**3. Multimodality treatment for MPM**

### **3.1 Bimodal and trimodal therapy in MPM**

The microscopic complete resection represents an unattainable goal for surgery alone in MPM disease. For this reason, in the last decades, the surgical approach is mainly used as cytoreduction with improved survival, but with the necessity at least to combine with a bimodal/trimodal treatment, although the income of the novel strategies as immunotherapy, are suggesting a multimodal approach [40, 62, 74, 75]. The debate regarding the possible surgical approach as the closest to the radicality for MPM is still opened [76, 77]. In particular, the believers for EPP as the most oncologically correct approach, strongly support the theory that a near-complete surgical resection associated with chemo-or high-dose aRT may be the best treatment for earlier stages [78]. Recent studies have shown improved survival with EPP associated with neoadjuvant or adjuvant chemoradiotherapy [79], in highly-selected patients, although this type of surgery is very aggressive and invasive and not far from postoperative complications with significant morbidity (25%) and mortality (4–15%) [5]. In 2011 the MARS-1 trial compared patients treated with EPP and patients without, defining this surgery as not effective for the high morbidity and 30-day mortality. Particularly, it was a feasibility multicentre randomized controlled trial carried on between October 2005 and November 2008 in 12 English Hospitals. It included 112 patients aged 18 years or older affected by MPM and fit enough to undergo trimodal treatment. In the pre-randomization registration phase, all patients underwent induction platinum-based CT, followed by a clinical revaluation. The main reasons for not proceeding to randomization were a progression of the disease (33 patients), inoperability (five patients), and patient choice (19 patients). Finally, 50 patients were randomly assigned (1:1): 24 to EPP followed by radical RT and 26 to no EPP. The EPP was completed in 16 patients (in five patients it was not started and in three it was abandoned). The clinical outcomes evaluated were the proportion of patients of the EPP group who completed the trimodal treatment; perioperative mortality; quality of life; OS; and disease-free survival. Of the 16 surgical treated patients, there were tw perioperative deaths, while eight completed the trimodal protocol receiving the radical RT. Serious adverse events were higher in the EPP group (n = 10) than in the no EPP group (n = 2). The median OS for the EPP and the no EPP group were 14.4 months and 19.5 months, respectively. The median DFS for the EPP and the no EPP group were 7.6 months and 9 months, respectively. There was a statistically significant difference in the survival outcomes, while a trend toward a lower quality of life in the EPP group was reported.

Following the MARS-1 trial, the scientific community and surgeons focused their attention on PD, which is for sure less invasive than EPP, but not less effective than EPP [80, 81]. In particular, in the last decades, some retrospective studies and systematic reviews described a comparable survival between the two procedures, but with less morbidity and mortality for the patients treated with PD [51, 74, 82–85] with the association of improved quality of life [84–86], although there are also research groups showing no difference in morbidity and mortality [87–89]. For the fact that data are still extremely different [90], the most focused expert for MPM suggests that a multidisciplinary approach and randomized controlled trials need to be set to further define the best surgery in MPM [42, 90–94]. In particular, the MARS-2 trial is trying to set if PD plus iCT may offer an improvement of the survival than the only CT [48, 91, 95]. Regarding the most updated recommendation, several scientific societies use a trimodal approach (surgery, CT and RT) for MPM) [1, 6, 7, 96]. This has been also confirmed by the BTS and the European Respiratory Society for clinical trials [5, 97]; although the timing for this therapy is still unknown as well as also the sequences of each treatment [97]. However, even in the case of the trimodal approach, the long-term survival of these patients remains still poor and only 5% survive at 5 years [98]. The association of pemetrexed (folate antimetabolite) plus B12 and folic acid supplementation [1, 5–7, 97] is an association with the most standard platinumbased therapy, cisplatin, typically, or carboplatin [99, 100], seems to improve the survival by 2.8 months compared with single drug treatment, probably for the fact that B12 and folic acid supplementation reduce the toxicity, especially in elderly patients [101]. In a recent large phase III trial, MAPS, even the use of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor in combination with pemetrexed/cisplatin is strongly recommended, which compares pemetrexed/cisplatin alone [102]. In particular, this trial showed improved survival of 2.7 months in unresectable MPM [102]. The ASCO has suggested vinorelbine as second-line treatment, although the NCCN suggested immunotherapy and CT as second-line treatment [1]. In particular, the second-line pemetrexed seems to have some effect against tumor, reducing the tumor progression, as described in a phase III trial [103]; for vinorelbine, the recent randomized controlled trials showed improved survival in patients treated with this drug [104] with good control of symptoms. There are other treatments as PD with intraoperative intracavitary hyperthermic CT, although more studies need to support and analyze concerning the long-term results [105–113]. The majority of studies that evaluate the trimodal approach are retrospective reviews [114–119]. Since 2007, a multicentric clinical trial demonstrated that iCT plus EPP is feasible [41] showing an OS of 23 months compared with patients not treated with surgery with a survival of 19.8 months [41]. An Italian study published similar results [120]. The combination with neoadjuvant cisplatin/pemetrexed treatment has been discussed since 2009 in a multicentric phase II clinical trial in which patients in stage I-III MPM underwent 4 cycles of cisplatin/pemetrexed. Of these patients, who showed a good response to this medical treatment has been then underwent EPP followed by adjuvant hemithoracic radiation [121] with a median survival of 29.1 months with a 2 year survival of 61.2% [122]. These data let the researcher to conclude that a trimodal therapy may be effective and beneficial [122]. In 2010 the European Organization for Research and Treatment of Cancer (EORTC) published a similar multicentre phase II study [121], in which 65% of the patients underwent EPP 65% plus aRT showed a good result for the 42% of patients, although the neoadjuvant therapy associated with EPP, and adjuvant therapy have been shown to be challenging for the poor long term results [41, 116–119]. With regards to the less invasive surgical treatment in MPM, represented by PD, few studies considered the use of trimodal therapy with PD. In particular, in 2012, a non-randomized prospective trial compared EPP to PD in trimodal approach [82] comparing 3 cycles of either cisplatin/gemcitabine or cisplatin/pemetrexed before EPP and aRT to PD with hyperthermic pleural lavage with povidone-iodine and aCT [82]. However, the median survival was 12.8 months for

