Pleural Mesothelioma

When new, particularly unilateral, pleural effusions occur, pleural mesothelioma should be considered as part of the differential diagnosis. Among a total of 2,263 patients with unilateral pleural effusions, mesothelioma was diagnosed in just under a quarter within one year [36, 37, 38, 39, 40, 41, 42, 43]. Based solely on medical history, clinical symptoms, and radiological imaging, the diagnosis of pleural mesothelioma cannot be confirmed or ruled out with sufficient certainty. Therefore, if pleural mesothelioma is suspected, histological evaluation should be pursued to establish a definitive diagnosis. Due to the relatively low incidence of pleural mesothelioma, diagnosis and treatment planning for this condition should be conducted at a center specializing in this disease. If pleural mesothelioma is suspected, in addition to the clinical history, an occupational history of both the patient and their spouse should be obtained to assess potential asbestos exposure.

In addition to the physical examination, at least a standard ultrasound of the pleura (while the patient is seated) or a chest X-ray should be performed initially to check for pleural effusion. However, particularly when determining the justification for a chest X-ray, it is important to note that follow-up examinations will generally be necessary. These include more sensitive procedures such as a contrast-enhanced chest computed tomography (CT) [44, 45] or a Fibroblast Activation Protein Inhibitor Positron Emission Tomographie-CT (FAPI-PET-CT) [46]. If a pleural effusion is present and pleural mesothelioma is suspected, it should be evaluated via video-assisted thoracoscopy (VATS) with a pleural biopsy to enable a definitive histological diagnosis [47]. Similarly, in cases of clinical and/or radiological suspicion of pleural mesothelioma, even in the absence of pleural effusion, histological evaluation via VATS should be pursued. It is important during the biopsy procedure to obtain a sample of the subpleural adipose tissue to assess the invasiveness. If possible, biopsies should be taken from multiple sites. The uniportal surgical approach should, if possible, be positioned at the level of a subsequent thoracotomy to prevent implantation metastases. In patients with a histologically confirmed diagnosis of pleural mesothelioma, a FAPI-PET-CT scan may be performed prior to planned curative surgical therapy [48, 49, 50]. If a PET-CT cannot be performed, a CT scan of the abdomen should be performed in addition to a chest CT, both with contrast medium if possible. A contralateral VATS or laparoscopy should be considered if there is radiological suspicion of contralateral or peritoneal involvement and clinical indications warrant it. To investigate infiltration of the chest wall, particularly the ribs or vertebral bodies, or to assess the presence of transmural diaphragmatic infiltration, a thoracic MRI may be performed if clinically indicated. Prior to planned curative surgical therapy, invasive lymph node staging should be performed using endobronchial ultrasound (EBUS) or, if necessary, mediastinoscopy [51, 52].

figure 3 summarizes the diagnostic approach for suspected pleural mesothelioma.

The histopathological diagnosis of pleural mesothelioma should be based on a representative tumor specimen and is clearly superior to a diagnosis based solely on cytology, e.g., from a pleural effusion. For differential diagnosis to rule out lung adenocarcinoma, the mesothelioma markers calretinin, mesothelin, cytokeratins 5/6, Wilms tumor 1 (WT-1), and D-240 should be assessed by immunohistochemistry. Likewise, the adenocarcinoma markers TTF1, CEA, and Ber-EP4 should be evaluated for differential diagnosis to adenocarcinoma [53]. The histological subtype of the mesothelioma should be specified, along with a statement regarding the certainty of the diagnosis according to the criteria of the European Mesothelioma Panel [https://www.pathologie-bochum.de/mesotheliom-panel.html].

Molecular pathological analyses, which are firmly established in routine pre-treatment diagnostics for other tumor types, such as NSCLC, are not yet available for routine diagnostics in pleural mesothelioma.

