Malignant pleural mesothelioma: New hope in the horizon with novel therapeutic strategies

Cancer Treatment Reviews 41 (2015) 27–34

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

New Drugs

Malignant pleural mesothelioma: New hope in the horizon with novel therapeutic strategies J. Remon a,⇑, N. Reguart b,1, J. Corral c,2, P. Lianes a,3 a

Hospital de Mataró, Barcelona, Spain Hospital Clínic, Barcelona, Spain c Hospital Universitario Vírgen del Rocío, Sevilla, Spain b

a r t i c l e

i n f o

Article history: Received 25 August 2014 Received in revised form 26 October 2014 Accepted 28 October 2014

Keywords: Malignant pleural mesothelioma Epidemiology Chemotherapy Immunotherapy Second line Maintenance

a b s t r a c t Malignant pleural mesothelioma (MPM) is a rare but aggressive malignancy of the pleura, with a strong causal link to asbestos exposure. MPM incidence has been increasing in recent years and it is not expected to fall off in the next two decades. Prognosis of MPM patients is modest since the vast majority of patients are diagnosed at advanced stage and because platinum-based chemotherapy remains the cornerstone of treatment, with no standard second line treatment. Most current efforts to improve outcomes are based on a better understanding of the stromal compartment and deregulated pathways leading ultimately to the design of clinical trials based on novel therapeutic approaches such as immunotherapy or molecular-directed compounds. This review seeks to update the last clinical trials investigating novel agents in unresectable MPM. Ó 2014 Elsevier Ltd. All rights reserved.

Introduction Malignant mesothelioma (MM) is a rare but aggressive form of cancer arising from the mesothelial cells of the pleura (80% of all mesotheliomas originate in the pleura), peritoneum or pericardium, which has a strong causal link to asbestos exposure. Although some reports suggest a correlation between time of asbestos exposure and the risk of developing MM, data from five large studies published over the last decade provide evidence that the risk of MM is not appreciably modified by longer exposures time. Therefore, stopping asbestos contact does not subsequently modify the risk of developing MM [1].

⇑ Corresponding author at: Medical Oncology Department, Hospital de Mataró, Carretera de la Cirera, s/n, 08304 Mataró, Barcelona, Spain. Tel.: +34 937 417 700; fax: +34 937 417 780. E-mail addresses: [email protected] (J. Remon), [email protected] (N. Reguart), [email protected] (J. Corral), [email protected] (P. Lianes). 1 Address: Medical Oncology Department, Hospital Clinic de Barcelona, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 932 275 400; fax: +34 934 546 500. 2 Address: Medical Oncology Department, Instituto de Biomedicina de Sevilla-IBIS, Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot, s/n, 41013 Seville, Spain. Tel.: +34 955 012 000; fax: +34 954 232 992. 3 Address: Medical Oncology Department, Hospital de Mataró, Carretera de la Cirera, s/n, 08304 Mataró, Barcelona, Spain. Tel.: +34 937 417 700; fax: +34 937 417 780. http://dx.doi.org/10.1016/j.ctrv.2014.10.007 0305-7372/Ó 2014 Elsevier Ltd. All rights reserved.

The WHO estimates that at least 125 million people globally are exposed to asbestos in the workplace. MPM incidence is variable within and between countries because of differences in asbestos consumption [2]. Based on the International Agency for Research on Cancer (IARC), among 120,544 new cases of MM were reported during the period 1988-2002, there was a geographic distribution with 58% of these cases from North American region, 33% from European region, 5% from Oceania region, and 3% from Asian region [3]. However, global magnitude of MM is likely to be underestimated by unreported cases in mortality registries of developing countries [4], and inaccurate death certification [5]. All of these factors could explain the discrepancy in age-standardized mesothelioma incidence worldwide (Table 1) [6]. Although, the use of asbestos has already been prohibited in 55 countries worldwide, it is unlikely we see an impact on the incidence of asbestos-related diseases due to the long latency period of MM. Therefore, MPM incidence has continued rising worldwide [2], and it is not expected to drop until sometime between 2015 and 2030 [7]. Based on the World Health Organization (WHO) mortality database (1994–2008), the worldwide age-adjusted mortality rate (AAMR) for mesothelioma was 4.9 per million, increasing significantly at annual rate of 5.4%. Moreover, analysis of trends by country revealed a significant annual increase in Japan (3.5%) and a decrease in the United States (0.84%) [8], suggesting that disease burden is slowly shifting toward those countries that used asbestos more recently.