#### *Surgical Management of Malignant Pleural Mesothelioma: From the Past to the Future DOI: http://dx.doi.org/10.5772/intechopen.103686*

EPP patients, although a better survival of 23 months has been noted for the second group of patients. These results demonstrated that PD is a more feasible approach with better outcomes for MPM patients underwent trimodal therapy [82]. The role of adjuvant or neoadjuvant radiation therapy is not yet been clarified. In particular, the classic hemithoracic radiation of the entire pleural cavity after EPP is not a problem [123], although the lungs and the other organs cannot be spared from the radiation [124]. However, recent retrospective studies have shown an increased local recurrence in patients treated with adjuvant IMRT following EPP [125]. Recently, the SMART trial concluded the analysis about the role of neoadjuvant IMRT in T1–3N0 MPM followed by EPP, associated with aCT (cisplatin and an anti-folate) in case of mediastinal lymph nodes involvement, achieving encouraging survival results. The results were satisfying in consideration of a median OS of 42.8 months for the epithelial subtype, compared with 18 months for the biphasic one. The authors postulated that a probable mechanism for the distant spread is the spillage of the tumor cells into the coelomic cavities during EPP, hence the IMRT immediately before surgery could inactive these cells making them non-viable, preventing distant seeding with better survival outcomes. Probably the epithelial subtype is more sensible to the action of IMRT. Possible confounder factors for these promising survival results may be as follow: firstly, the criteria for inclusion in the trial were strict leading to a possible selection bias, secondly, the presence of BAP1 mutations (associated with better OS regardless of therapy) was not routinely investigated, so the potential inclusion of these patients in the trial could confound. [43]. In 2016 a group from Memorial Sloan Kettering Cancer Centre (MSKCC) showed the feasibility of IMRT and iCT and PD in IMPRINT phase II trial [126]; however, the same researcher's group published a retrospective study comparing PD trimodal therapy with conventional RT to hemithoracic IMRT [126] with better survival for the patients treated with IMRT [127]. In US both ASCO and NCCN- guidelines strongly support the multimodality treatment for stages I-III epithelioid MPM [128]. The upcoming MARS-2 results may be very helpful to clarify the feasibility and benefits of the multimodality treatment [128]. **Table 5** summarizes the main studies commented on in this paragraph.

#### **3.2 New target therapies in MPM**

Although the scientific community is studying genes and proteins which may be used to set new treatments against MPM, the targets for mesothelioma have not been clearly yet identified. Besides the fact that the common MPM treatments including surgery, CT and radiation therapies show a poor OS from 9 to 17 months from the diagnosis [120, 129, 130], new emerging treatments are setting from the scientific community to improve the quality of life and the survival. The most used approach in this field is immunotherapy which seems to play an important role in MPM for the connections and reactions with the patient immunity, driving immunoregulatory mechanisms with a direct good response [131, 132]. In particular, in patients with MPM showing a high infiltrate of cytotoxic CD8+ T associated with programmed death-ligand 1 (PDL-1) expression, the use of pembrolizumab and nivolumab, or nivolumab with the cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody ipilimumab showed very encouraging results [133, 134].