In the prospective registry study of the NCT/DKTK-MASTER program [54], a comprehensive genomic and transcriptomic characterization was performed in patients with pleural and peritoneal mesothelioma. A high prevalence of recurrent alterations in classic tumor suppressor genes (including BAP1, CDKN2A, NF2, SETD2, TP53) as well as in genes involved in homologous recombination (HR), often with evidence of an HR-deficiency signature. Based on these findings, a molecular tumor board was able to identify potential targeted or immuno-oncology treatment strategies in the majority of cases and implement them with clinically relevant benefit in a subset of patients. The data underscore the central role of pathology in the integration of high-throughput molecular techniques (whole-exome/whole-genome sequencing, RNA sequencing) into the diagnosis of mesothelioma.

However, further clinical and preclinical studies are necessary to substantiate the significance of molecular pathological testing in pleural mesothelioma and, if appropriate, to firmly integrate it into the clinical diagnostic process with regulated cost reimbursement. In individual cases, molecular pathological testing may be pursued, for example, through inclusion in a clinical trial or as part of an approved off-label use. This would be particularly the case if a therapeutic option is available based on the molecular pathological findings. At the time of this guideline update (September 2026), however, molecular pathology is not reimbursable in routine clinical practice, at least within the statutory health insurance system, and there are no approved therapeutic options independent of off-label use that depend on the results of molecular pathology.

Systemic therapy plays a particularly important role in the treatment of pleural mesothelioma, as complete resection of the tumor is practically impossible even in localized stages; therefore, treating systemic micrometastases is crucial for achieving the best possible long-term prognosis.

The first evidence of the efficacy of a combination therapy consisting of cisplatin and pemetrexed, administered over a median of 6 cycles, was demonstrated in a phase III study of unresectable patients by Vogelzang et al., showing an improvement in overall survival (OS) from 9.3 to 12.1 months (HR: 0.77; p-value = 0.02), as well as progression-free survival (PFS) of 5.1 vs. 3.9 months (p-value = 0.001), and a response rate of 41.3% vs. 16.7% (p-value < 0.0001) [58]. Since then, the neoadjuvant or adjuvant administration of 4 cycles of cisplatin and pemetrexed has become an empirically and clinically recognized standard of care.

If there are contraindications to cisplatin and/or pemetrexed, pemetrexed can be replaced, for example, with vinorelbine or gemcitabine, and in cases of clear contraindications to cisplatin, it can be substituted with carboplatin if indicated [59, 60, 61].

The goal of surgical resection is the macroscopically complete removal of the tumor to achieve the maximum possible cytoreduction. The indication for surgical resection should be determined for very carefully selected patients at an experienced center. Only patients with an epithelioid subtype without lymph node involvement, in good general health (ECOG 0-1), at a (very) early stage of disease, and without significant comorbidities should be selected for a multimodal approach consisting of surgical resection accompanied by neoadjuvant or adjuvant chemotherapy.

In the British multicenter phase III MARS 2 trial [62], patients with resectable pleural mesothelioma were randomized after two cycles of induction chemotherapy with platinum/pemetrexed to receive either (extended) pleurectomy/decortication followed by chemotherapy or continued chemotherapy alone. The primary endpoint was OS from the time of randomization. OS was significantly worse in the surgery arm (median OS 19.3 vs. 24.8 months; negative difference in restricted mean survival time at 2 years of 1.9 months; p=0.019). Significantly more severe adverse events (grade ≥ 3) and postoperative complications occurred in the surgery arm. Perioperative morbidity and mortality were higher than in the chemotherapy arm, and quality of life was impaired in the short term in the surgery arm, with no benefit observed in the long term.

The pragmatic design, which included numerous centers with varying levels of surgical experience, led to considerable heterogeneity in surgical quality and perioperative care. Patient selection was suboptimal, with a significant proportion of non-epithelial tumors or tumors subsequently classified as biphasic, as well as locally advanced (in some cases metastatic) stages and patients who had experienced disease progression during neoadjuvant therapy. Traditionally, little benefit from surgical therapy is expected for these patient groups. Commentaries emphasize that the results argue against routine radical surgical cytoreduction in unselected populations but should not be interpreted as a general contraindication for surgery in highly selected patients at experienced centers. The authors of this guideline interpret the results of the MARS 2 study such that, given the criticisms outlined, no general contraindication against surgery can be derived from them [63]. However, the study underscores the importance of strict patient selection for a treatment plan involving surgery [63].