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MPM is a less common disease in women (with a male to female ratio of 3.8:1) [3], and has a much favourable outcome (5y-OS: 13.4% vs. 4.5, p < 0.0001) independent of confounders such as age, stage and treatment [9]. The majority of MPM patients present with unresectable disease or deemed inoperable due to age or medical comorbidities and are primarily treated with systemic therapies with the goals of improve quality of life and survival prolongation. However, MPM eventually becomes resistant to initial therapy and therefore patients have a limited life expectancy [10]. Based on the increasing incidence and the dismal prognosis, new therapeutic approaches are long awaited in MPM. This review seeks to update the state of the art for advanced MPM treatment as well as novel agents under clinical investigation such as cytotoxic therapies, targeted therapies and immunotherapy (Table 2 and Fig. 1).

Cytotoxic therapy: standard-of-care combination chemotherapy Cisplatin and antifolate-based combination chemotherapy is the current standard first-line treatment for advanced and unresectable MPM patients. Two phase III trials showed that the combination of at least 6 cycles of cisplatin with an antifolate (pemetrexed or raltitrexed) conferred 3 months median overall survival (mOS) benefit over cisplatin alone (12.1 vs. 9.3 months or 11.4 vs. 8.8 months, respectively) [11,12] (Table 3). The substitution of cisplatin by carboplatin is widespread by the perception of lesser toxicity. Although carboplatin use is not supported by randomised evidence, three phase II studies reported that the combination of pemetrexed–carboplatin was also effective in MPM (time to progression 7 months and OS 14 months), without differences in outcome between age groups (<70 years vs. patients P 70 years) and only a greater hematological toxicity was observed in the older population subgroup [13,14]. Moreover, an expanded access program (EAP) showed a slightly lower response rate (RR) for carboplatin-based therapy compared with cisplatin plus pemetrexed (26% vs. 21%), but 1-yOS was similar both groups (63% vs. 64%, respectively) [15]. Cisplatin and gemcitabine were incorporated into clinical practice following results from two phase II trials [16,17]. Evidence suggests that the activity of platinum based gemcitabine is as effective as platinum based pemetrexed [18,19], even with prolonged infusion of low-dose of gemcitabine [20]. However, given the lack of phase III evidence, the use of gemcitabine as first-line treatment is not supported. Pemetrexed continuation maintenance therapy in patients who did not progress during four cycles of pemetrexed–cisplatin therapy significantly increases progression free survival (PFS) and OS over placebo in patients with advanced non-small cell lung cancer (NSCLC) [21]. Although a small Dutch study has demonstrated the safety and feasibility of continuing single agent pemetrexed after 6 courses of pemetrexed-containing regimen in MPM [22], the maintenance strategy has not yet been validated in a prospective Table 1 Age-standardised world (ASR-W) mesothelioma incidence per 100,000. The table includes the upper and the lower incidence by gender and continent.

Africa America, Central and South America, North Asia Europe Oceania

ASR-W male

ASR-W female

0.1–0.4 0.0–1.2 0.1–2.7 0.1–1.1 0.2–4.0 0.1–4.7

0.3 0.0–0.8 0.1–0.5 0.0–0.8 0.1–1.0 0.6–0.6

Created by information from Cancer incidence in Five continents, volume X.

