study was a comprehensive review of the studies focusing on the treatment of MPM with anti-PD-1 pembrolizumab.
2.2. Data sources and search strategy
A systematic search was conducted in eligible databases and search engines like Web of Science, PubMed/MEDLINE, EMBASE, Science Direct, CINAHL, the Cochrane Library, and Google Scholar. The search keywords were (pembrolizumab OR Keytruda OR MK-3475 OR lambrolizumab OR anti-PD-1 OR PD-1 inhibitor) AND (pleura OR pleural OR pleurae) AND (mesothelioma OR asbestos cancer OR cancer OR carcinoma OR tumor OR tumors OR cancers OR malignancy OR malignancies OR neoplasm OR malignance OR cancerous OR mesothelium).
2.3. Eligibility criteria
The eligible studies to be included were those that primarily focused on the outcomes of treating MPM with pembrolizumab, regardless of study design, line of therapy, mode of therapy (either monotherapy or combination), and ECOG performance status. Studies that had only abstracts available, pre-prints and non-pleural mesothelioma were not included. All studies’ publishers were assessed for reliability (fully peer-reviewed) using Kscien’s List . A total of 54 studies were found in the search, of which 28 were excluded prior to the initial screening (only abstract = 15, duplicate = 11, non-article = 2). After the initial and full-text screenings, 15 studies remained eligible (Figure 1) [1,14,16-28].
Figure 1. Study selection PRISMA flow chart.
2.4. Study selection and data items
Several authors initially screened the titles and abstracts of the identified studies. Subsequently, they conducted a full-text screening to assess whether the studies met the inclusion criteria. Two independent authors evaluated the study's quality. In case of any discrepancies, a third author intervened to resolve them.
The variables extracted from the studies included the study design, number of cases, demographics, histological subtypes of mesothelioma, treatment lines, and modes, previous treatment, doses, and modes of administration, adverse events, treatment interruption due to adverse events, death due to adverse events, objective response (OR), progression-free survival (PFS), stable disease (SD), and overall survival (OS).
2.5. Statistical analysis
The Statistical Package for the Social Sciences software (version 25) was utilized to analyze the data qualitatively (descriptive analysis). The data were represented as frequencies, mean, and percentages.
The review included 15 publications: one randomized controlled trial, three non-randomized controlled trials, two cohort studies, two case series, and seven case reports. The total number of cases was 454 with a mean age of 68.13 years (calculated as the mean of means), of which males (79.7%) were the predominant gender (Tables 1 and 2). Most of the cases were affected by epithelioid mesothelioma (76.7%), followed by sarcomatoid mesothelioma (7.9%). Regarding the previous treatment prior to pembrolizumab, platinum pemetrexed was more commonly used (28.2%), followed by carboplatin/pemetrexed (25.3%), and cisplatin/pemetrexed (20.5%). Pembrolizumab was used as the first line of treatment in only 62 (13.7%) cases. In 92.73% of cases, the therapy mode was pembrolizumab monotherapy. The second frequent mode was a combination of pembrolizumab and nintedanib (Table 2). A total of 68 different adverse events were recorded. The most commonly associated adverse events were fatigue (14.8%), pruritis/rash (13.7%), and diarrhea (9.7%) (Table 3). Adverse events caused temporary and permanent treatment interruptions equally (4.6%). Only two cases (0.4%) died due to the adverse events; one due to dyspnea, lung infiltration, and worsening pleural effusion, and the other due to cardiopathy. An OR was achieved in 17.8% of the patients (partial = 16.7%, complete = 1.1%), and SD was noticed in 35.7% of cases. In addition, PFS was about 47.6% with a mean of 4.73 months, and 117 cases (25.8%) could reach treatment-related survival (Table 4).
Table 1: The general characteristics of the studies on the treatment of MPM with pembrolizumab.