Today, the surgical procedure of choice is considered to be extended pleurectomy/decortication ((e)P/D), i.e., the complete removal of the parietal and visceral pleura while preserving the lung parenchyma, supplemented, if necessary, by diaphragmatic and/or pericardial resection. Preservation of the diaphragm results in fewer postoperative complications, improved postoperative quality of life, and shorter surgical time and hospital stay without reducing overall survival [64, 65]. The extrapleural pneumonectomy (EPP) procedure is considered obsolete, even in light of the aforementioned MARS 2 study.

Histological confirmation and staging should be performed as described in chapter 5.1. Patients in good general condition (ECOG 0) with localized stage I-IIIA epithelioid mesothelioma may be offered (e)PD, provided they have adequate pulmonary function, either following neoadjuvant chemotherapy or as primary therapy followed by adjuvant chemotherapy with cisplatin and pemetrexed.

In this context, it should be noted that neoadjuvant chemotherapy consisting of 4 cycles of a platinum-based combination is generally much easier to administer than adjuvant therapy following (e)P/D, in which the dose density usually must be reduced due to postoperative limitations. On the other hand, it should be noted that the postoperative recovery period is generally significantly longer following neoadjuvant chemotherapy.

Based on the available study data, no evidence can be derived to support a general preference for neoadjuvant over adjuvant chemotherapy. A randomized phase II study (EORTC-1205) [66] found no evidence of a clinical benefit for either treatment sequence. The timing of systemic therapy should therefore be determined on an individual basis by a multidisciplinary tumor board, taking patient preferences into account.

The treatment goal of the combination of surgical cytoreduction and systemic therapy is to achieve the longest possible disease control while maintaining a good quality of life. A formally curative treatment approach involving radical (R0) tumor resection is practically impossible in malignant pleural mesothelioma. In individual cases, long progression-free periods of >10 years can be achieved; however, in the long term, a relapse, usually local, almost always occurs. Depending on the location and extent of the relapse, local therapeutic approaches in combination with systemic therapy may then be offered again if necessary.

The treatment plan should be developed during a multidisciplinary conference at a facility experienced in the treatment of pleural mesothelioma, ideally at a DKG-certified lung cancer center with a mesothelioma unit.

Immune checkpoint inhibitors (ICI) are not yet approved for neoadjuvant or adjuvant use. A phase II study [67] investigated the perioperative use of nivolumab alone or nivolumab in combination with ipilimumab in patients with resectable, epithelioid pleural mesothelioma. The objective was to evaluate the feasibility and safety of neoadjuvant and adjuvant immune checkpoint blockade in conjunction with the planned resection. The dual primary endpoints were “feasibility” (including the proportion of patients who underwent the planned Surgery) and safety. The treatment proved feasible, with a high proportion of surgeries actually performed (over 80% in both arms). In the nivolumab arm, the median disease-free survival (DFS) among patients who underwent surgery was 9.6 months, and the median OS was 19.3 months. In the nivolumab + ipilimumab arm, the median DFS was 19.8 months and the median OS was 28.6 months. The observed adverse events included the typical spectrum of immune-mediated toxicities associated with nivolumab and ipilimumab, including grade 3/4 events, but were generally manageable in the perioperative setting without excessive perioperative mortality. Key limitations include the non-randomized phase II design, the limited number of cases, and the absence of a control arm without immunotherapy. The study should therefore be interpreted primarily as a feasibility and hypothesis-generating study. It is not yet possible to draw conclusions regarding an actual survival benefit compared to established multimodal approaches.