randomized clinical trial. The ongoing randomized phase II CALGB 30901 trial is trying actually to validate this hypothesis (NCT 01085630), consequently, maintenance treatment is not standard of care. Moreover, in MPM there is no widely approved salvage therapy beyond antifolates treatment. In the phase III pemetrexed/cisplatin trial, the use of post-study chemotherapy was analysed suggesting that second–line treatment may yield survival improvement in MPM [23]. The only randomised trial in this setting was performed before the widespread use of pemetrexed as first-line treatment, comparing pemetrexed over best supportive care (BSC). The trial showed an improvement in PFS without advantage in quality of life or OS, probably as a consequence of crossover in the BSC arm [24]. Data from the EAP also suggests that pemetrexed alone or in combination with cisplatin could be feasible as second-line treatment in pemetrexed-naïve patients [25,26]. Moreover, pemetrexed retreatment is a feasible option in fit patients, especially among those patients with longer elapsing time (>12 months) from the end of first line pemetrexed treatment until the start of second line therapy [27,28]. Despite it looks like an old standard, an exploratory analysis from the MS01 trial reported a survival advantage that approached significance with BSC plus vinorelbine vs. BSC alone (HR 0.80, 95% CI: 0.63–1.02, p = 0.08), suggesting clinical activity with this drug [29]. Then, vinorelbine appears to be a reasonable palliative option mainly in patients with ECOG PS 0 and with prolonged PFS after pemetrexed therapy [30]. In vitro, data suggests that vinorelbine requires BRCA1 (thought to be absent in 38% of mesothelioma samples) in order to induce apoptosis in mesothelioma [31]. A phase II trial (NCT02139904) is trying to validate the efficacy of oral vinorelbine efficacy over placebo by measuring levels of BRCA1 expression as a putative predictor of sensitivity. Likewise, in this setting, phase I clinical trials may be a reasonable option for fit patients without any treatment option [32]. Probably cytotoxic therapies have reached a plateau in MPM and new approaches based on deregulated pathways and targeted therapies are necessary to improve survival in MPM. Targeted therapies Further comprehension of molecular pathogenesis in MPM is required for developing new diagnostic tools and new-targeted therapies such as druggable mutations in NSCLC. However, MPM is being molecularly characterised mostly by the loss of tumor suppressors genes, rather than gain of function mutations. A series of 123 advanced MPM tissue samples (96 epihelioid, 22 biphasics, 5 sarcomatous histologic subtypes) were retrospectively analysed through Next-Generation Sequencing (NGS) to explore the genomic profiling. The most frequent mutated gens were BAP1, APC, FLT3, TP53, KDR, KIT, PIK3CA, and accumulation of mutations in several key pathways was significantly associated with an increased risk of disease progression [33]. In a recent report, none of 63 MPM samples examined showed overexpression or translocation of Anaplastic Lymphoma Kinase (ALK), excluding this gene as a possible biomarker applicable to MPM [34]. Therefore, NGS might provide a good opportunity for elucidating the molecular landscape of MPM and to identify deregulated pathways for customized therapy. The improvement of treatment selection on basis of individual characteristics and biomarkers represents a relevant challenge in the treatment of MPM. BAP1 mutation Because only a small fraction of asbestos-exposed individuals develop MPM, and because mesothelioma clustering is observed

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J. Remon et al. / Cancer Treatment Reviews 41 (2015) 27–34 Table 2 Selected ongoing studies in malignant pleural mesothelioma. Drug

Trial

Phase

Setting

References

Pemetrexed Bevacizumab Cediranib Nintedanib NGR-hTNF

CALGB 30901 MAPS SWOG 0905

II II/III I/II II II III IIb I/II II II II II IIb

Maintenance Induction & maintenance Induction & maintenance Induction & maintenance Maintenance 2nd line Maintenance Induction & maintenance 2nd line 2nd in Merlin/NF2 negative tumor 2nd line 2nd line-according BRCA1 level 2nd line

NCT 01085630 NCT 00651456 NCT 01064648 NCT01907100 NCT 01358084 NCT 01098266 NCT 01870609 NCT 01590160 NCT 00770120 NCT 01024946 NCT 01279967 NCT02139904 NCT01843374

NGR019 NGR015 COMMAND MESO02 SWOG 0722 MSKCC ADAM VIM

Defactinib Ganetespib Everolimus ADI-PEG20 Vinorelbine Tremelimumab

Bevacizumab Nintedanib Cediranib NGR- hTNF

Anangiogenic therapy BAP1 mutaon

HDACi

20%

TSG Lost of NF2

NGS

mTOR and FAK inhibitors

Merlin silencing

40%

Mutaons

APC, FLT3, TP53, KDR, KIT, PIK3CA

Clinical Trials

PDL-1

Clinical Trials

CTLA4

Tremelimumab

An-Mesothelin

Amatuximab, CRS-207, SS1P

Stromal modulaon

TGFβ

Fresolimumab

Anmetabolites

ASS1-deficient

Arginine-lowering agents

Immunotherapy

Fig. 1. New therapies in malignant pleural mesothelioma. TSG: tumor suppressor gene. NGS: next generation sequencing.

Table 3 Main efficacy results of two phase III trials in the first-line setting in patients with advanced MPM. EMPHACIS Trial

