In 2003, the EMPHACIS [4] phase 3 trial established cisplatin and pemetrexed as the standard first-line regimen for unresectable mesothelioma. It proved a significant gain in median overall survival (mOS) for the doublet when compared to cisplatin alone (12.1 vs. 9.3 months, p = 0.020), as well as better median progression-free survival (mPFS, 5.7 vs. 3.9 months, p = 0.001) and overall response rate (ORR, 41.3% vs. 16.7%, p < 0.0001).

A similar phase 3 trial, investigating the combination of cisplatin and a different antifolate, raltitrexed, again proved the superiority of a chemotherapy doublet compared to cisplatin monotherapy (mOS: 11.4 months vs. 8.8 months) [5]. It should be noted, however, that raltitrexed is not registered in many European countries for this indication.

In elderly or unfit populations, carboplatin is a reasonable alternative to cisplatin to decrease toxicity. There are no randomized trials comparing cisplatin vs. carboplatin in MPM, however, data on systematic review and Expanded Access Program (EAP) show that the combination of carboplatin/pemetrexed is not significantly different from cisplatin/pemetrexed in PFS and OS [6,7].

Several attempts have been made to improve the results of the EMPHACIS trial with the use of maintenance therapies, all unsuccessful. A phase 2 trial of Cancer and Leukemia Group B (CALGB) showed that pemetrexed continuation after 4–6 cycles of doublet chemotherapy induction did not improve PFS compared with observation [8], and a randomized phase 2 trial (NVALT19) investigating a switch to maintenance gemcitabine after first-line chemotherapy failed to prove an OS benefit, despite a longer PFS [9]. Since then, several new targets and strategies have been investigated.

The combination of anti-programmed cell death protein 1 (PD-1) antibody Nivolumab and anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) Ipilimumab has shown clinical benefit in different tumor types, including mesothelioma.

The randomized phase 3 trial CheckMate 743 [10] investigated this combination vs. platinum-pemetrexed chemotherapy in the first-line setting. The study met its primary endpoint with a mOS of 18.1 months vs. 14.1 months (HR 95% CI, 0.73 [0.61–0.87]). The benefit of immunotherapy was found regardless of programmed death-ligand 1 (PD-L1) expression and regardless of histological subtypes, although the benefit was greater in patients with non-epithelioid histology. In fact, while mOS in non-epithelioid and epithelioid subtypes treated with immunotherapy were similar (18.1 vs. 18.2 months), mOS in patients treated with chemotherapy differed between non-epithelioid and epithelioid (8.8 months vs. 16.7 months, respectively). Thus, the positive result of the trial is in part driven by the great benefit of immunotherapy in patients with non-epithelioid histology. Furthermore, CheckMate 743 provided interesting data on durable responses: at 3 years, 28% of patients in the nivolumab plus ipilimumab group had ongoing responses, vs. 0% in the chemotherapy group. Safety was acceptable, with comparable percentages of all grade 3–4 treatment-related adverse events in both arms of the trial.

Following the results of Checkmate 743, the combination of Nivolumab and Ipilimumab has become a viable first-line option, to be especially preferred in non-epithelioid histologies. Moreover, other than on its own, the use of immunotherapy drugs has been investigated in combination with standard chemotherapy in a series of trials.

The anti-PD-L1 monoclonal antibody, Durvalumab, has been investigated in combination with platinum-pemetrexed as first-line treatment in two different phase-2 trials: DREAM and PrECOG 0505. In the single-arm DREAM trial [11] patients received a combination of chemotherapy plus Durvalumab for a maximum of six cycles, followed by maintenance with Durvalumab for a maximum of 12 months. In total, 57% of patients were alive and progression-free at 6 months, meeting the primary endpoint of the trial. ORR was 48% and mOS was 18.4 months. Similarly, the PrECOG 0505 trial [12] also met its primary endpoint, with a mOS of 20.4 months vs. 12.1 in the control arm with cisplatin-pemetrexed. The estimated percentages of progression-free patients at 6, 12, and 24 months were 67.3%, 18.2%, and 6.1%, respectively, and ORR was 56.4%. Given these promising results, this strategy is currently under investigation in the randomized phase 3 trial DREAM3R (NCT04334759) [13].

Other two phase 3 trials evaluating chemotherapy and immune checkpoint inhibitors are ongoing: the IND227 trial is examining the combination of anti-PD-1 Pembrolizumab and platinum-pemetrexed chemotherapy (NCT02784171) [14], while the ETOP BEAT-meso trial is evaluating the addition of anti-PD-L1 Atezolizumab to carboplatin/pemetrexed/bevacizumab (NCT0376201) [15].

Malignant mesothelioma cell lines express elevated levels of both VEGF (vascular endothelial growth factor) and the VEGF receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR), compared to normal mesothelial cells, and a correlation between VEGF serum levels and OS has been observed in MPM patients [16,17]. Thus, several trials have tried to target this important signaling pathway.