In cases of unresectable disease and/or non-epithelioid histology, therapy consisting of the combination of the ICI nivolumab and ipilimumab is considered the current first-line standard of care. In the randomized phase III CheckMate743 trial, the ICI combination demonstrated significant superiority in OS compared to cisplatin/carboplatin and pemetrexed in patients with non-epithelioid histology, with a 9.3-month extension in median OS (18.1 vs. 8.8 months; HR: 0.46)) [68]. In patients with epithelioid histology, median OS tended to be better, though not statistically significant, compared with treatment with cisplatin/carboplatin and pemetrexed, at 18.7 months in the ICI arm and 16.5 months in the chemotherapy arm (HR: 0.86). For the entire patient population, median OS was also longer in the immunotherapy arm (18.1 vs. 14.1 months; HR: 0.74; p-value = 0.002) than in the chemotherapy arm. Regardless of histological subtype, a retrospective subgroup analysis showed that patients with PD-L1 expression of ≥ 1% on the tumor surface (TPS) benefited more from the immunotherapy combination than patients with PD-L1 expression of < 1% TPS (PD-L1 ≥ 1% TPS: median OS 18.0 vs. 13.3 months (HR: 0.69); PD-L1 < 1% TPS: median OS 17.3 vs. 16.5 months (HR: 0.94)). Due to the retrospective nature of the subgroup analysis and the small number of cases, making a treatment decision based solely on PD-L1 status is not recommended. However, in Switzerland, PD-L1 expression is sometimes relevant with regard to the approval of nivolumab and ipilimumab (see below). Median PFS was comparable across the entire patient population in both study arms (6.8 months in the immunotherapy arm and 7.2 months in the chemotherapy arm (HR: 1.00)). However, progression occurred more frequently in the ICI arm than in the chemotherapy arm during the first 6 months [68]. The median duration of response in the overall patient population was 11.0 months in the ICI arm and 6.7 months in the chemotherapy arm, meaning that patients benefited from a response to ICI therapy for a longer period. In both study arms, the objective response rate was comparable, at 40% in the ICI arm and 43% in the chemotherapy arm.

In the CheckMate 743 study, the ICI arm demonstrated better control of disease-related symptoms—anorexia (HR: 0.51), fatigue (HR: 0.43), pain (0.55), dyspnea (HR: 0.75), and cough (HR: 0.78), as well as a better overall quality of life, as measured by the standardized questionnaires LCSS-Meso ASBI (HR: 0.52) and LCSS-Meso 3-IGI (HR: 0.61) [68, 69]. Since the study met its primary endpoint (improvement in OS across the entire study population), patients may benefit from the possibility of a longer-lasting treatment response, and since symptom control and quality of life were more favorable in the checkpoint inhibitor arm, treatment with nivolumab and ipilimumab can be considered a potential treatment option for both histological subtypes.

In a retrospective, multicenter registry analysis conducted at 12 German cancer centers, the combination of nivolumab and ipilimumab showed comparable results in patients potentially eligible for the study as in the CheckMate 743 trial; however, the results were poorer in the overall study population [60]. Of particular interest was the finding that patients with (low-grade) immune-mediated adverse events had a better outcome [70].

In Switzerland, the combination of nivolumab and ipilimumab is approved for non-epithelioid histology regardless of PD-L1 status; for epithelioid histology, however, it is approved only for PD-L1 expression with a TPS of ≥1%. In clinical practice in Switzerland, in cases of epithelioid histology with negative PD-L1 expression, submitting an application for coverage of treatment with bevacizumab (in combination with platinum and pemetrexed) is a common procedure. The approval rate for such applications by SUVA is relatively high in Switzerland. For data on bevacizumab, please refer to the following section of this chapter as well as to chapter 6.4.1.1.