EORTC Trial

Cisplatin plus pemetrexed

Cisplatin

Cisplatin plus raltitrexed

Cisplatin

N RR, % p value

226 41.3

222 16.7

126 23.6

124 13.6

OS, months HR p value

12.1

9.3

11.4

TTP, months HR p value

5.7

<0.0001

0.56

0.77 0.02 3.9 0.68 0.001

8.8 0.76 0.048

5.3

4 0.78 0.058

Germline BAP1 mutations have also been identified in nonasbestos induced familiar mesotheliomas, which usually belong to the long survivor group and BAP1 is most probably functioning differently than in sporadic cases [37]. Germline mutations of BAP1 also predispose to other several different tumors such as uveal and cutaneous melanoma and renal cell carcinoma suggesting the existence of BAP1-related cancer syndrome, targeting tissues of multiple organs. However, the exact phenotype remains unclear [35]. Preclinical models suggest that BAP1 mutation carriers are predisposed to the tumorigenic effect of asbestos [38]. However, BAP 1 expression by immunohistochemistry (IHC) in 123 MPM tissue samples was not associated with asbestos exposure and inversely correlated with survival, suggesting that its role in MPM may be independent from the known asbestos-related oncogenic pathway [37]. Therefore, identification of germline mutations could help identifying individuals at high risk of MPM who could be targeted for early intervention. BAP1 has a role in DNA repair and control of gene expression through histone modification. The possible involvement of BAP1 in modulating histone modifications prompted a study of HDA inhibitors in BAP1-deficient uveal melanomas but the growth inhibitory effects on the cell lines were independent of BAP1 status [39]. Similarly, in vitro, it does not seem to be a significant effect on sensitivity of histone deacetylase inhibitor suberoylanilide hydroxamic acid (vorinostat) on BAP1-knockdown MPM cell lines MPM lines. Furthermore, a recently completed Phase III trial (VANTAGE 014) of vorinostat over BSC in 660 pre-treated advanced MPM patients [40] observed few significant responses, well below what would be expected if BAP1-mutated cases were preferentially sensitive, with no improvement in OS (30.7 vs. 27.1 weeks, p = 0.858) and only a marginal improvement in PFS (6.3 vs. 6.1 weeks, p < 0.001). Therefore the relationship between HDACi and BAP1-mutated MPM remains poorly understood. NF2 suppression and FAK inhibitors

HR: hazard ratio; OS: overall survival; RR: response rate; TTP: time to progression.

in some families, some studies have focused on identifying genetic alterations that predispose individuals to MPM. Somatic inactivation of tumor suppressor gene located at 3p21.1, BRCA associated protein 1 (BAP1), has been described in MPM. A recent study has suggested that BAP1 inactivation may be more characteristic of the epithelioid MPM, but this observation requires further evaluation [35]. In a retrospective study, somatic BAP1 mutation occurred in 24 out of 121 (20%) MPM. Smoking exposure was the only clinical feature associated with this mutation and no differences were observed in survival [36].

Neurofibromatosis type 2 (NF2) is a tumor suppressor gene located on chromosome 22q12 and encodes for the protein Merlin. Loss of NF2 function occurs in approximately 40% of patients with MPM. Merlin mediates cell proliferation through inhibition of mTOR in an AKT-independent manner [35]. Moreover, preclinical data indicates that Merlin inactivation is a critical step in MPM pathogenesis increasing its invasiveness through upregulation of focal adhesion kinase (FAK) expression [41]. A recently reported phase I study of GSK2256098 (an oral FAK inhibitor) that included 23 patients with recurrent MPM suggested that Merlin loss patients might result in improved PFS response to FAK inhibition, suggesting patient’s selection by Merlin status [42]. Based on the preclinical hypothesis that Merlin-null mesothelioma