The randomized phase 3 MAPS trial [17] evaluated the addition of bevacizumab, a VEGF antibody, to cisplatin-pemetrexed therapy in 448 treatment naïve patients. The primary outcome of the trial, mOS, was positive (18.8 vs. 16.1 months, p = 0.0167), although a higher percentage of adverse events, related to the antiangiogenic drug, was noted. Around 24.3% of patients had to stop treatment due to toxicities, compared to 6% in the standard group. After the initial 4–6 cycles of cisplatin-pemetrexed + anti-VEGF, bevacizumab was continued until disease progression: this trial is the first positive evidence for maintenance therapy with an anti-VEGF agent [17].

Another antiangiogenic agent investigated in the first-line setting is Nintedanib, an oral triple angiokinase inhibitor targeting VEGF receptors 1–3, PDGF receptors α and β, FGF receptors 1–3, and Src and Abl kinases. Despite initial promising data, the phase 3 trial LUME Meso investigating the addition of Nintedanib to cisplatin-pemetrexed failed to reach its primary endpoint, PFS [18].

The use of vaccines has been explored in different settings within the first-line realm: as first-line treatment in conjunction with chemotherapy and as maintenance following chemotherapy.

The CRS-207 vaccine is a weakened Listeria monocytogenes strain capable of stimulating the immune system. It has been investigated in a phase 1b trial [19], followed by pemetrexed and cisplatin chemotherapy, obtaining a DCR of 89% and ORR of 57%. Of note, tumor reduction was observed post-vaccine and prior to chemotherapy in 31% of patients. Similarly, since mesothelioma cancer cells often have an abundant expression of WT1 (Wilms’ tumor suppressor gene), a trial using dendritic cells (DC) targeting WT1, in conjunction with chemotherapy (platinum/pemetrexed), is ongoing [20]. This idea was based on initial trials on pretreated mesothelioma patients (although with different types of vaccines) that proved the activation of CD4+ and CD8+ T cells and initial clinical response [21].

Another strategy under study is the use of a maintenance vaccine after first-line chemotherapy. Several trials have used autologous dendritic cells loaded with tumor cell lysate [22,23,24]. A phase I trial using dendritic cells plus low dose cyclophosphamide after chemotherapy +/− surgery proved an acceptable safety and obtained a DCR in 8 out of 10 patients, although patients mostly exhibited early-stage disease [23]; another phase 1 trial obtained a DCR in 4/10 patients, with 1 partial response [24]. A phase 2/3 trial is ongoing [25].

The idea of targeting the unique metabolism of cancer cells is being explored in several ways in mesothelioma patients, mostly but not exclusively in the first-line setting. Arginine is a semi-essential amino acid involved in tumor growth, which can be synthesized by the enzyme argininosuccinate synthase 1 (ASS1). Intratumoral deficiency of ASS1 has been detected in a significant number of patients with cancers, including mesothelioma [26]. Tumors with ASS1 loss are unable to synthesize arginine and they depend on extracellular arginine for survival. Thus, a promising therapeutic strategy may involve the depletion of systemic arginine by using pegylated arginine deiminase (ADI-PEG). In the phase 2 ADAM trial, patients with ASS1-deficient MPM, chemotherapy naïve or progressing to first-line chemotherapy, were randomized to receive ADI-PEG20 plus best supportive care or best supportive care alone. Patients who received ADI-PEG20 had a significantly longer mPFS of 3.2 months vs. 2.0 months of the control group [27]. Promising results were also seen in the phase 1 TRAP study, in which ADI-PEG was added to cisplatin-pemetrexed in treatment naïve patients with ASS1-deficient MPM [28]. This strategy is also currently under investigation in the phase 2/3, randomized, double-blind, ATOMIC trial, involving patients with sarcomatoid or biphasic mesothelioma (NCT02709512) [29].

Another strategy involves targeting the production of adenosine triphosphate (ATP), which is normally achieved through purine synthesis or the adenine salvage pathway, involving the breakdown of methylthioadenosine (MTA) by the enzyme methylthioadenosine phosphorylase (MTAP). The loss of MTAP has been reported in a variety of solid tumors, including mesothelioma [30]. Thus, MTAP-deficient tumors are dependent on the de novo purine synthesis pathway, which can be inhibited by several drugs. One of these drugs is L-alanosina, which has been evaluated in a phase 2 trial including 65 patients with MTAP-deficient solid tumors (16 mesotheliomas): there were no objective responses, although 24% had stable disease, including 2 patients with mesothelioma [31]. Another strategy to exploit this metabolic pathway is being evaluated in a phase ½ study, utilizing MRTX1719, a potent PRMT5-MTA inhibitor in pretreated patients with MTAP-deficient solid tumors (NCT05245500) [32].

Heat shock protein 90 (Hsp90) is a chaperone that allows the correct maturation and stability of a variety of proteins. Its inhibition leads to the degradation of its client proteins, thus impairing the growth and survival of cancer cells [33]. MESO-02 is a phase 1/2 trial of first-line Ganetespib, an Hsp90 inhibitor, with pemetrexed-platinum in patients with MPM. This study was not powered to detect improvements in efficacy but the results were encouraging. Overall, partial response was observed in 14 out of 27 patients (52%) and DCR was 81%, and for patients treated at the maximum tolerated dose of Ganetespib, 10 out of 18 patients (56%) had a partial response and all had disease control (100%) [34]. No other trials are ongoing.