However, for patients with a high need for treatment and remission and epithelioid histology, treatment with cisplatin and pemetrexed should continue to be used as the standard of care based on the data presented above [68]. Similarly, patients with a contraindication to ICI therapy should also receive cisplatin and pemetrexed as first-line therapy, provided there are no contraindications to this regimen [68].

In the randomized phase III study IND.227 [71], the combination of pembrolizumab and platinum-based pemetrexed chemotherapy was compared with platinum plus pemetrexed therapy alone in previously untreated patients with advanced pleural mesothelioma. The primary endpoint was OS. The pembrolizumab combination demonstrated a survival benefit (median OS 17.3 vs. 16.1 months; hazard ratio 0.79; p=0.0324; however, the hazard ratio did not meet the threshold for statistical significance) as well as a higher 3-year survival rate (25% vs. 17%). The survival benefit was most pronounced in the group with non-epithelioid mesotheliomas (median OS 12.3 vs. 8.2 months in favor of the pembrolizumab arm; HR: 0.57). For the group with epithelioid mesotheliomas, the median OS in the chemotherapy arm was 18.2 months compared with 19.8 months in the pembrolizumab arm (HR: 0.89). Thus, the survival benefit observed in the overall patient population in the pembrolizumab arm is primarily attributable to the benefit in the group with non-epithelioid mesotheliomas. Grade 3/4 adverse events and treatment-related hospitalizations occurred more frequently in the pembrolizumab arm than with chemotherapy alone. Isolated cases of treatment-related deaths were reported. The toxicity profile was consistent with the known combination of platinum-based chemotherapy and PD-1 blockade, featuring hematologic toxicities and immune-mediated events. Due to the clear survival benefit observed in the non-epithelioid mesothelioma group, pembrolizumab in combination with platinum and pemetrexed was approved in Germany for patients with non-epithelioid mesothelioma. When examining the OS data for epithelioid and non-epithelioid histologies, it is notable that dual checkpoint inhibition in the Checkmate 743 study (nivolumab + ipilimumab) showed comparable results for both histologies (non-epithelioid/epithelioid: 18.1/18.7 months). In the IND.227 study, the pembrolizumab arm showed numerically better median OS for the epithelioid histology than for the non-epithelioid histology (19.8 vs. 12.3 months). This suggests that monotherapy with an ICI in non-epithelioid mesothelioma may not be able to compensate for the low efficacy of chemotherapy in this patient group. For this reason, the use of nivolumab and ipilimumab within the scope of the existing approval is primarily recommended for non-epithelioid histology. If there are contraindications to ipilimumab but not to a PD-1 inhibitor, treatment with platinum, pemetrexed, and pembrolizumab should be considered.

The PD-L1-targeted ICI durvalumab was evaluated in the open-label, multicenter phase III DREAM3R trial [72] for pleural mesothelioma. In this trial, patients with untreated, advanced pleural mesothelioma were randomized in the first-line setting to receive durvalumab in combination with platinum/pemetrexed or platinum/pemetrexed chemotherapy alone. The primary endpoint was OS. The study was terminated early due to slow recruitment, with a significantly lower number of cases than planned. Numerical advantages were observed in favor of the durvalumab combination in terms of median OS, median PFS and objective response rates (median OS 21 vs. 18 months, HR 0.92, median PFS 8 vs. 7 months, HR 0.7, objective response rate 58% vs. 35%); however, these differences were not statistically significant for median OS and PFS. The adverse event profile was consistent with that of a combination of platinum/pemetrexed chemotherapy and PD-L1 inhibition, with expected hematologic and immune-mediated toxicities. Serious treatment-related adverse events were more frequent in the combination arm than with chemotherapy alone, but remained manageable overall. The main limitation of the study is its premature termination with a significantly smaller number of patients than planned, which considerably limits the statistical power needed to reliably assess a survival benefit. Furthermore, the open-label design is susceptible to bias in the assessment of endpoints and subsequent therapies, and changes in standard of care during the study period (introduction of ipilimumab/nivolumab) complicate interpretation in the context of current treatment algorithms. As of the date of this guideline update (September 2026), durvalumab is not approved in Germany for pleural mesothelioma.