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cells are especially sensitive to FAK inhibitors [43], a phase IIB (COMMAND, NCT 01870609) is testing an oral FAK inhibitor (VS-6063, defactinib) as maintenance strategy as compared with placebo in advanced MPM. Randomization will be stratified by Merlin status (high vs. low) and patients will receive VS-6063 400 mg twice daily continuously or matched to placebo. PI3K/AKT/mTOR pathway In Merlin-silenced tumors, there is an upregulation of multiple mitogenic signalling pathways such as mTOR leading an increased cell proliferation. These data provide the rationale for studying mTOR inhibitors in MPM. The mTOR inhibitor everolimus was tested in a phase II trial S0722 (NCT 00770120) as second- and third-line treatment. Preliminary data from 35 out of 57 patients available reported no RR and disease control rate (DCR) was 40%. The estimated 4 months PFS was 34% that was far below the pre-specified endpoint of 4 months improvement in PFS from 30% to 50%. Thus, it seems that there is no role for this agent in unselected pre-treated MPM patients [44]. Another phase II trial is investigating the role of everolimus but in this case, selecting patients with Merlin/NF2-lost of function (NCT 01024946). The mTOR inhibition alone produces compensatory upregulation of PI3KCA and thereby allows restoration of PI3K and downstream AKT signalling [45]. To address this mechanism of mTOR resistance, dual PI3 K/mTOR agents such as GDC0980 are being tested, but pulmonary toxicity of these agents may limit their application in clinical setting [46]. In spite of these incoherent results, the certain role of PI3K/AKT/mTOR survival pathway upregulation in MPM deserves further evaluation in clinical trials [47] (NCT01655225, NCT01991938). Antiangiogenic and vascular disrupting agents Based on the hypothesis that MPM is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular factors (VEGF), several maintenance strategies with anti-angiogenic therapies have also been tested. Thalidomide as maintenance treatment in a randomized phase III trial (NVALT 5) did not show any benefit in PFS either OS compared with placebo in 222 randomized patients after induction therapy with pemetrexed–cisplatin [48]. Bevacizumab is a VEGF-blocking monoclonal antibody, which has also been tested as a continuous treatment strategy in MPM. Two non-randomized phase II trials of bevacizumab as maintenance strategy after 6 cycles of platinum–pemetrexed plus bevacizumab induction did not demonstrate an improvement in median PFS compared with historical controls treated with pemetrexed/platinum combinations [49,50]. In a double blind, placebo-controlled randomized phase II trial the addition of bevacizumab to gemcitabine-cisplatin followed by bevacizumab did not improve PFS or OS in previously untreated MPM patients. However, a subset analysis suggested that pretreatment plasma VEGF concentration was inversely correlated with prognosis, independent of treatment arm [51]. Of note, median survival in these three phase II trials with bevacizumab reached 15 months, which is better than most other multicentre studies in MPM, suggesting a possible effect of antiangiogenic therapies in MPM. Probably the existence of a predictive biomarker for this drug might help to better selection of patients. The ongoing phase II-III MAPS trial (NCT 00651456) is comparing cisplatin and pemetrexed with or without bevacizumab followed by bevacizumab until progression in the experimental arm. Preliminary results suggest better 6 months’ disease control rate in experimental arm (73.5% vs.

43.2%, p = 0.01) [52]. This trial might help to clarify the effectiveness of bevacizumab therapy in MPM. The strategy of combination chemotherapy and antiangiogenic therapy as maintenance therapy has failed to demonstrate any advantage in OS in advanced NSCLC [53]. In MPM, a prematurely ended study by slow accrual (NCT 0060441) reported 33% of partial responses (PR) and PFS of 7.8 months with carboplatin– pemetrexed–bevacizumab induction therapy followed pemetrexed–bevacizumab maintenance strategy. However, the small accrual (only 13 patients were included) and the non-randomised design, does not allow to drawn any conclusion about the role of this combination-maintenance strategy in MPM. Nintedanib (BIBF 1120) is a potent oral multikinase inhibitor that targets the pro-angiogenic pathways. In NSCLC patients, the phase III LUME-Lung 1 study reported that second-line nintedanib plus docetaxel significantly improve PFS and OS in patients with adenocarcinoma histology compared with docetaxel alone [54]. In unresectable MPM patients, a phase II exploratory study will evaluate the safety and efficacy of nintedanib in combination with pemetrexed/cisplatin followed by maintenance nintedanib over chemotherapy alone (NCT 01907100). Cediranib (an oral VEGFR/PDGFR multikinase inhibitor) combined with pemetrexed/cisplatin for six cycles followed by maintenance cediranib is also being tested in a phase I/II trial (NCT01064648). Preliminary data from the first 20 patients included recommend cediranib at 20 mg daily based on the toxicity profile, with preliminary RR of 53% and promising mPFS of 10 months and mOS of 16 months [55]. Cediranib, was also tested as monotherapy in second line at doses of 45 mg daily showing a DCR of 42% [56]. However, in another phase II trial cediranib did not meet it’s primary endpoint and only higher doses were associated with improved DCR but at the cost of higher toxicity. There is some data suggesting hypertension as a potential clinical surrogate for this drug [57]. Other antiangiogenic therapies such as sorafenib [58], sunitinib [59,60] and tumor vascular disrupting agents such as BNC105P [61] have shown limited activity in MPM. Based on these unpromising results, further trials of angiogenesis inhibitors as monotherapy in unselected patients with MPM as second-line therapy are not warranted. NGR-hTNF is a novel vascular targeting agent, which selectively binds to CD13, a receptor selectively expressed by tumor blood vessels. In a phase II trial (NGR010 trial), 57 chemo-pre-treated patients with MPM who received NGR-hTNF as monotherapy – either every three weeks or weekly, reported promising disease control rate of 46%, a median PFS and OS of 4.7 and 12.1 months, respectively, longer than historical controls. The comparison of the 3-year OS rates between the weekly and every-three-week cohorts showed a clear advantage of the dose intensification approach [62]. Prompted by these promising results, a multicentre phase III trial NGR015 trial (NCT 01098266) has just completed the enrollement of 390 pemetrexed-previously treated MPM patients. The trial is powered to detect an OS benefit for NGR-hTNF (0.8 lg/m2 weekly) over placebo, when combined with best investigator’s choice (BIC), which includes either BSC alone or combination with chemotherapy (either doxorubicin, or gemcitabine, or vinorelbine). There is another double blind placebo-randomized phase II NGR019 trial (NCT 01358084) that seeks to document the efficacy of this agent as maintenance monotherapy administered at weekly schedule in advanced MPM who did not progress after six cycles of standard pemetrexed-based treatment. Heat shock protein S90 inhibitors: ganetespib Heat shock protein S90 (HSP90) is a chaperone that mediates in maturation and stability of a variety of client proteins associated with the growth and survival of different tumors including MPM,