|Author||Study design||No. of case(s)||Gender||Age||Histological subtype||Therapy Mode|
|Popat et al15||RCT||73||58||15||67.7*||0||66||0||0/7||Monotherapy|
|Alley et al1||NRCT||25||17||8||65*||2||18||2||0/3||Monotherapy|
|Danlos et al16||NRCT||30||20||10||69*||4||25||1||0||Combination|
|Yap et al17||NRCT||118||85||33||68*||9||82||10||0/17||Monotherapy|
|Metaxas et al18||Cohort||93||85||8||68*||0||67||15||10/1||Monotherapy|
|Ahmadzada et al14||Cohort||95||87||8||70*||8||74||8||0/5||Monotherapy|
|Shalata et al19||Case series||1||0||1||50||0||1||0||0||Combination|
|Zhou et al20||Case series||12||5||7||71**||0||11||0||1/0||Monotherapy|
|Bickel et al21||Case report||1||1||0||62||1||0||0||0||Monotherapy|
|Hearon et al22||Case report||1||1||0||66||0||1||0||0||Monotherapy|
|Mampuya et al23||Case report||1||1||0||72||0||0||0||0/1||Combination|
|Minchom et al 24||Case report||1||0||1||77||0||1||0||0||Monotherapy|
|Rittberg et al25||Case report||1||1||0||68||0||1||0||0||Combination|
|Baldauf et al26||Case report||1||0||1||61||0||0||0||0/1||Monotherapy|
|Schiopu et al27||Case report||1||1||0||75||0||1||0||0||Monotherapy|
RCT: Randomized controlled trial
NRCT: Non- Randomized controlled trial
Table 2: The baseline characteristics of the cases treated with pembrolizumab
|Variables||No. Cases/ frequency|
|Age (mean of means)||68.13 yrs.|
|Histological subtypes of mesothelioma|
|Biphasic (Mixed)||35 (7.7%)|
|Platinum pemetrexed||128 (28.2%)|
|Cisplatin/pemetrexed and carboplatin/pemetrexed||8 (2%)|
|Platinum gemcitabine||4 (0.9%)|
|Carboplatin/Pemetrexed + Bevacizumab||4 (0.9%)|
|Cisplatin/pemetrexed + durvalumab||1 (0.2%)|
|CB 839 glutaminase inhibitor||1 (0.2%)|
|Therapy line of pembrolizumab|
|Dose and mode of administration|
|200 mg, Q3W||323 (71.14%)|
|10 mg, Q2W||26 (5.72%)|
|Varying dose, Q2W and Q3W||93 (20.5%)|
|Combination with nintedanib||30 (6.61%)|
|Combination with radiotherapy||2 (0.44%)|
|Combination with lenvatinib + gemcitabine +Ipilimumab||1 (0.22%)|
Table 3: The adverse events of the treatment with pembrolizumab
|Adverse events||No. Cases/ frequency|
|Pruritis/ rash||62 (13.7%)|
|Loss of appetite||24 (5.3%)|
|Dry skin||12 (2.6%)|
|Rash maculopapular||11 (2.4%)|
|CNS+PNS* disorder||7 (1.5%)|
|Nephrotic syndrome||6 (1.3%)|
|Dry mouth||5 (1.1%)|
|Cardiac disorder||4 (0.9%)|
|Aspartate aminotransferase increased||4 (0.9%)|
|Alanine aminotransferase increased||4 (0.9%)|
|Lipase increased||4 (0.9%)|
|Creatine Phosphokinase increased||3 (0.7%)|
|Weight loss||3 (0.7%)|
|Musculoskeletal stiffness||3 (0.7%)|
|Gamma-glutamyl Transferase (GGT) increased||3 (0.7%)|
|Chest pain||2 (0.4%)|
|Mucosal inflammation||2 (0.4%)|
|Myasthenia Gravis||2 (0.4%)|
|Abnormal thyroid function test||2 (0.4%)|
|Creatinine increased||1 (0.2%)|
|White blood cell count decreased||1 (0.2%)|
|Vitreous floaters||1 (0.2%)|
|Pleuritic pain||1 (0.2%)|
|Platelet count decreased||1 (0.2%)|
|Neutrophil count decreased||1 (0.2%)|
|Infusion-related reaction||1 (0.2%)|
|Haemoglobin decreased||1 (0.2%)|
|Cancer pain||1 (0.2%)|
|Blood alkaline phosphatase increased||1 (0.2%)|
|Balance disorder||1 (0.2%)|
|Lung infiltration||1 (0.2%)|
|Worsening pleural effusion||1 (0.2%)|
|Diabetes mellitus||1 (0.2%)|
|Minimal change disease||1 (0.2%)|
|Nonsystemic vasculitic mononeuritis multiplex (NSVM)||1 (0.2%)|
*CNS+PNS: central nervous system and peripheral nervous system.
