Real-world outcomes of first-line immunotherapy and subsequent systemic therapies in pleural mesothelioma: a multicenter study in China

Introduction

Background

Pleural mesothelioma (PM) is a rare and aggressive malignancy strongly associated with asbestos exposure, characterized by poor prognosis and marked biological heterogeneity (1,2). Before the advent of immunotherapy, systemic treatment primarily relied on platinum plus pemetrexed as the standard first-line regimen; however, survival benefits remained modest. The addition of bevacizumab to this backbone conferred only a small improvement in overall survival (OS) at the cost of increased toxicity and has not been universally adopted as a standard of care (3,4).

Recent pivotal trials have demonstrated that dual immune checkpoint blockade with nivolumab and ipilimumab significantly prolongs OS compared with chemotherapy in the first-line setting, with the greatest benefit observed in patients with non-epithelioid histology (5,6). These findings have reshaped the frontline treatment landscape for PM. In the relapsed or second-line setting, nivolumab has also been shown to improve survival over placebo (7), while several randomized trials have investigated chemo-immunotherapy as an alternative first-line strategy (8-11).

Rationale and knowledge gap

Despite these advances, several key questions remain unresolved. First, real-world patients often differ from those enrolled in clinical trials in terms of Eastern Cooperative Oncology Group (ECOG) performance status (PS), prior radiotherapy, and tumor burden, making the generalizability of first-line immunotherapy uncertain. Second, there is a paucity of comparative evidence among different second-line regimens following failure of first-line chemotherapy. Third, data on systemic treatment pathways after first-line immunotherapy failure are scarce. In particular, multicenter real-world data from China are limited regarding which patients derive the greatest benefit from first-line immunotherapy and how to optimize Subsequent Therapies according to prior treatment.

Objective

Therefore, this multicenter retrospective real-world study aimed to compare OS and progression-free survival (PFS) between first-line immunotherapy and chemotherapy ± targeted therapy in patients with PM. Furthermore, within chemotherapy-start and immunotherapy-start populations, we assessed OS across three second-line strategies—chemotherapy, chemo-immunotherapy, and dual immunotherapy—to characterize real-world treatment patterns from first-line through subsequent therapies and to provide evidence for identifying immunotherapy-benefiting subgroups and optimizing second-line treatment strategies. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1347/rc).

Methods

Study design and setting

This was a multicenter, retrospective, real-world cohort study designed to evaluate the effectiveness and survival outcomes of first-line and subsequent systemic therapies in patients with PM. Data were obtained from the electronic medical records, imaging archives, and follow-up systems of several tertiary hospitals across China and were analyzed according to a pre-specified statistical analysis plan. All cases were fully de-identified prior to analysis. Follow-up was ascertained from electronic medical records and hospital follow-up systems; patients without documented death were censored at the date of last contact, and overall follow-up was censored on 1^st November 2025, with the median follow-up duration estimated using the reverse Kaplan-Meier method.

Study population

We consecutively enrolled patients with PM who received systemic therapy between January 2015 and January 2025 at three participating tertiary hospitals in China, including Peking Union Medical College Hospital, The First Affiliated Hospital of Guangzhou Medical University, and The Second Xiangya Hospital, Central South University. The inclusion criteria were as follows: (I) pathologically confirmed PM; (II) age ≥18 years; (III) receipt of at least one line of systemic therapy (chemotherapy ± targeted therapy or immunotherapy); and (IV) availability of efficacy and safety data.

The exclusion criteria were as follows: (I) concomitant primary malignancies that could interfere with outcome assessment; (II) best supportive care without systemic therapy; and (III) missing key exposure or outcome data. Clinical data were independently extracted by two investigators at each center and cross-checked, with discrepancies resolved by a third investigator.

Treatment groups and index date

First-line treatment was defined according to the actual initial systemic regimen and categorized as either chemotherapy ± targeted therapy or immunotherapy. To minimize time-related biases, the time origin (“time zero”) for each analysis was uniformly defined as the date of the first dose of the corresponding treatment line, and only patients who initiated that line were included.

For later-line therapy analyses, patients were divided into two mutually exclusive cohorts: (I) the “chemo-start” cohort, comprising patients who received first-line chemotherapy and subsequently experienced disease progression; and (II) the “immuno-start” cohort, comprising patients who received first-line immunotherapy and subsequently progressed. Within each cohort, second-line regimens were further classified into three groups: chemotherapy, chemo-immunotherapy, and dual immune checkpoint inhibition.