J. Remon et al. / Cancer Treatment Reviews 41 (2015) 27–34

and its inhibition may be a therapeutic strategy in this disease [63]. Ganetespib, a novel HSP90 inhibitor exhibited promising efficacy combined with docetaxel as second line treatment in advanced NSCLC [64]. The phase I/II MESO02 trial (NCT 01590160) explores the efficacy of Ganetespib as maintenance treatment compared with placebo after cisplatin–pemetrexed–ganetespib induction treatment. Arginine depletor: ADI-PEG20 Arginine is a key amino acid for tumorigenesis. Argininosuccinate synthetase (ASS1) is a rate-limiting enzyme in arginine production. ASS1-deficient MPM cells are sensitive to arginine deprivation as a novel antimetabolite strategy [65]. The multicentre phase II ADAM trial assesses the arginine-lowering agent ADI-PEG20 (and BSC) vs. BSC alone in patients with ASS1-deficient MPM, which can be detected in 46% of chemotherapy naïve and relapsed patients. The study achieved the primary end point, with a PFS favouring experimental arm (98 vs. 59 days, HR 0.53, p = 0.02) being SD the best response by modified RECIST. The main grade 3–4 toxicities were neutropenia, fatigue and anaphylactic reactions (7%) [66]. Immunotherapy in malignant pleural mesothelioma The huge numbers of genetic and epigenetic changes that are inherent to most cancer cells provide plenty of tumor-associated antigens that the host immune system can recognize. The ability of cancer cells to evade anti-tumor T-cell activity in the microenvironment is a hallmark of cancer progression. Tumor antigen recognition by T-cells is dependent on T-cell receptor (TCR) recognition of a peptide ligand major histocompatibility complex (MHC). Following TCR engagement, T-cell activation and acquisition of effector functions requires co-stimulatory signals mediated by CD28 binding to a B7 family molecule (B7.1 or B7.2) on the antigen-presenting cell (APC). This process induces upregulation of inhibitory receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) both expressed on activated effectors T-cells. One way to evade immune destruction is by expression of endogenous immune checkpoints that normally terminate immune responses after antigen activation. CTLA-4 is a coinhibitory receptor, structurally related to the stimulatory co-receptor CD28, and competes for binding to common B7 ligands expressed on antigen-presenting cells. CTLA-4 regulates T-cell activity at an early immunological stage. PD-1 receptor is expressed on activated T lymphocytes, including those that infiltrate into human tumors and mediates immune suppression by binding to its ligands (PDL-1 and PDL-2). By upregulating PD-1 ligands, tumors can block immune activation [67,68] (Fig. 2). MPM is commonly associated with a prominent inflammatory reaction, though it remains unknown whether this relates to

