**3. Immune checkpoint inhibitors**

Anti-CTLA-4 antibodies include tremelimumab and ipilimumab. Drugs that block PD-(L)-1 include pembrolizumab, nivolumab, durvalumab, and avelumab.

#### **3.1 Nivolumab monotherapy**

The MERIT trial was a phase 2, single-phase study that evaluated the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent MPM, who were refractory or intolerant to 1–2 regimens of therapy [15]. In that study, 34 patients received nivolumab (240 mg intravenously) every 2 weeks, until they displayed progressive disease or unacceptable toxicity. The primary endpoint was the objective RR, which was 29.4% (10/34). The median OS and PFS times were 17.3 and 6.1 months, respectively. Among the 34 patients, 11 (32%) experienced grades ≥3 treatment-related adverse events, including 4 patients (12%) with adverse events that led to study treatment discontinuation (2 events of interstitial pneumonia, and 2 events of pneumonitis). Based on those results, nivolumab was approved for patients with MPM that were refractory or intolerant to prior chemotherapy.

The therapeutic efficacy of nivolumab was confirmed in a phase III trial, which demonstrated that single-agent nivolumab provided a significant improvement in both OS and PFS [16]. In that study, 332 adult patients with previously treated, unresectable, histologically confirmed malignant mesothelioma were randomized to nivolumab or placebo. The median OS was immature, but it was significantly prolonged with nivolumab (9.2 vs. 6.6 months; HR: 0.72; 95% CI: 0.55–0.94; p = 0.02). The median PFS was also prolonged with nivolumab compared to placebo (3.0 vs. 1.8 months; HR: 0.62; 95% CI: 0.49–0.78; p < 0.001). Grades 3–4 treatment-related adverse events occurred in 19% of the nivolumab arm and 6.3% of the placebo arm. Treatment discontinuation due to toxicity occurred in 13.1% of the nivolumab arm, versus 2.7% of the placebo arm.

#### **3.2 ICI-ICI combination**

The MAPS2 trial was a multicenter randomized, open-label, phase 2 trial that investigated nivolumab plus ipilimumab versus single-agent nivolumab, as a salvage treatment [17]. In the intention-to-treat population, 12-week disease control was achieved by 32 of 62 patients (52%; 95% CI: 39–64) in the nivolumab plus ipilimumab group and 25 of 63 patients (40%; 95% CI: 28–52) in the nivolumab group. Asthenia was among the most frequent grade 3 adverse events (n = 3 [5%] in the combination arm and n = 1 [2%] in the nivolumab arm).

The CheckMate 743 trial was a global, open-label, randomized, phase 3 study that investigated first-line nivolumab plus ipilimumab versus the standard platinum plus pemetrexed chemotherapy [18]. In that study, 605 patients with previously untreated, unresectable MPM were randomly assigned to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks), administered for up to 2 years, or platinum (cisplatin or carboplatin) plus pemetrexed chemotherapy, administered once every 3 weeks for up to 6 cycles. The primary endpoint was OS. The OS was significantly extended in the nivolumab plus ipilimumab arm, with a median of 18.1 months (95% CI: 16.8–21.4), compared to 14.1 months (95% CI: 12.4–16.2) in the chemotherapy arm. The HR was 0.74 (96.6% CI: 0.60–0.91). The 1-year and 2-year OS rates were, respectively, 68% (95% CI: 62.3–72.8) and 41% (95% CI: 35.1–46.5) in the nivolumab plus ipilimumab arm, and 58% (95% CI: 51.7–63.2) and 27% (95% CI: 21.9–32.4) in the chemotherapy arm. Across most subgroups, OS was more favorable with nivolumab plus ipilimumab compared to chemotherapy. The most frequently reported grade 3 or higher serious treatment-related adverse events were colitis (3%), in the nivolumab plus ipilimumab arm, and anemia (2%) in the chemotherapy arm.

#### **3.3 ICI-chemotherapy combination**

The DREAM trial was a multicenter, single-arm, open-label, phase 2 trial conducted in 9 institutions in Australia [19]. In that study, 54 patients received cisplatin, pemetrexed, and durvalumab, in 3-week cycles, for up to 6 cycles. Durvalumab was continued for maintenance for up to 12 months. The primary endpoint was PFS at 6 months. Among 54 patients, 31 (57%; 95% CI: 44–70) were alive and progressionfree at 6 months. The most frequent grade 3–4 adverse events were neutropenia (13%), nausea (11%), and anemia (7%). Five patients died during the study treatment, but none of the deaths were attributed to the study treatment.

The efficacy and safety of cisplatin, pemetrexed, and nivolumab were tested as first-line therapy for MPM in a phase II study, called JME-001 [20]. Cisplatin, pemetrexed, and nivolumab were administered intravenously every 3 weeks, for a total of 4 to 6 cycles. Patients that did not progress during the combination phase received maintenance therapy with nivolumab until disease progression or unacceptable toxicity. Among 18 enrolled patients, 14 (77·8%; 95% CI: 52·4–93·6) showed an objective response. Ten (55·6%) patients experienced grade 3 or worse adverse events, including disorders of metabolism or nutrition (33·3%), loss of appetite (27·8%), anemia (16·7%), and hyponatremia (11·1%). No treatment-related deaths occurred.

The efficacy and safety of pembrolizumab in combination with standard pemetrexed and platinum-based chemotherapy is currently being tested as a first-line treatment for MPM in phase II/III randomized study (NCT02784171) and in multicenter, open-label, non-randomized study (NCT04153565). Those results will be disclosed within a couple of years.