Atezolizumab, another ICI that targets PD-L1, was evaluated in the BEAT-meso study [73] for pleural mesothelioma. In this randomized phase III trial, first-line therapy with carboplatin/pemetrexed and bevacizumab, with or without atezolizumab, was investigated in patients with advanced pleural mesothelioma. The primary endpoint was OS. The primary endpoint was not met (median OS 20.5 vs. 18.1 months; HR 0.84; p=0.14), while PFS was significantly longer in the atezolizumab arm (9.2 vs. 7.6 months; HR 0.72; p=0.0021). Exploratory analyses revealed a marked OS benefit for non-epithelioid histology (OS-HR 0.51), but not for epithelioid tumors (OS-HR 1.01). Grade ≥3 adverse events were more common in the atezolizumab arm (55% vs. 47%), with the toxicity profile reflecting that of intensified chemo-anti-VEGF immunotherapy. Quality of life remained comparable overall between the arms. Since the primary endpoint of OS was not met, the regimen, in the absence of approval, cannot be recommended as a treatment option for the overall population or the non-epithelioid subgroup. The post hoc-identified subgroup superiority in non-epithelioid tumors is exploratory and requires prospective confirmation. The complexity and cost of a triple combination (chemotherapy + bevacizumab + atezolizumab) are offset by only limited additional benefit.

The eVOLVE-Mesostudy (phase III) is evaluating the bispecific antibody volrustomig (anti-PD-1 and anti-CTLA-4) in combination with platinum and pemetrexed in untreated pleural mesothelioma patients against “investigator’s choice” therapy (either nivolumab and ipilimumab or platinum and pemetrexed). The analysis of the study and the final results are pending (NCT06097728).

Pegargiminase (also known as ADI-PEG 20) is an enzyme-based drug that specifically breaks down arginine in the body. It is used to treat tumors that lack the enzyme arginine succinate synthetase 1 (ASS1), since these cancer cells rely on an external supply of arginine to survive. It was investigated in the ATOMIC-Meso study in patients with pleural mesothelioma. The ATOMIC-Meso study [74] is a phase II/III study in chemotherapy-naive patients with non-epithelioid pleural mesothelioma, in which an arginine-depleting therapy with pegargiminase (ADI-PEG20) plus pemetrexed/platinum was compared to placebo plus pemetrexed/platinum. The primary endpoint of the phase III component was OS. The combination with pegargiminase resulted in a significant prolongation of median OS (9.3 vs. 7.7 months; HR 0.71; p=0.02) and PFS (6.2 vs. 5.6 months; HR 0.65; p=0.02). A higher rate of grade 3/4 adverse events was observed in the pegargiminase arm. The spectrum included, in particular, hematologic toxicities and common treatment-related events that require close monitoring. The survival benefit is quantitatively limited and has not yet been translated into broad approval, which restricts its practical availability. The study is limited to non-epithelioid histologies. Therefore, it is not applicable to epithelioid tumors. Although biomarker-guided selection (e.g., ASS1 status) is biologically plausible, it has not yet been widely implemented in routine clinical practice. As of the date of this guideline update (September 2026), pegargiminase is not approved in the EU, Switzerland, the United Kingdom or North America. An application for approval has been submitted to the U.S. Food and Drug Administration (FDA), which had not yet been decided upon at the time of the guideline update. The European Medicines Agency (EMA) granted the active ingredient orphan drug designation at an early stage [75].

For patients with very significant comorbidities, a severely compromised general condition, or those who refuse treatment, it may be appropriate, as part of a joint, individualized decision between the patient and the treating physician, to forgo active tumor therapy and instead pursue a purely palliative approach of “best supportive care.” However, this is always an individual decision for which no generally applicable recommendations can be made due to a lack of randomized data.

At the time of this guideline update (September 2026), there are no evaluated randomized phase II or III studies on treatment options following disease progression during first-line therapy with ICIs.