31

asbestos-induced chronic inflammation or an anti-tumor immune response [69]. In MPM, PDL-1 expression by immunohistochemistry (IHC) with two different antibodies, 5H1 and E1L3N, has been reported in 40% [70] and 20% [71] of archived samples, respectively. PDL-1 overexpression was more common in non-epithelioid histology and in both studies was a negative prognostic factor, with a median OS of 5 months in PDL-1 positive patients. In both studies, in a multivariable model, PDL1 expression remained significantly associated with worse survival (HR 2.18, p = 0.013 and HR 2.08, p = 0.021, respectively). The different percentage of PDL-1 expression in these studies could be as a consequence of different cut-off point with two different antibodies. These preliminary results suggest that immunotherapy with anti-PDL1 agents might be appropriate in MPM. However, it is unknown whether PDL-1 expression is really a potential predictive biomarker for immunotherapy and whether PDL-1 expression may change over time with chemotherapy exposure because PDL-1 is an inducible marker that can be upregulated or downregulated over the time calling into question if archival tumor samples are optimal for assessing PDL-1 status. Likewise, in other malignancies such as NSCLC, the sensitivity and specificity of PDL-1 detection can vary by the assay type, the quality of the tissue sample, and the selected cut-off point, and even objective responses have been seen in NSCLC patients whose tumors were tested negative for PDL-1 expression [72]. Immune check-point blockade: anti-CTLA4 antibodies A single-arm phase II trial (MESOT-TREM 2008) evaluating a fully human anti-CTLA4 immunotherapy (tremelimumab) in 29 chemo-resistant advanced mesothelioma patients reported objective RR in 2 out of 29 patients. However, SD was noted in nine patients (31%), all with epithelioid histology. The 1- and 2-year survival rates were 48.3% and 36.7%, respectively, which was considered noteworthy. These preliminary results suggested that anti-CTAL4 immunotherapy, although generally not effective at reducing MPM volume, could have an encouraging long-lasting clinical activity and a good safety profile in pre-treated MPM patients, possibly resulting in extended survival [73]. MESOT-TREM-2012 has recently corroborated these findings. Tremelimumab at 10 mg/kg every 2–3 weeks achieved a 14% of RR by immune-related RECIST of median duration of 7.7 months and median OS of 11.3 months. Grade 3 adverse events were only reported in 3.4% of patients [74]. Based on this clinical activity a phase 2b global trial (NCT01843374) is ongoing and approximately 564 subjects will be enrolled. However, the identification of biomarkers that might predict the activity of CTLA4-blocking agents is urgently needed. For example, in MESOT-TREM-2008, the increase in the absolute number of circulating CD4 T lymphocytes in the early phase of tremelimumab the treatment, was predictive of an improved survival [73].

Acvaon Signals MHC

TCR

B7

CD28

TCR

Cancer Cell

T cell

Dendric Cell B7

CTLA-4

MHC

PD-1

PDL-1

Fig. 2. Stimulatory and Inhibitory coreceptors regulate T-cell responses to tumor antigens. B7 ligands include: B7.1 (CD80) and B7.2 (CD86). TCR: T-cell receptor. MHC: major histocompatibility complex.

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Passive immunotherapy: mesothelin-targeted antibodies Mesothelin is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in MPM. The biologic function of mesothelin overexpression in MPM is unknown, but preclinical data suggest that it is probably involved in cell adhesion and tumor invasion [75]. Mesothelin-targeted immunotoxin therapy, specially combined with host immune depletion as chemotherapy, has shown promising efficacy in MPM. Amatuximab (MORAb-009) is a high affinity chimeric monoclonal antibody against mesothelin. In a phase I trial, in 24 previously treated patients (including 13 patients with MPM), amatuximab was well tolerated, and 11 patients had SD after receiving at least one cycle [76]. In a single-arm multicentre phase II trial, 89 MPM patients received amatuximab plus CT (pemetrexed/cisplatin) for 6 cycles followed by amatuximab as maintenance treatment in case of objective RR. Of note, 63% of patients received maintenance therapy. According to independent radiological review, 39% of patients achieved a PR and 51% had SD of long lasting. The median OS was 14.8 months, better than with chemotherapy alone, suggesting that amatuximab in this population should be studied in a randomized trial [77]. Moreover, in an ad hoc post study analysis those patients with higher trough serum amatuximab levels achieved a statistically significant improvement in PFS and OS over those with serum concentrations below the median [78]. CRS-207 is an engineered anti-mesothelin vaccine generated from Listeria monocytogenes. In front-line treatment in 19 MPM patients, CRS-207 administered as 2 vaccinations before and after 6 cycles of cisplatin and pemetrexed chemotherapy, reported a 60% of PR and 27% of patients achieved SD with transient side effects attributable to CRS-207, mainly grade 1 or 2, and only 7% grade 3 (fever and hypotension) [79]. These promising results warrant further evaluation. SS1P is a fusion of an antimesothelin antibody fragment linked to a portion of Pseudomonas exotoxin A. In preclinical models, cells with strong mesothelin expression by IHC were sensitive to SS1P [80]. In chemo-refractory MPM, SS1P plus two drugs that suppress immune system (pentostatin and cyclophosphamide) produced significant shrinkage in 3 of 10 patients and SD in another 3 of 10 patients. Additionally, tumor shrinkage in two patients was not evident until 4–7 months after initiation of SS1P treatment. This reality suggests the delayed tumor response with immunebased therapies seen in other malignancies [81]. Recently, in a phase I trial with chemotherapy-naïve MPM patients, SS1P in combination with cisplatin and pemetrexed showed antitumor activity with partial response in 12 out of 20 patients (60%), and the maximum tolerated dose of SS1P was established as 45 mcg/kg. Additionally, serum mesothelin levels correlated with radiological response [82]. Preliminary data suggests that immunotherapy offers a targeted approach for MPM patients generally with manageable toxicity profile and further refinement of patient’s selection may yield in survival improvement. However, most effective immunotherapy approaches should probably integrate multimodality regimens based on the fact that human MPM tissues can harbour significant levels of immunosuppressive T lymphocytes cells in stroma impeding the optimal clinical effectiveness of immunotherapy [83]. Chemotherapy combined with immunotherapy could have a synergistic effect in MPM by augment in antitumor efficacy via multiple immune-mediated mechanisms [84]. Anti-transforming growth factor b Transforming growth factor b (TGFb) is a pleiotropic cytokine. Under normal conditions, TGFb is a potent growth inhibitor. However, advanced tumors frequently loss their negative growth

