Original Article Multimodal therapy of epithelioid pleural mesothelioma: improved survival by changing the surgical treatment approach Laura V. Klotz, Hans Hoffmann, Rajiv Shah, Florian Eichhorn, Christiane Gruenewald, Elena L. Bulut, Raffaella Griffo, Thomas Muley, Petros Christopoulos, Philip Baum, Peter Huber, Seyer Safi, Marc Kriegsmann, Michael Thomas, Helge Bischoff, Hauke Winter, Martin E. Eichhorn

Pleural mesothelioma is an aggressive malignancy arising from pleural mesothelial cell lining, predominantly associated with prior exposure to asbestos. The ban on asbestos use has led to its lower incidence in many countries, but globally the disease burden is expected to rise. Therefore, well-planned research is needed to develop more effective, tolerable and affordable drugs. The development of novel treatment has been too slow, with only two regimens of systemic therapy with robust phase 3 data approved formally to date. The treatment scenario for resectable disease remains controversial. However, recent developments in the understanding of disease and clinical trials have been encouraging, and may add better treatment options in the coming years. In this review, we discuss the current treatment options for pleural mesothelioma and shed light on some recent studies and ongoing trials.

Despite the approval of nivolumab/ipilimumab, the prognosis of patients with pleural mesothelioma (PM) remains poor. Although this combination has shown improved survival in the landmark CheckMate (CM)-743 trial, evidence from real-world settings remains limited. In this retrospective, multicenter study, the outcome and safety data for 135 consecutive patients with first-line nivolumab/ipilimumab were evaluated among 1,575 adult patients with PM from 12 German cancer centers. Radiologic response and progression were analyzed according to the revised modified RECIST criteria. The median overall survival (OS) was 13.1 months for the unselected real-world cohort, and 15.5 months for CM-743-eligible patients (16.7 months for the non-epithelioid and 10 months for the epithelioid subtypes). Patients who experienced partial responses to nivolumab/ipilimumab had significantly longer survival than those without (24 months vs. 10.3 months; p = 0.00026). 37 % of patients experienced immune-related adverse events (irAEs), among whom 58 % had grade 3/4 toxicity. IrAEs of any grade were associated with longer survival (17.3 months vs. 11.7 months for patients without irAEs; p = 0.022). Furthermore, grade 1/2 irAEs were associated with even better outcomes when compared to grade 3/4 toxicities (22.7 months vs. 16.7 months median OS) and absence of toxicity (p < 0.0167 for trend). Overall survival with first-line nivolumab/ipilimumab in the real-world setting is comparable to the CM-743 results among trial-eligible patients, especially with non-epithelioid tumors, but shorter for the unselected cohort. IrAEs, in particular those of low-grade, were associated with better outcomes. In the absence of predictive biomarkers and with few therapeutic options available, both dual checkpoint blockade and platinum-pemetrexed chemotherapy remain viable first-line regimens.

Background: Immunotherapy has significantly improved overall survival in patients with pleural mesothelioma, yet this benefit does not extend to those with the epithelioid subtype. Tumor growth is believed to be influenced by the immune response. This study aimed to analyze the tumor microenvironment to gain a better understanding of its influence on tumor growth. Methods: The tumor immune cell infiltration of 188 patients with pleural mesothelioma was characterized by multiplex immunofluorescence staining for CD3+ cells (CD3+), CD4+ cells (CD3+/CD4+), CD8+ cells (CD3+/CD8+), Treg (CD3+/CD4+/CD8-/CD163-/Foxp3+), PD1 cells (PD1+), and T helper cells (CD3+/CD4+/CD8-/CD163-/FoxP3-). The distribution of specific immune cells was correlated with clinical parameters. Results: A total of 188 patients with pleural mesothelioma (135 epithelioid, 9 sarcomatoid, 44 biphasic subtypes) were analyzed. The median age was 64.8 years. Overall survival was significantly longer in the epithelioid subtype than in the non-epithelioid subtype (p = 0.016). The presence of PD-L1 expression had a negative effect on overall survival (p = 0.041). A high ratio of CD4+ cells to regulatory T cells was associated with a significantly longer overall survival of more than 12 months (p = 0.015). The ratio of CD4+ cells to regulatory T cells retained its significant effect on overall survival in the multivariate analysis. Conclusions: Distinct differences in the T cell immune infiltrates in mesothelioma are strongly associated with overall survival. The tumor microenvironment could therefore serve as a source of prognostic biomarkers.