For patients who have not received treatment with nivolumab and ipilimumab as first-line therapy in an inoperable disease setting, treatment with nivolumab and ipilimumab should be considered for “off-label use” based on data from the CheckMate743 study [69], provided there are no contraindications. To ensure reimbursement of costs, an application must be submitted to the health insurance provider.

In cases of disease progression during or after treatment with ipilimumab and nivolumab, treatment with cisplatin and pemetrexed should be administered for up to six cycles; a potential OS of 12.1 months has been reported for this regimen in first-line therapy [58]; see chapter 6.1.1. In a randomized phase II trial (CALGB 30901), maintenance therapy with pemetrexed showed no clinically relevant or statistically significant benefit in terms of PFS or OS [76] and cannot currently be recommended. Switch maintenance therapy with gemcitabine following first-line therapy with platinum and pemetrexed demonstrated an extension of median PFS from 3.2 to 6.2 months compared with best supportive care (HR: 0.44; p-value <0.0001) [77]. However, the data are not robust enough to support a general recommendation for switch maintenance therapy with gemcitabine.

Re-exposure to pemetrexed upon disease progression showed, in patients who had responded to first-line therapy with platinum and pemetrexed for at least 6 months, a disease control rate of 66% in a multicenter retrospective analysis, with a reduction in pain in 43% of patients, a time to progression of 5.1 months, and an overall survival of 13.6 months [78]. Another multicenter, retrospective analysis [74] showed, for patients pretreated with pemetrexed, a disease control rate of 70.7%, PFS of 6.2 months, and OS of 10.6 months upon re-treatment with pemetrexed. As part of this retrospective analysis, patients who had been previously treated with pemetrexed also received second-line therapy consisting of pemetrexed and a platinum derivative [79]. The group of patients who had been retreated with platinum and pemetrexed achieved, compared to those treated with pemetrexed as a single agent, achieved a longer median OS (13.4 vs. 4.2 months; p-value <0.001) and a longer median progression-free survival (6.4 vs. 2.4 months; p = 0.003).

A case series involving four patients who had been treated with platinum and pemetrexed as first-line therapy reported partial remission and three cases of stable disease following re-treatment with platinum and pemetrexed [80].

Another case series reported PFS of 5.0 and 8.2 months in four comparable patients who responded to re-treatment with platinum and pemetrexed [81]. A single-arm observational study involving 31 patients who had been retreated with, among other agents, platinum and pemetrexed (16 patients) (second or subsequent line of therapy) showed a median OS of 10.5 months and a median PFS of 3.8 months [81]. The duration of PFS and OS correlated with the duration of response to first-line therapy with platinum and pemetrexed [82].

Thus, in patients who achieved a response or disease stabilization lasting at least 6 months following therapy with platinum and pemetrexed, re-exposure to pemetrexed, either as a single agent or in combination with a platinum derivative, may be considered in the event of disease progression. In this context, the decision as to whether treatment should be administered as monotherapy or combination therapy should be based on the presence of adverse effects from the previous line of therapy, such as polyneuropathy or hearing loss, as well as on comorbidities and the patient’s general condition.

For patients who have achieved a treatment response or disease stabilization lasting less than 6 months while on platinum and pemetrexed therapy, or who cannot receive pemetrexed therapy due to contraindications, treatment with vinorelbine or gemcitabine should be administered as monotherapy or in combination [83, 84, 85, 86, 87, 88]. The advantages or disadvantages of combination therapy compared to monotherapy have not been explored by randomized data.

In the randomized phase II VIM trial, oral vinorelbine plus active symptom management resulted in a statistically significant improvement in PFS of 4.2 versus 2.8 months compared with active symptom management alone [HR 0.60; p = 0.002] [87].

For vinorelbine, two retrospective analyses in the second or later lines of therapy reported a median PFS of 1.7 and 2.3 months and a median OS of 5.4 and 6.2 months [83, 84].