Table 4: The outcomes of treating cases of MPM with pembrolizumab
|Variables||No. Cases/ frequency|
|Treatment interruption due to adverse events|
|Death due to adverse events|
|Dyspnea, lung infiltration and worsening pleural effusion||1 (0.2%)|
|Cardiopathy resulting in thrombosis and mesenteric ischemia||1 (0.2%)|
|Partial response||76 (16.7%)|
|Complete response||5 (1.1%)|
|Stable disease||162 (35.7%)|
|Progression-free survival||216 (47.6%)|
|Mean and median duration of progression-free survival (Min-Max)||4.73 and 4.8 months (2.1 – 9)|
|Overall survival (cases alive till the end of the study)||117 (25.8%)|
The MPM is a cancer form that develops in the pleural serous membrane lining due to long-term exposure to environmental silicate minerals like asbestos. Persistent exposure to asbestos microparticles causes inflammation, inflammatory macrophage recruitment, formation of an immunosuppressive protumoral microenvironment, and pathological neoangiogenesis with hypoxia. It ultimately transforms serous cells into an aggressive phenotype, leading to the development of metastatic disease . The disease can be categorized into three histological subtypes: epithelioid, sarcomatoid, and mixed (biphasic). The epithelioid subtype is associated with a better prognosis and a better response to treatment, affecting approximately 50–60% of patients. On the other hand, the sarcomatoid subtype has a lower probability of responding to therapy and occurs in about 20% of patients. Furthermore, several remarkable predictors are linked to improved survival in mesothelioma, including female gender, being under 45 years old, undergoing a combination of chemotherapy and radiation therapy in addition to surgery, and having no history of smoking .
The MPM is commonly diagnosed at an advanced stage, making it challenging to effectively treat. Common treatment approaches including surgery, radiation, and chemotherapy have demonstrated limited efficacy in managing the disease [1,12-14]. At present, the FDA has exclusively approved the cisplatin/pemetrexed combination regimen as the primary treatment option for MPM . In a phase III trial comparing pemetrexed/cisplatin to cisplatin alone, the pemetrexed/cisplatin arm exhibited a superior median OS of 12.1 months, whereas the cisplatin arm demonstrated a median OS of 9.3 months .
In patients with MPM, angiogenesis inhibitors like bevacizumab have also indicated anti-tumor activity. In a phase III trial evaluating the use of bevacizumab for unresectable MPM, the cisplatin/pemetrexed/bevacizumab treatment group showed a median OS of 18.8 months in comparison to the cisplatin/pemetrexed group, which yielded a median OS of 16.1 months . Even though the utilization of this treatment was linked to a substantial level of toxicity, among the individuals who received bevacizumab, 71% reported experiencing grade 3–4 adverse events, whereas the percentage was 62% for those who did not receive bevacizumab . In a randomized phase II trial, Nintedanib, an oral triple receptor tyrosine kinase inhibitor, showed notable efficacy when used in combination with chemotherapy for treating MPM . However, this positive outcome could not be replicated in a later phase III trial . By reviewing the included studies in this systematic review, it was found that the mean age of the patients was 68.13 years, with a predilection towards males. The epithelioid subtype accounted for the majority (76.7%) of histologic subtypes, while the sarcomatoid subtype constituted approximately 7.9%. These findings revealed a higher percentage of epithelioid and a lower percentage of sarcomatoid subtypes compared to a previous study that reported epithelioid to be around 50-60% and sarcomatoid to be approximately 20% . Over 86% of the patients in this review had previously undergone various treatment regimens without achieving satisfactory outcomes. Among them, the most commonly administered regimen was platinum pemetrexed, which was received by 28.2% of the patients. This was followed by carboplatin/pemetrexed (25.3%) and cisplatin/pemetrexed (20.5%). Only 13.7% of the cases had been directly treated with pembrolizumab, highlighting the need for further studies to investigate the efficacy of this treatment as a first-line therapy for patients with MPM.
Despite all of that, there are currently no approved treatments available for patients with relapsed MPM after being treated with standard first-line therapy . Gemcitabine and vinorelbine are often considered potential second-line treatment options. Recently, the use of immune checkpoint inhibitors (ICI) has gained interest as a promising approach for managing MPM . The introduction of ICI has revolutionized the treatment approach for patients with metastatic cancer. However, it is important to acknowledge that only a minority of patients with different tumor types show a positive response to these therapies. Investigating PD-L1 inhibitors in MPM has shown overall response rates (ORR) ranging from 10% to 29%. Ongoing endeavors are focused on improving therapeutic outcomes by synergistically combining immunotherapy with classic oncological interventions such as chemotherapy, radiotherapy, and anti-angiogenic therapy .