Outcomes and assessment

The primary outcome was OS, defined as the time from treatment initiation to death from any cause. Patients alive at last contact were censored at the date of the last follow-up. The secondary outcome was PFS, defined as the time from treatment initiation to radiographic disease progression or death, whichever occurred first.

The objective response rate (ORR) and disease control rate (DCR) were determined based on the best overall response. Tumor response was primarily assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) for mesothelioma; if imaging did not meet mRECIST requirements, RECIST version 1.1 was applied instead. All imaging assessments were independently reviewed by radiologists and medical oncologists who were blinded to treatment allocation.

Covariates

Prespecified covariates, selected based on clinical relevance and previous literature, included age, sex, ECOG PS, histologic subtype (epithelioid vs. non-epithelioid), prior radiotherapy, documented asbestos exposure, disease stage, surgical history, and major comorbidities. These variables were used to describe baseline characteristics and to construct propensity scores.

Statistical analysis

To account for baseline imbalances between treatment groups, overlap weighting (OW) based on generalized propensity scores was applied. After OW, the effective sample size (ESS) was calculated to assess the amount of information retained in the weighted sample (Table S1). Covariate balance before and after weighting was evaluated using standardized mean differences (SMDs), with an absolute SMD <0.10 considered indicative of adequate balance (Figure S1). Weighted Kaplan-Meier curves were generated and compared using the log-rank test. Weighted Cox proportional hazards models with robust (sandwich) variance estimators were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

In the first-line analysis, OS and PFS were compared between the chemotherapy and immunotherapy groups. In later-line analyses within the chemo-start and immuno-start cohorts, the three second-line strategies were compared, and pairwise weighted Cox models were fitted to estimate treatment effects between individual strategies. Pre-specified subgroup analyses according to ECOG PS, histologic subtype, prior radiotherapy, and age strata were conducted to explore potential heterogeneity of treatment effects.

All analyses were performed using R software (version 4.5.1; R Foundation for Statistical Computing, Vienna, Austria). Key packages included survival, survminer, weightIt, CBPS, cobalt, survey, sandwich, nnet, mice, and ggplot2. All statistical tests were two-sided, and a P value <0.05 was considered statistically significant.

Ethical approval and consent

The study protocol was reviewed and approved by the Institutional Review Board of Peking Union Medical College Hospital (approval No. K9593). All participating hospitals were informed of and agreed to the conduct of this study. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and the reporting follows the Committee on Publication Ethics guidelines. Given the retrospective design and the use of de-identified data, the requirement for written informed consent was formally waived by the Institutional Review Board.

Results

Patient characteristics and follow-up

A total of 78 patients with PM who received first-line systemic therapy were included (chemotherapy ± targeted therapy group, n=50; immunotherapy group, n=28) (Table 1). The median ages were 61.5 [interquartile range (IQR), 56.2–66.0] and 62.5 (IQR, 56.0–71.0) years, respectively. The proportions of male patients were 58.0% and 57.1%, and epithelioid histology accounted for 72.0% and 57.1% in the two groups, respectively. To account for temporal changes in first-line treatment strategies, we summarized first-line systemic therapies by era (2015–2019 vs. 2020–2025), demonstrating a marked shift from predominantly chemotherapy-based regimens to increased use of immunotherapy in the later period (Table S2).

The median follow-up duration for the whole cohort was 35.7 months (95% CI: 26.2–not reached), with a maximum follow-up of 88.0 months. All baseline covariates achieved adequate balance after OW and were included in subsequent weighted analyses.

First-line treatment outcomes and subgroup analyses

In the unweighted cohort, the median PFS was 8.3 months (95% CI: 5.6–11.6) in the chemotherapy ± targeted therapy group and 12.2 months (95% CI: 6.3–not reached) in the immunotherapy group, with no significant difference between groups (log-rank P=0.09). After OW, the HR for PFS with immunotherapy vs. chemotherapy ± targeted therapy was 0.64 (95% CI: 0.34–1.17), which remained not statistically significant (Figure 1A,1B).

