**1. Introduction**

Malignant pleural mesothelioma (MPM) is an extremely aggressive plural malignancy, which is mainly caused by asbestos exposure [1]. The benefit of surgical resection is controversial, because only a minority of patients with MPM meets the criteria for surgery, and it is unrealistic to assume that surgery will achieve a complete tumor resection without a micro residual tumor. Systemic chemotherapy with platinum plus pemetrexed is the recommended first-line systemic therapy for advanced MPM. However, the median overall survival (OS) is only approximately 12 months [2]. For patients that fail first-line chemotherapy, a standard second-line chemotherapy has not been defined [3]. Hence, it is critically essential to develop a new treatment option.

Recently, immunocheckpoint inhibitors (ICIs) have achieved great success in treating several cancer types [4–7]. Basic research about the immune-suppressive tumor microenvironment in MPM has suggested that MPM might be a good candidate for immune therapy [8, 9]. CD8+ tumor-infiltrating lymphocytes were reported to predict a favorable prognosis after a resection of MPM [10]. In fact, recently, ICIs have shown promising results for patients with MPM.

In this chapter, we summarize recent studies on immunotherapy for MPM.

### **2. Anti-cytotoxic T-lymphocyte antigen 4 antibody**

Anti-cytotoxic T-lymphoctye antigen 4 (CTLA-4) antibody was the first reported ICI for treating MPM. To date, three clinical trials have tested anti CTLA 4 antibody monotherapy for MPM.

In the first phase II trial (MESOT-TREM-2008), the anti-CTLA-4 monoclonal antibody, tremelimumab (15 mg/kg) was administered intravenously once every 90 days to patients with MPM [11]. Twenty-nine patients with MPM that had failed a first-line platinum-based regimen were enrolled. Of these, no patients achieved a complete response, 2 patients achieved a partial response, and 7 others achieved durable disease control. The median progression-free survival (PFS) was 6.2 months, and the median OS was 10.7 months. The second phase II trial (MESOT-TREM-2012), enrolled 29 patients with MPM that were treated with 10 mg/kg tremelimumab, initially every 4 weeks for 6 doses, then every 12 weeks [12]. The disease control rate was slightly improved after this regimen modification; one patient achieved a partial response, and 11 patients achieved disease control.

Based on these two trials, a large scale, randomized trial (DETERMINE) was conducted [13] with 571 patients with MPM. Of these, 382 patients were assigned to tremelimumab and 189 patients were assigned to placebo. However, there was no significant difference in PFS or OS between these two groups. After the DETERMINE trial, anti-CTLA-4 antibodies were investigated only in combination with an anti-programmed cell death protein 1 (anti-PD-1) antibody or antiprogrammed death ligand 1 (PD-L1) antibody.

#### **3. Anti-PD-L1 antibody**

Mansfield et al. reported that PD-L1 was expressed in approximately 42 of 106 MPM specimens, and that PD-L1 expression was significantly correlated with poor survival (OS: 5 months in a PD-L1-positive group vs. 14.5 months in a PD-L1-negative group) [14]. Cedrés et al. also reported that PD-L1 expression was a negative prognostic factor in patients with MPM [15]. These results supported the notion that PD-L1 might serve as a potential target for immunotherapy in MPM.

Avelumab is a human IgG1 monoclonal antibody that binds to PD-L1 [16]. Hassan et al. described a phase I trial (JAVELIN Solid Tumor) that enrolled 53 patients with unresectable MPM. Those patients had failed first-line chemotherapy with platinum and pemetrexed. When they were treated with avelumab, the objective response rate was 9% (one complete response and four partial responses) [17]. Responses were durable (median, 15.2 months), and they were observed both in patients with PD-L1-positive tumors (objective response rate [ORR]: 19%) and in those with PD-L1-negative tumors (ORR: 7%). The median PFS was 4.1 months, and median OS was 10.7 months.

Another anti-PD-L1 antibody, durvalumab, was recently evaluated for efficacy in 54 patients with MPM that were not treated previously. Durvalumab was combined with cisplatin and pemetrexed as a first-line chemotherapy (DREAM trial) [18]. The ORR was 48%, and, 31/54 (57%) patients were progression-free at 6 months. Based on the phase II trial results, a phase III trial is currently planned.

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*Immunotherapy in Malignant Pleural Mesothelioma DOI: http://dx.doi.org/10.5772/intechopen.95823*

achieved disease control. The median OS was 18 months.

PFS was 4.8 months, and the median OS was 9.5 months [22].

another 8 patients (24%) displayed stable disease at 12 weeks.

PFS was 5.7 months and the median OS was 16.6 months.

**5. Combination therapy with ICIs**

maximize T-cell activation.

Pembrolizumab is an antibody against PD-1. Pembrolizumab was tested for efficacy in 25 patients with PD-L1-positive MPM in a non-randomized, phase Ib trial [19]. Five patients (20%) achieved a partial response, and 72% of patients

A phase II trial of pembrolizumab monotherapy was conducted in 65 patients with MPM that had been treated previously [20]. Among those patients, 19% achieved a partial response to pembrolizumab. The median PFS and OS were 4.5

Based on these two trials, pembrolizumab was administered, off-label, to 93 patients with MPM in Switzerland and Australia [21]. The ORR was 18%, and the median PFS and OS were 3.1 months and 7.2 months, respectively. Patients with high PD-L1 expression showed improved ORR (44%) and PFS (6.2 months). Recently, a retrospective study from Australia analyzed data from patients with MPM that received pembrolizumab as the first-, second-, or subsequent-line treatment. They found an ORR of 18%, and a disease control rate of 56%. The median

Nivolumab is a fully humanized monoclonal anti-PD-1 antibody. It was first tested in 34 patients with recurrent MPM in the Netherlands [23]. In that singlecenter trial, patients with MPM received 3 mg/kg intravenous nivolumab every 2 weeks. Among 34 patients, 8 patients (24%) achieved a partial response, and

A Japanese group also evaluated the efficacy and safety of nivolumab in 34 patients with advanced MPM. That study tested nivolumab as a salvage therapy in a single-arm phase II study (MERIT study) [24]. Patients received 240 mg nivolumab intravenously every 2 weeks. Ten (29%) patients showed an objective response. The median duration of the response was 11.1 months, and the disease control rate was 68%. The median PFS and OS were 6.1 and 17.3 months, respectively. Among patients with PD-L1-positive tumors (≥1% expression), the ORR was 40%. Based on those results, nivolumab was approved in Japan for unresectable recurrent MPM.

Based on the favorable results obtained with ICI monotherapy, recent investigations tested combination treatments, with an anti-PD-1 or anti-PD-L1 antibody combined with an anti-CTLA-4 antibody. This combination was expected to

NIBIT-MESO-1 was open-label, non-randomized, phase II trial, in which 40 patients with MPM received at least one dose each of tremelimumab and durvalumab [25]. Eleven patients (28%) displayed an objective response. The median

IFCT-1501 MAPS2 was a multicenter, open-label, randomized, phase II trial, in which 108 patients with MPM were randomly assigned to receive intravenous nivolumab or intravenous nivolumab plus ipilimumab. In the intention-to-treat population, 12-week disease control (primary endpoint) was achieved by 25/63

**4. Anti-PD-1 antibody**

and 11.5 months, respectively.

**4.2 Nivolumab**

**4.1 Pembrolizumab**