Several trials have been published showing the use of *immunotherapy* in advanced MPM alone or with standard CT. In particular, pembrolizumab seems to improve by 22%, the response rate compared with gemcitabine or vinorelbine which showed a 6% of response [135]. However, other immunotherapies have been analyzed in the last


*Surgical Management of Malignant Pleural Mesothelioma: From the Past to the Future DOI: http://dx.doi.org/10.5772/intechopen.103686*


*OS: overall survival; EPP: extrapleural pneumonectomy; iCT: induction chemotherapy; aRT: adjuvant radiotherapy; aCT: adjuvant chemotherapy; PD: pleurectomy/decortication; ASC: active symptom control; HIOC: heated intraoperative chemotherapy; NR: not reported; iRT: induction radiotherapy; IMPRINT: intensity-modulated pleural radiotherapy; IMRT: intensity-modulated radiotherapy.*

#### **Table 5.**

*Summary of the main studies commented in Section 3.1.*

decades, for example, in MAPS2 open-label, phase 2 trial that has been studied in 21 French hospitals aiming to set nivolumab alone or combined with ipilimumab. This study showed a 12-weeks disease control in 44% of patients who received only nivolumab, compared with the 50% who underwent nivolumab plus ipilimumab [130]. In January of this year, the Checkmate 743 study was published in Lancet, which reported the superiority of the combination of nivolumab (3 mg/kg every 2 weeks) + ipilimumab (1 mg/kg every 6 weeks) over the above standard. With a significant advantage in the entire study population, particularly marked in the sarcomatoid subtype [136]. For patients progressing to the first line, however, no scheme has been shown to improve survival; however, these patients can be offered gemcitabine, vinorelbine or rechallenge with pemetrexed mono-CT, with unfortunately marginal benefits. Nivolumab, on the other hand, in a phase 3 study (CON-FIRM) conducted against placebo in a heavily pretreated population, has shown efficacy in improving both progression-free survival and OS, but at the moment the drug is not approved in Italy. this indication [137].

From preclinical evidence, the role of angiogenesis in the development of this disease and the potential efficacy of inhibiting this mechanism appears to be relevant, although in lines subsequent to the first some *antiangiogenic drugs* have already been

tested without success [138]. In particular, there is a strong rationale for angiogenesis inhibition in mesothelioma. VEGF plays an important role as an autocrine growth factor and strong mitogen in mesothelioma. Furthermore, the abnormal tumor vasculature increases the interstitial pressure and hypoxia, which may hinder the effect of the anticancer drugs against mesothelioma cells. Ramucirumab is a fully humanized monoclonal antibody directed against the VEGF receptor 2 (VEGFR-2), currently reimbursed in Italy for use in clinical practice in gastric cancer and tested in numerous other solid tumors [139]. VEGFR-2 is expressed not only in 90% of mesothelioma cells but also on the surface of macrophages present in the tumor microenvironment, considered to be responsible for the resistance to chemo- and immunotherapeutic treatments [140]. Inhibiting this receptor seems to allow the switch from a hypoxic and treatment-resistant environment to a more sensitive and immuno-permissive tumor milieu. In this context, the RAMES study was born, a multicentre, phase 2, randomized and double-blind trial [141]. In the study, which involved 26 Italian centres, patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2 and diagnosed with progressive MPM during or after a first-line with platinum and pemetrexed were enrolled. Patients were randomized to a second line with gemcitabine 1000 mg/m<sup>2</sup> on days 1 and 8 of every 21 plus placebo (in the control group) or ramucirumab (an anti-VEGFR2 antibody) at 10 mg/m<sup>2</sup> on day 1 of each cycle up to progression or severe toxicity. Central randomization was performed according to a minimization algorithm, using the following stratification factors: ECOG PS, age, histology and time to first-line progression (>/<6 months) [141]. The primary endpoint of the study was OS. Secondary aims were progression-free survival, objective response rate, disease control rate, drug safety, patient quality of life and the possible presence of predictive markers. It was planned to enroll 156 patients to obtain a power of 80% assuming a benefit of the experimental treatment of 13% at 1 year compared to the standard arm. From December 2016 to July 2018, 165 patients were enrolled, of whom 161 were correctly assigned and received treatment, 83 in the placebo arm and 81 in the experimental arm. The median age was 69, with about 40% over seventy in both arms. 74% of patients were male and 99% had an ECOG PS of 0– 1 [141]. The database was closed in March 2020 and, after a median follow-up of 21.9 months, the observed OS was higher in the experimental arm (Hazard Ratio 0.71; p = 0.028). Specifically, in the ramucirumab arm, the median survival was 13.8 months versus only 7.5 months in the placebo arm and the one-year probability of survival improved from 33 to 56% with the addition of ramucirumab [141]. Progression-free survival was also higher in the experimental arm (median 6.4 versus 3.3 months), but without reaching statistical significance (p = 0.082). Disease control was achieved in 73% of patients treated in the ramucirumab group versus 52% in the placebo arm [141]. A post hoc analysis showed a duration of response of 8.4 months in the experimental arm versus 5.4 months in the standard arm [141]. The pre-specified analysis of the subgroups shows that the survival advantage was independent of the histological subtype and the time of progression of the tumor to the first line [141]. No unexpected toxicities occurred. Grade 3–4 adverse events were recorded in 44% of patients treated with gemcitabine + ramucirumab compared to 30% in the gemcitabine + placebo arm. In particular, the most frequent severe toxicities were neutropenia (20% and 12% in the experimental and standard arms, respectively), arterial hypertension (6% with ramucirumab, 0 with placebo) and fatigue (5% and 4% respectively) [141]. The authors conclude that the association between ramucirumab and gemcitabine significantly improved the OS of patients with progressive MPM following standard first-line CT, with a favorable safety profile. It is