In a retrospective analysis, gemcitabine monotherapy in the second or later lines of treatment yielded a PFS of 1.6 months and a median OS of 4.9 months [78].

The randomized phase II RAMES trial compared gemcitabine plus placebo with a regimen consisting of gemcitabine and the anti-VEGFR2 antibody ramucirumab in second-line therapy [85]. In this study, the median OS for gemcitabine plus placebo was 7.5 months, compared with 13.8 months in the gemcitabine plus ramucirumab arm (HR: 0.71; p = 0.028). In the gemcitabine/ramucirumab arm, the median PFS was 8.3 months compared with 6.6 months in the gemcitabine/placebo arm (HR: 0.79; p = 0.12).

However, as of the date of this guideline update (September 2026), ramucirumab is not approved for pleural mesothelioma in Germany, Austria, or Switzerland (off-label use).

The randomized phase III ETOP9-15 trial (PROMISE-Meso trial) compared a chemotherapy arm, in which patients received either gemcitabine or vinorelbine (selected by the investigators), with the PD-1 inhibitor pembrolizumab [87]. The median PFS was 3.4 months in the gemcitabine or vinorelbine arm compared with 2.5 months in the pembrolizumab arm (HR: 1.06; p = 0.76). A median OS of 12.4 months was reported in the gemcitabine or vinorelbine arm, compared with 10.7 months in the pembrolizumab arm (HR: 1.12; p = 0.59).

The single-arm phase II PEMMELA study [89] evaluated the combination of pembrolizumab and the multi-tyrosine kinase inhibitor lenvatinib in patients with pleural mesothelioma whose disease had progressed following platinum-based pemetrexed chemotherapy and who had not received prior immunotherapy. The primary endpoint was the objective response rate according to modified RECIST criteria (Response Evaluation Criteria in Solid Tumors). A high response rate of 58% (local assessment; 45% in the independent review) was observed in a total of 38 evaluable patients. The combination was associated with significant toxicity: common grade ≥3 adverse events included hypertension (21%), anorexia, and lymphopenia (11% each), as well as one treatment-related death due to myocardial infarction. In 76% of patients, at least one dose reduction or interruption of lenvatinib was required, underscoring its limited tolerability. The single-arm design without a control group does not allow for a definitive conclusion regarding superiority over standard second-line therapies. The study population is small and selected (single center, ECOG 0-1, no prior immunotherapy), so the generalizability is limited, particularly to the current setting of patients previously treated with ICIs. The pronounced toxicity restricts its use, especially in older patients and those with comorbidities.

For the anthracyclines doxorubicin and epirubicin, efficacy has been reported in patients with unresectable pleural mesothelioma [89, 90, 91, 92]. Due to the availability of more effective agents with a stronger body of clinical evidence, doxorubicin or epirubicin are now administered in clinical practice, if at all, only as monotherapy in advanced stages of treatment following failure of ICIs, platinum derivatives combined with pemetrexed, gemcitabine, and vinorelbine.

In two phase III trials in first-line therapy, doxorubicin demonstrated a median OS of 8.2 and 10 months [80, 82]. In two single-arm phase II trials in first-line therapy, epirubicin demonstrated a median OS of 7.5 and 10 months, as well as response rates of 5% and 15% [93, 94].

Due to the limited efficacy of treatment options in second-line and subsequent lines of therapy for pleural mesothelioma, enrollment of patients in clinical trials is generally recommended.

Vinorelbine is a vinca alkaloid and can be administered as monotherapy or in combination with gemcitabine in the second-line setting or in subsequent lines of therapy; see chapter 6.1.3. Vinorelbine, when used as monotherapy in the second-line or later treatment lines, can achieve a median OS of 5.4-12.4 months [64, 65, 67, 68]; see chapter 6.1.3. Common side effects of vinorelbine include anemia, thrombocytopenia, leukopenia, and polyneuropathy.