response to TGFb, and often produce large amounts of this cytokine. Then, TGFb promotes remodelling of the microenvironment to support tumor growth and facilitate metastases and also attenuates host antitumor immune responses. In many different malignancies, elevated TGFb plasma levels correlate with advanced tumor stage, metastases, and poor survival. Preliminary data with GC1008 (fresolimumab), a human monoclonal antibody that neutralizes all three human isoforms of TGFb in 13 pre-treated MPM patients reported 23% SD and a median OS of 12 months compared favourably to second line single-agent studies with an acceptable toxicity profile. However, there was a suggestion that blockade of TGFb might support the growth of susceptible premalignant or malignant cells in a minority of subjects [85]. Conclusions Because of the rarity of this disease, large randomized clinical trials should be averted and replaced by smaller randomized phase II trials, avoiding erroneous conclusions taken from single-arm phase II trials. Going forward, it would be of interest to pursue for agents with relevancy in the biology of this disease. The identification of driver and germline mutations may help to customize treatment in MPM and identify individuals at high risk of MPM, respectively. The success of phase II and III clinical trials in MPM as in other thoracic malignancies depends on the proper selection of patients based on biomarkers. Results of ongoing trials investigating antiangiogenic therapies, and new agents in maintenance and second-line based on deregulated pathways may hopefully improve the still dismal prognosis of these patients. Immunotherapy in MPM warrants further evaluation considering the innate long latency period of this disease after asbestos-exposition suggesting some kind of deregulation in immune system that may precipitate the onset of MPM. The encouraging preliminary data with immunotherapy, especially with anti-CTLA4 agents, opens up a new phase towards the identification to guide patient’s selection. Conflicts of interest The authors declare that they do not have any conflicts of interest that could inappropriately influence their work. References [1] La Vecchia C, Boffetta P. Role of stopping exposure and recent exposure to asbestos in the risk of mesothelioma. Eur J Cancer Prev 2010;21:227–30. [2] Stayner L, Welch LS, Lemen R. The worldwide pandemic of asbestos-related disease. Annu Rev Public Health 2013;34:205–16. [3] Soeberg MJ, Takahashi K, Movahed M, et al. Global patterns in the incidence of malignant mesothelioma, 1988-2002, using data published by the international Agency for Research on Cancer (IARC). J Thorac Oncol 2013; 8(P2.14-007). [4] Park EK, Takahashi K, Hoshuyama T, et al. Global magnitude of reported and unreported mesothelioma. Environ Health Perspect 2011;119:514–8. [5] Robinson B. Malignant pleural mesothelioma: an epidemiologic prospective. Ann Cardiothorac Surg 2012;1:491–6. [6] www.iarc.fr/en/publications/pdfs-online/epi/sp160/ (Accessed on 18.06.14). [7] Craighead JE. Epidemiology of mesothelioma and historical background. Rec Res Cancer Res 2011;189:13–25. [8] Delgermaa V, Takahasi K, Park EK, et al. Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008. Bull World Health Organ 2011;89:716–24. [9] Taioli E, Wolf AS, Camacho-Rivera M, Flores RM. Women with malignant pleural mesothelioma have a threefold better survival rate than men. Ann Thorac Surg 2014;98:1020–4. [10] Fennell DA, Gaudino G, O’Byrne KJ, et al. Advances in the systemic therapy of malignant pleural mesothelioma. Nat Clin Pract Oncol 2008;5:136–47. [11] Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636–44. [12] van Meerbeeck JP, Gaafar R, Manegold C, et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research

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