*Surgical Management of Malignant Pleural Mesothelioma: From the Past to the Future DOI: http://dx.doi.org/10.5772/intechopen.103686*

clear, however, that in light of the new standard of treatment with the immunotherapy brace nivolumab + ipilimumab, the scheme proposed by the RAMES study [141] is part of a therapeutic context that has changed from the one that had seen the start of the study: in particular, the scheme gemcitabine—ramucirumab has not been tested in patients who have received the combination of the 2 immunotherapies. In addition, the treatment landscape of pleural mesothelioma may still change, pending the results of randomized trials, following interesting phase 2 data for first-line chemoimmunotherapy (NCT02899195 and NCT04334759). Taking this into account, ramucirumab, given its action not only on cancer cells but also on the immune infiltrate and tumor microenvironment, could continue to play a role in patients progressing to chemo-immunotherapy, but further studies will need to be conducted.

Another important drug is the *CTLA-4 inhibitor* tremelimumab which has been studied in a randomized phase II trial (DETERMINE) in 571 patients with a median survival of 7.7 months compared with patients who underwent placebo with 7.3 months of survival: although its safety profile was consistent, tremelimumab did not significantly improve OS [142].

#### **3.3 T-cell therapies**

Adoptive T-cell therapy seems to be promising in MPM and this has been highlighted in a recent phase I trial studying the *chimeric antigen receptor (CAR) T-cell therapy* targeting mesothelin in MPM patients. Of 18 patients treated with a single dose of CD28-costimulated MSLN CAR-T cells plus the I-caspase-9 safety gene treated intrapleurally showed that in 14 patients, 2 had complete remission, 5 partial, and 4 patients showed the stability of the disease [143]. In the context of safety, no CAR-T cell-related toxicities have been noted. The most promising approach seems to be represented by the combination between CAR-T cells and *anti- programmed death-1 (PD-1) therapy* [144], although these considerations need to be further investigated.

#### **3.4 Vaccines**

One of the most considered new therapies against MPM is vaccine therapy. In particular, the *Wilms tumor-1 (WT1) protein* in MPM is highly expressed and it is considered a future target for the setting of a cancer vaccine. A recent phase II randomized trial evaluated a WT1 analogue peptide vaccine associated with immunologic adjuvants, showing an improved survival at 1 year (45%) compared with the control group with a 33% of survival rate. However, the OS for vaccinated patients was 22.8 months compared with patients not treated (18.3 months) [145].

Other new target agents as *dendritic cells (DC) therapy* started to be recently considered to investigate the anti-tumor immune response [146, 147].

#### **3.5 Other investigational therapies**

Besides the vaccines and the T-cells therapies which are coming up for the better control of MPM, the oncolytic viruses and other targets as some vascular endothelial growth factors receptors (*VEGFR*), the platelet-derived growth factor receptor (*PDGFR*), and the fibroblast growth factor receptor (*FGFR*) tyrosine-kinase inhibitor, are under consideration. Some phase I/II clinical trials are running at the moment to evaluate the safety of the biological effects [148–152].