Figure 1 Kaplan-Meier curves of PFS and OS by first-line treatment, before and after OW. Kaplan-Meier curves comparing first-line Chemo+Targ vs. Immuno for PFS [(A) unweighted; (B) overlap weighted] and OS [(C) unweighted; (D) overlap weighted]. HRs are from Cox models (log-rank P values shown for unweighted curves). (B,D) The risk tables report the weighted number at risk, defined as the sum of OW within each risk set, rather than the raw patient counts. The ESS after OW was 64.8 overall (43.3 vs. 25.9 by group). 1L, first-line; Chemo+Targ, chemotherapy ± targeted therapy; CI, confidence interval; ESS, effective sample size; HR, hazard ratio; Immuno, immunotherapy; mo, months; NR, not reached; OS, overall survival; OW, overlap weighting; PFS, progression-free survival.

The median OS was 15.4 months (95% CI: 13.3–21.6) in the chemotherapy ± targeted therapy group and 35.8 months (95% CI: 18.6–not reached) in the immunotherapy group, with a significant between-group difference (log-rank P=0.02). After OW, first-line immunotherapy was associated with significantly longer OS (weighted HR, 0.47; 95% CI: 0.23–0.95) (Figure 1C,1D).

Subgroup analyses showed that the OS benefit of immunotherapy was more pronounced in patients with ECOG PS 0–1 (HR, 0.44; 95% CI: 0.21–0.93), no history of radiotherapy (HR, 0.29; 95% CI: 0.12–0.68), and non-epithelioid histology (HR, 0.30; 95% CI: 0.10–0.97) (Figure 2). In multivariable Cox regression models adjusting for treatment modality, ECOG PS, histological subtype, history of radiotherapy, and asbestos exposure, first-line immunotherapy remained an independent protective factor for OS (HR, 0.34; 95% CI: 0.13–0.90; P=0.03), as did radiotherapy (HR, 0.35; 95% CI: 0.14–0.86; P=0.02) (Table 2).

Figure 2 Subgroup forest plots of OS comparing first-line Immuno with Chemo±Targ in the unweighted cohort (A) and after OW (B). Chemo+Targ, chemotherapy ± targeted therapy; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; Immuno, immunotherapy; OS, overall survival; OW, overlap weighting; PS, performance status.

The ORR was 39.3% in the immunotherapy group and 40.0% in the chemotherapy group, while the DCR was 64.3% and 60.0%, respectively; none of these differences were statistically significant. Among the 28 patients who received immunotherapy, 14 (50.0%) experienced immune-related adverse events, including rashes, thyroiditis, pneumonitis, myositis/myocarditis, and adrenal insufficiency. Most events were grade 1–2, and no immune-related deaths were reported (Figure 3).

Figure 3 Spectrum and severity of ICI-related adverse events (n=14). Bars show the proportion of patients with each adverse event among all patients who developed immune-related adverse events. Severity is categorized as mild, moderate, or severe according to the CTCAE. CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitor.

Subsequent-line treatment outcomes

In the chemo-start cohort, subsequent systemic therapy included chemotherapy (n=36), chemo-immunotherapy (n=8), and dual immunotherapy (n=6). OW Cox analysis showed a significant difference in OS among the three groups (weighted Cox P=0.006). In pairwise comparisons, dual immunotherapy significantly improved OS compared with chemo-immunotherapy (HR, 0.13; 95% CI: 0.03–0.62; P=0.01), whereas the difference vs. chemotherapy did not reach statistical significance (HR, 0.43; 95% CI: 0.17–1.11; P=0.08). No significant difference was observed between chemo-immunotherapy and chemotherapy (HR, 2.08; 95% CI: 0.94–4.57; P=0.07) (Figure 4).

Figure 4 OS by post-line regimen in the chemo-start cohort (PM only). (A) Unweighted Kaplan-Meier curves for OS according to post-line regimen: Chemo, Immuno+Chemo, and Dual immuno. (B) Overlap-weighted Kaplan-Meier curves for OS for the same three post-line regimens. Chemo, chemotherapy alone; Dual immuno, dual immune checkpoint inhibition; Immuno+Chemo, chemo-immunotherapy; OS, overall survival; PM, pleural mesothelioma.

In the immuno-start cohort, twelve patients received subsequent therapies (chemotherapy, n=5; chemo-immunotherapy, n=3; dual immunotherapy, n=4). Owing to the limited sample size, no significant differences in OS were observed among the three regimens (weighted Cox P=0.31), and these findings should be interpreted descriptively (Figure S2).