PD-1 is a complex protein found on activated T lymphocytes that functions as an inhibitory receptor. When tumor cells express the corresponding ligands, known as PD-L1, and engage with these receptors, it causes the suppression of tumor-specific T effector cells, permitting the tumor to evade immune detection. By binding to PD-1, pembrolizumab, a humanized IgG4 antibody, disrupts the inhibitory interaction between T cells and the tumor microenvironment (TME) at this specific immune checkpoint. This blockade leads to an enhancement of the immune response against the tumor, facilitating a more potent antitumor reaction by T cells [22,23]. Compared to the standard burdensome nine-month trimodal regimen with its potential for severe complications, the use of this ICI as the primary treatment option appeared preferable to both the physician and the patient. Furthermore, the positive response of MPM to pembrolizumab persisted even after discontinuation of the drug, as previously observed in patients with melanoma .
Previous clinical studies have provided evidence supporting the effectiveness and safety of pembrolizumab in individuals with advanced MPM, particularly those who have undergone prior chemotherapy without experiencing improvement [1,18,19]. In the KEYNOTE-028 phase Ib trial conducted by Alley et al., it was observed that out of 25 patients with PD-L1-positive MPM who had previously not responded to standard therapy, five individuals achieved a partial metabolic response (PMR) when treated with pembrolizumab. Furthermore, 13 patients (52%) experienced stable disease and an overall disease control rate (DCR) of 72% with a median PFS of 5.4 months was achieved . In a study conducted by Metaxas et al., a group of 93 patients with MPM who received palliative treatment with pembrolizumab as a first-line or second-line therapy was examined. Among the included cases, 16 individuals (17.2%) achieved a PMR, and one patient (1%) achieved a complete metabolic response, resulting in an ORR of 18% with a median PFS of 3.1 months . Desai et al. conducted a phase II trial evaluating pembrolizumab in a population of 65 patients with malignant mesothelioma, including 56 individuals with pleural involvement, who had experienced disease progression after platinum/pemetrexed chemotherapy. The results showed that 19% of the cases achieved a PMR, and 47% had stable disease, with a DCR of 66% .
Another study showed that the combined administration of pembrolizumab and radiotherapy can result in a favorable response in cases of MPM . In a case managed by Mampuya et al., following an initial partial response to pembrolizumab, the patient experienced disease progression in the right mediastinum and pleura after one year. While pembrolizumab treatment was ongoing, palliative radiotherapy was administered to the mediastinum. Remarkably, the patient exhibited a systemic abscopal response in the non-irradiated pleural areas. The authors considered the observed response to be an abscopal effect, as it occurred following disease progression despite 20 cycles of pembrolizumab. This suggested that radiotherapy triggered a systemic immune response. The upregulation of PD-L1 induced by radiation was mediated through the increased production of IFNc by T cells that infiltrated the TME after radiotherapy. Consequently, this caused the expression of PD-L1 on tumor cells. Thus, the concurrent application of radiotherapy and an anti-PD-L1 antibody might have circumvented tumor T-cell exhaustion, ultimately enhancing the potential for an effective immune response against the tumor . The combination of pembrolizumab (200 mg every three weeks (Q3W)) and nintedanib (150 mg) has also shown remarkable antitumor activity and manageable toxicity in MPM cases who have not received prior immunotherapy and have been refractory to platinum-based chemotherapy as the first-line treatment .
Another study suggested that the administration of pembrolizumab as monotherapy in MPM patients was deemed safe. Nonetheless, the authors mentioned that not all patients could get benefit from this therapeutic approach . This assumption aligns with the outcomes of phase III prospective randomized PROMISE-Meso trial . The results of the trial demonstrated that there was no improvement in PFS when using pembrolizumab compared to chemotherapy in patients with MPM. In the trial, 144 patients with relapsed MPM were randomly assigned in a 1:1 ratio. One group received a fixed dose of 200 mg pembrolizumab intravenously (Q3W) (n=73), while the other group received chemotherapy, which consisted of gemcitabine (1000 mg/m2 - Q3W), vinorelbine (30 mg/m2- Q3W), or vinorelbine (60 or 80 mg/m2 - Q3W) (n=71). The PFS was 2.5 months for the pembrolizumab group, whereas it was 3.4 months for the chemotherapy group. In addition, the grade 3 treatment-related adverse events were similar for both groups .
