Dual immune Checkpoint Inhibitors in The Treatment of Malignant Pleural Mesothelioma

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Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive and incurable cancer that originates from the mesothelial cells of the pleural cavity [1]. It is associated with a long latency period of inhalation of asbestos fibers of 20-40 years [2]. There are three subtypes of MPM, such as epithelioid (60%), sarcomatoid (10%), and biphasic (30%), which comprise both epithelioid and sarcomatoid histological features. Treatment: The standard first-line chemotherapy for MPM consists of the doublet cisplatin plus pemetrexed. The regimen has a low response rate ranging from 26.3% to 41% [3], and extends the median overall survival (OS) by 2-3 months. Addition of bevacizumab a vascular endothelial growth factor (VEGF) inhibitor to cisplatin plus pemetrexed has been shown to extend the median overall survival up to 19 months, versus 16 months with cisplatin plus pemetrexed chemotherapy [4]. Tumour cells express immune suppressive receptors known as immune-checkpoints (IC), which inhibits T cell immune response, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4 [5], programmed cell death-1, and its ligands PD-1/PD-L1/1, and lymphocyte activation gene-2 [6]. Currently, there are several monoclonal antibodies which have been developed to block the immune checkpoints, such as nivolumab, ipilimumab, and durvalumab [7]. The combination of nivolumab a CTLA-4 inhibitor, and ipilimumab a PD-1 inhibitor has been shown to be superior compared with nivolumab alone in the treatment of MPM. The dual ICI has been shown to significantly improve the disease control rate (DCR) to 52% versus 40% compared with nivolumab alone, and to increase the objective response rate (ORR) to 28% vs 19%, and the median progression free survival (PFS) to 5.6 months versus 4 months compared with nivolumab alone [8]. However, dual ICI treatment was associated with higher treatment-related adverse effects (93% vs 89%) [8]. Updated results of the IFCT-1501 MAPS2 results revealed median overall survival of 15.9 months (10.7-22.2) in patients treated with nivolumab plus ipilimumab compared with 11.9 months (6.7-17.4) in patients treated with nivolumab alone [9]. The CheckMate trial has shown that the median OS with this treatment was almost similar in the epithelioid histopathology, and non epithelioid histopathology subtypes (18.7 months versus 18.1 month, respectively) [10]. There was significant benefit observed in the non-epithelioid subgroup for the checkpoint inhibitor combination versus the standard of care chemotherapy (18.7 month vs 8.8 months). However, this might have been attributed to the established inferior effect of chemotherapy in the non-epithelioid histological subtype [10]. Conclusions: Dual immune checkpoint inhibitors, such as nivolumab plus ipilimumab significantly improve the ORR, DCR, median OS, and PFS, and are effective in both the epithelioid and non-epithelioid histology subtypes of MPM. Dual ICI therapy is superior to SoC chemotherapy, particualaly in the non-epithelioid histotype, which has a poor ORR to chemotherapy. Currently, nivolumab plus ipilimumab immunotherapy is recommeded as first-line therapy for MPM.

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