Discussion

Key findings

This multicenter, real-world study from China systematically evaluated survival outcomes associated with first-line and subsequent systemic therapies in patients with PM. First, compared with chemotherapy ± targeted therapy, first-line immunotherapy significantly prolonged OS but did not significantly improve PFS. The survival benefit of immunotherapy was more pronounced in patients with ECOG PS 0–1, no prior radiotherapy, and non-epithelioid histology. Second, among patients who progressed after first-line chemotherapy, OS differed across subsequent systemic strategies: dual immune checkpoint blockade showed a significant advantage over chemo-immunotherapy, whereas its superiority over chemotherapy alone could not be confirmed, and chemo-immunotherapy did not outperform chemotherapy. Third, in the smaller immuno-start cohort, no clear differences in subsequent-line outcomes were observed, and these results should be interpreted descriptively. Overall, our data support first-line immunotherapy as a key treatment option for eligible patients and suggest that dual immunotherapy may be a promising subsequent-line approach after chemotherapy failure.

Strengths and limitations

There are several strengths in this study. It reflects real-world practice across multiple tertiary centers in China, providing complementary evidence to randomized controlled trials (RCTs) in an under-represented population. Detailed longitudinal data allowed us to examine not only first-line regimens but also subsequent systemic pathways, which remain poorly characterized in PM. Methodologically, we used OW based on generalized propensity scores to balance measured baseline covariates, thereby reducing confounding by indication and improving the comparability between treatment groups.

However, several limitations must be acknowledged. The overall sample size, particularly in subsequent-line subgroups, was modest, resulting in limited statistical power and wide CIs. Treatment selection and timing were determined by treating physicians, introducing potential residual confounding and selection bias that cannot be fully eliminated despite weighting and multivariable adjustment. Regimen heterogeneity within each category (e.g., different checkpoint inhibitors or chemotherapy backbones) may also have obscured regimen-specific effects. The use of chemo-immunotherapy also reflects real-world clinical decision-making and practical considerations, including treatment accessibility and cost, rather than strict adherence to guideline-preferred regimens. Furthermore, the small number of patients in the immuno-start cohort precluded robust comparisons of post-immunotherapy strategies, and post-progression analyses should be viewed as exploratory and hypothesis-generating. Additionally, in this multicenter retrospective cohort, the proportion of patients with a documented history of asbestos exposure was lower than that reported in some previous studies. Several factors may contribute to this observation. First, given the long study period and the real-world retrospective design, asbestos exposure history was not collected as a standardized variable in earlier cases, and incomplete documentation cannot be excluded. Second, asbestos exposure may be indirect or unrecognized, as patients may be unaware of exposure through occupational environments or environmental contact with asbestos-containing materials. Third, the exposure patterns of PM may vary across geographic regions, and the reported prevalence of asbestos exposure in Chinese cohorts has been lower than that in Western populations (12,13). In addition, germline genetic testing, including assessment for BAP1 tumor predisposition syndrome, is not routinely performed in clinical practice and was not systematically evaluated in this retrospective study. These factors should be considered when interpreting the observed asbestos exposure rate in our cohort. Finally, biomarker information such as PD-L1 expression or tumor mutational burden was not systematically available, limiting our ability to integrate biological predictors into treatment decision-making.

Comparison with similar research

Our findings are broadly consistent with, and extend, existing trial data. Early RCTs such as the study by Vogelzang et al. established platinum plus pemetrexed as the long-standing first-line standard after demonstrating superior OS over platinum monotherapy (14). The MAPS trial showed that adding bevacizumab to platinum-pemetrexed further improved OS but at the cost of increased toxicity and resource demands, limiting widespread use (4,9). Subsequently, immunotherapy-based regimens reshaped the treatment landscape. CheckMate 743 demonstrated that nivolumab plus ipilimumab significantly prolonged OS compared with platinum-pemetrexed, particularly in patients with non-epithelioid histology, while median PFS and ORR were similar between arms (5). Phase II studies such as DREAM and PrE0505 reported median OS of approximately 18–21 months with durvalumab plus platinum–pemetrexed, and the IND227/KEYNOTE-483 trial confirmed that pembrolizumab combined with platinum-pemetrexed modestly improved OS and PFS and significantly increased ORR compared with chemotherapy alone (8,15,16). Collectively, these trials established immunotherapy-based regimens as superior to conventional chemotherapy in prolonging OS, especially in non-epithelioid disease, while gains in PFS and ORR remained modest.