Out of the studies reviewed in this review, pembrolizumab monotherapy was the predominant therapy mode. However, a combination of pembrolizumab and nintedanib was utilized in 30 cases, pembrolizumab with radiotherapy in 2 cases, and pembrolizumab in combination with lenvatinib, gemcitabine, and ipilimumab in one case, respectively. The effectiveness of these combination therapies in treating MPM seems to demand further investigation, particularly through trials with larger sample sizes. The most common associated adverse events were fatigue, pruritus/rash, and diarrhea. Unfortunately, we were unable to classify the adverse events precisely based on their grades, as the grades were not specified in all studies. Treatment interruptions due to adverse events in the management with pembrolizumab were found to occur in 9.2% of cases, with 4.6% of those interruptions being permanent due to the high grade of the adverse events. Among the adverse events, two cases resulted in fatalities. One case involved dyspnea, lung infiltration, and worsening pleural effusion, while the other involved cardiopathy leading to thrombosis and mesenteric ischemia. This systematic review showed that the overall OR of MPM to pembrolizumab was 17.8%, with 16.7% partial and 1.1% complete responses. Stable disease, PFS, and OS were achieved in 35.7%, 47.6%, and 25.8%, respectively. The median duration of PFS was 4.8 months.
Considering the relatively underwhelming results of the PROMISE-Meso trial , two general strategies have been proposed to enhance patient outcomes. The first approach entails combining PD-1 or PD-L1 inhibition with other treatment modalities with the aim of augmenting the efficacy of the overall therapeutic approach. Positive outcomes were observed in both mesothelioma and other tumor types when immunotherapy was combined with chemotherapy or when different ICIs were targeted in combination. . The second strategy involves identifying individuals who are more likely to benefit from immunotherapy as a standalone treatment. In MPM cases, the expression of PD-L1 has been proposed as an unfavorable prognostic biomarker, particularly in the nonepithelioid subtype . In contrast, patients with strong PD-L1 expression (≥50%) have shown a noteworthy association with a higher ORR (44%) and an increased DCR (89%) . Other scholars also confirmed that patients who had a PD-L1 tumor proportion score of ≥ 1% demonstrated a greater likelihood of responding positively to pembrolizumab treatment. Moreover, these individuals tended to experience prolonged PFS and OS when compared to those who did not show PD-L1 staining [14,36]. Alley et al. reported that pembrolizumab demonstrated notable clinical effectiveness in patients with PD-L1-positive MPM. Moreover, the treatment exhibited a manageable toxicity and safety profile, as evidenced by the absence of treatment-related mortality and no discontinuations caused by treatment-related adverse events . However, it is worth noting that responses to pembrolizumab have also been observed in MPM patients, regardless of their PD-L1 status. The findings of the Yap et al. study have shown antitumor activity in both positive and negative PD-L1 MPM patients . Currently, no definitive correlation has been established between PD-L1 expression and the response to immunotherapy involving PD-1 or PD-L1 checkpoint blockade in MPM . A study discussed that the most favorable prognostic biomarker during and after treatment for MPM was a significant reduction in tumor FDG avidity on interim positron emission-computed tomography scans. This reduction has been demonstrated to correlate with improved PFS and OS in MPM patients who received non-surgical treatment . Given the heterogeneity of the included studies, variations in study designs, and the use of different detection methods, it was not possible for us to draw any conclusions regarding the role of PD-L1 expression as a biomarker in determining the effectiveness of MPM.
Pembrolizumab can serve as a viable alternative in the treatment of MPM, offering satisfactory outcomes and acceptable safety profiles. However, there is a need for further research to identify biomarkers that can predict treatment efficacy in MPM, and investigations are necessary to explore the optimal utilization of pembrolizumab, whether as a monotherapy or in combination with other treatments, to enhance patient outcomes in MPM management.
6.1 Conflicts of interest
The author(s) have no conflicts of interest to disclose.
6.2. Ethical approval
Not applicable, as systematic review do not require ethical approval.
6.3. Patient consent (participation and publication)
6.4. Funding sources
The current study did not receive any funding
None to be declared
6.6 Authors' contributions
BAA, HMR and HMH participated in data collection; FHK designed the study; RQS performed the data analysis; MNS, SJH participated in preparing the manuscript; BHA, SFA and RMA critically revised the manuscript; FHK, HOA confirmed the authenticity of the data; all authors approved the final version of the manuscript.
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