Real-world evidence has highlighted the gap between trial populations and routine practice. National registry data from the United Kingdom and Denmark, as well as large US electronic health record analyses, indicate that only about one-third of patients receive first-line systemic therapy and many are managed with supportive care alone; median OS in these cohorts ranges from 8 to 13 months, substantially shorter than in RCTs (17-21). Our Chinese cohort showed a similar pattern: immunotherapy improved OS but had limited impact on PFS and ORR. After OW, first-line immunotherapy significantly reduced the risk of death vs. chemotherapy ± targeted therapy, while PFS showed only a non-significant trend toward improvement and ORR/DCR were comparable between groups.

In the subsequent-line setting, our observations also align with existing data. Historically, second-line chemotherapy regimens such as pemetrexed rechallenge or vinorelbine/gemcitabine yielded ORRs of 10–20%, median PFS of 2–4 months, and median OS of 5–11 months, with the RAMES trial representing a notable exception by demonstrating OS improvement with ramucirumab plus gemcitabine (22-26). Phase II studies KEYNOTE-028, NivoMes, and MERIT reported ORRs of ~20% and median OS of 11–18 months with single-agent PD-1/PD-L1 inhibitors in platinum-pretreated PM, while the CONFIRM trial showed that nivolumab improved OS and PFS vs. placebo; by contrast, pembrolizumab did not outperform chemotherapy in PROMISE-meso (7,27-29). Trials such as MAPS2 and INITIATE further suggested that nivolumab plus ipilimumab increases DCR and median OS in relapsed PM, supporting dual checkpoint blockade as a promising subsequent-line strategy (30,31). Real-world cohorts from Australia and Europe have reported ORRs of 10–20%, median PFS of 2–4 months, and median OS of 7–12 months with pembrolizumab or nivolumab monotherapy, with safety profiles consistent with RCTs (32,33). Our finding that dual immunotherapy showed better OS than chemo-immunotherapy, and at least numerically better OS than chemotherapy alone, is concordant with this body of evidence, whereas the lack of benefit with chemo-immunotherapy over chemotherapy echoes the negative results of pembrolizumab vs. chemotherapy in PROMISE-meso.

Explanations of findings

Several factors may explain the pattern of outcomes observed in our study. The discrepancy between significant OS benefit and limited PFS or ORR improvement with immunotherapy suggests that its major advantage may lie in inducing durable, long-term responses in a subset of patients, thereby improving the tail of the survival curve rather than uniformly delaying early disease progression. This is consistent with the survival dynamics seen in CheckMate 743 and other immunotherapy trials.

The stronger OS benefit in patients with ECOG PS 0–1 and no prior radiotherapy indicates that preserved PS and lower cumulative treatment burden may be critical prerequisites for realizing the full potential of immunotherapy. Patients with better functional reserve may tolerate treatment longer, mount more effective anti-tumor immune responses, and be more likely to receive subsequent therapies upon progression. The greater benefit in non-epithelioid histology mirrors the histology-dependent advantage reported in CheckMate 743 (5), supporting the hypothesis that non-epithelioid tumors may be more immunogenic or more responsive to immune checkpoint blockade.

In the subsequent-line setting, the superior OS associated with dual immunotherapy compared with chemo-immunotherapy in the chemo-start cohort may reflect the higher anti-tumor activity of combined PD-1/PD-L1 and CTLA-4 blockade after chemotherapy-induced immunogenic modulation. By contrast, adding a single PD-1 inhibitor to chemotherapy did not confer stable benefit, which may relate to overlapping toxicities, suboptimal dosing, or insufficient immunologic synergy in heavily pretreated patients. The absence of clear differences among regimens in the immuno-start cohort is likely driven by the very small sample size and the heterogeneous clinical characteristics of patients who progress after first-line immunotherapy.

Implications and actions needed

Within the constraints of a retrospective real-world design, our findings have several clinical and research implications. For eligible patients with PM—particularly those with ECOG PS 0–1, non-epithelioid histology, and limited prior radiotherapy—first-line immunotherapy should be strongly considered as a core systemic option in routine practice. At the time of progression after first-line chemotherapy, dual immune checkpoint blockade appears to be a promising subsequent-line strategy and may be prioritized for patients who can tolerate intensified immunotherapy. Conversely, for patients with contraindications to immunotherapy or poor general condition, conventional chemotherapy remains a pragmatic and accessible treatment choice.

Future work should focus on larger, preferably prospective multicenter cohorts or pragmatic trials to validate the comparative effectiveness of subsequent-line strategies and to more precisely define the benefit boundaries of dual immunotherapy vs. chemotherapy. The integration of clinical factors (PS, histology, prior treatments) with biomarkers such as PD-L1 expression, genomic alterations, and immune signatures will be essential to refine patient selection and optimize sequential treatment algorithms. Finally, health-system-level efforts are needed to improve access to immunotherapy, support timely treatment sequencing, and ensure that real-world patients can benefit from advances demonstrated in clinical trials.

Conclusions

This multicenter real-world study from China demonstrates that first-line immunotherapy significantly improves OS in patients with PM compared with chemotherapy ± targeted therapy, while having limited impact on PFS and response rates. The survival benefit of immunotherapy is primarily observed in patients with favorable ECOG PS, non-epithelioid histology, and no prior radiotherapy. Following first-line chemotherapy failure, dual immune checkpoint blockade appears to offer superior survival over chemo-immunotherapy, although evidence to establish its superiority over chemotherapy alone remains inconclusive. These findings provide valuable real-world insights into treatment sequencing for PM, underscoring individualized therapy based on patient characteristics and prior treatment exposure. Larger multicenter prospective studies are warranted to refine optimal sequential strategies and identify subgroups most likely to benefit from immunotherapy.

Acknowledgments

We would like to acknowledge all participating hospitals, including Peking Union Medical College Hospital, The First Affiliated Hospital of Guangzhou Medical University, and The Second Xiangya Hospital, Central South University, for their support in patient recruitment and data collection.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1347/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1347/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1347/prf

Funding: This work was supported by the Beijing Natural Science Foundation, Beijing Economic and Technological Development Zone Innovation Joint Fund (Project No. L248072).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1347/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study protocol was reviewed and approved by the Institutional Review Board of Peking Union Medical College Hospital (approval No. K9593). All participating hospitals were informed of and agreed to the conduct of this study. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was waived due to the retrospective design and use of de-identified data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Fennell DA, Sekido Y, Baas P, et al. Pleural mesothelioma. Nat Rev Dis Primers 2025;11:56. [Crossref] [PubMed]
2. Zhang L, Huang M. Pleural Mesothelioma: Pathogenesis, Diagnosis, Treatment, Prognosis, and Survival. MedComm (2020) 2025;6:e70327.
3. Baas P, Fennell D, Kerr KM, et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26:v31-9. [Crossref] [PubMed]
4. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 2016;387:1405-14. [Crossref] [PubMed]
5. Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet 2021;397:375-86. [Crossref] [PubMed]
6. Reuss JE, Lee PK, Mehran RJ, et al. Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses. Nat Med 2025;31:4097-108. [Crossref] [PubMed]
7. Fennell DA, Ewings S, Ottensmeier C, et al. Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol 2021;22:1530-40. [Crossref] [PubMed]
8. Chu Q, Perrone F, Greillier L, et al. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Lancet 2023;402:2295-306. [Crossref] [PubMed]
9. Felip E, Popat S, Dafni U, et al. A randomised phase III study of bevacizumab and carboplatin-pemetrexed chemotherapy with or without atezolizumab as first-line treatment for advanced pleural mesothelioma: results of the ETOP 13-18 BEAT-meso trial. Ann Oncol 2025;36:548-60. [Crossref] [PubMed]
10. López-Castro R, Fuentes-Martín Á, Medina Del Valle A, et al. Advances in Immunotherapy for Malignant Pleural Mesothelioma: From Emerging Strategies to Translational Insights. Open Respir Arch 2024;6:100323. [Crossref] [PubMed]
11. Douma LH, van der Noort V, Lalezari F, et al. Pembrolizumab plus lenvatinib as second-line treatment in patients with pleural mesothelioma (PEMMELA): cohort 2 of a single-arm, phase 2 study. Lancet Oncol 2025;26:1676-84. [Crossref] [PubMed]
12. Mao W, Zhang X, Guo Z, et al. Association of Asbestos Exposure With Malignant Mesothelioma Incidence in Eastern China. JAMA Oncol 2017;3:562-4. [Crossref] [PubMed]
13. Robinson BM. Malignant pleural mesothelioma: an epidemiological perspective. Ann Cardiothorac Surg 2012;1:491-6. [Crossref] [PubMed]
14. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636-44. [Crossref] [PubMed]
15. Forde PM, Sun Z, Anagnostou V, et al. PrE0505: Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (MPM)—A PrECOG LLC study. J Clin Oncol 2020;38:9003.
16. Nowak A, Kok P, Lesterhuis W, et al. OA08. 02 DREAM-a phase 2 trial of durvalumab with first line chemotherapy in mesothelioma: final result. J Thorac Oncol 2018;13:S338-9.
17. Sørensen JB, Baas P, Szépligeti SK, et al. Patient characteristics, treatment patterns, and survival outcomes for patients with malignant pleural mesothelioma in Denmark between 2011 and 2018: a nationwide population-based cohort study. Acta Oncol 2024;63:649-57. [Crossref] [PubMed]
18. Waterhouse DM, Nwokeji ED, Boyd M, et al. Treatment patterns and outcomes of patients with advanced malignant pleural mesothelioma in a community practice setting. Future Oncol 2021;17:2439-48. [Crossref] [PubMed]
19. Baas P, Daumont MJ, Lacoin L, et al. Treatment patterns and outcomes for patients with malignant pleural mesothelioma in England in 2013-2017: A nationwide CAS registry analysis from the I-O Optimise initiative. Lung Cancer 2021;162:185-93. [Crossref] [PubMed]
20. Chow KVC, Turner C, Hughes B, et al. Real-world outcomes for patients with pleural mesothelioma: A multisite retrospective cohort study. Asia Pac J Clin Oncol 2024;20:723-30. [Crossref] [PubMed]
21. Schmid S, Holer L, Gysel K, et al. Real-World Outcomes of Patients With Malignant Pleural Mesothelioma Receiving a Combination of Ipilimumab and Nivolumab as First- or Later-Line Treatment. JTO Clin Res Rep 2024;5:100735. [Crossref] [PubMed]
22. Ceresoli GL, Zucali PA, De Vincenzo F, et al. Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural mesothelioma. Lung Cancer 2011;72:73-7. [Crossref] [PubMed]
23. Stebbing J, Powles T, McPherson K, et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 2009;63:94-7. [Crossref] [PubMed]
24. Zucali PA, Perrino M, Lorenzi E, et al. Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. Lung Cancer 2014;84:265-70. [Crossref] [PubMed]
25. Zauderer MG, Kass SL, Woo K, et al. Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. Lung Cancer 2014;84:271-4. [Crossref] [PubMed]
26. Pinto C, Zucali PA, Pagano M, et al. Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2021;22:1438-47. [Crossref] [PubMed]
27. Alley EW, Lopez J, Santoro A, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol 2017;18:623-30. [Crossref] [PubMed]
28. Okada M, Kijima T, Aoe K, et al. Clinical Efficacy and Safety of Nivolumab: Results of a Multicenter, Open-label, Single-arm, Japanese Phase II study in Malignant Pleural Mesothelioma (MERIT). Clin Cancer Res 2019;25:5485-92. [Crossref] [PubMed]
29. Popat S, Curioni-Fontecedro A, Dafni U, et al. A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Ann Oncol 2020;31:1734-45. [Crossref] [PubMed]
30. Scherpereel A, Mazieres J, Greillier L, et al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol 2019;20:239-53. [Crossref] [PubMed]
31. Disselhorst MJ, Quispel-Janssen J, Lalezari F, et al. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir Med 2019;7:260-70. [Crossref] [PubMed]
32. Ahmadzada T, Cooper WA, Holmes M, et al. Retrospective Evaluation of the Use of Pembrolizumab in Malignant Mesothelioma in a Real-World Australian Population. JTO Clin Res Rep 2020;1:100075. [Crossref] [PubMed]
33. Cantini L, Belderbos RA, Gooijer CJ, et al. Nivolumab in pre-treated malignant pleural mesothelioma: real-world data from the Dutch expanded access program. Transl Lung Cancer Res 2020;9:1169-79. [Crossref] [PubMed]