Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by very poor prognosis and lack of treatment options. Immunotherapy has rapidly emerged as an effective tool for MPM, particularly for tumors of non-epithelioid histology. At the same time, comprehensive genomic sequencing may open the way to new-generation targeted-drugs able to hit specific MPM molecular vulnerabilities. These innovations will possibly enrich, but also dramatically complicate, the elucidation of treatment algorithms. Multidisciplinary integration is urgently needed.
1. Introduction
Malignant pleural mesothelioma (MPM) is a deadly malignancy arising from mesothelial cells of the pleural surface, accounting for fewer than 1% of all cancers
[1,2,3][1][2][3]. Asbestos exposure, usually occurring in the workplace, is the leading cause of MPM through the induction of chronic inflammation and macrophages releasing DNA-mutagenic oxidizing agents. Other risk factors include occupational radiation and prior chest radiotherapy
[4]. Very rarely, germline mutations in breast-related cancer antigens (BRCA)-associated protein 1 (BAP1) can be passed in families
[5,6][5][6].
The histological classification of MPM includes three main subtypes: epithelioid, sarcomatoid (including the desmoplastic and lymphohistiocytic variants), and biphasic. The epithelioid histology is associated with a more favorable prognosis and occurs in 60–80% of patients, whereas the sarcomatoid histology (20% of cases) has worse outcomes, with a lower chance of response to therapy
[7].
Multimodality therapy including induction platinum-based chemotherapy, surgical resection (pleurectomy/decortication with mediastinal lymph node sampling or extrapleural pneumonectomy), and sometimes radiation therapy is generally offered to young patients with good performance status, localized disease, and epithelioid histological subtype
[8,9][8][9].
Based on the results of the EMPHACIS trial, combination therapy with cisplatin (CDDP) and pemetrexed (PEM) has been for long the cornerstone of first-line treatment for patients with advanced, unresectable MPM
[10]. The carboplatin–PEM regimen showed comparable efficacy to CDDP–PEM in a phase II study; therefore, in clinical practice it should be preferred for patients with a poor performance status (PS) and/or comorbidities
[11]. The clinical role of second-line therapy for progressive or relapsed disease is still undefined, and no post-progression validated treatment has emerged. Pemetrexed-based re-treatment should be considered for patients who have obtained a PFS greater than 3 months with first-line therapy
[12,13][12][13], while other active drugs, such as gemcitabine and vinorelbine, can be used for platinum-refractory patients with a good PS
[14,15,16][14][15][16].
However, in a comprehensive perspective, the introduction of the pemetrexed-based strategies has produced negligible survival improvements, and the prognosis of MPM is still very poor with an overall 5-year survival rate < 10%, further underscoring the urgent need for more effective therapies. In the last few years, new therapeutic approaches focusing on three different research areas (immunotherapy, functional loss of tumor suppressor genes, and angiogenesis) have been investigated for MPM treatment.
2. Immunotherapy
Immunotherapy (IO) has opened a new era in the management of thoracic malignancies, and several immune checkpoint inhibitors, targeting the cytotoxic lymphocyte antigen 4 (CTLA4) and programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) signaling axis, have been approved for the treatment of lung cancers.
In the last years, several clinical trials have successfully investigated the activity of IO in MPM treatment, firstly for recurrent/relapsed disease and, more recently, as an upfront treatment compared to platinum–pemetrexed-based chemotherapy ().
In a retrospective analysis conducted by Patil and colleagues
[17], a sample of 99 MPM specimens were profiled for immune gene expression and PD-L1 expression, proposing a classification in three subgroups according to the degree of inflamed phenotype: 60% of the samples analyzed showed an inflamed status, making mesothelioma a good theoretical candidate to immunotherapy.
Table 1. Selected Clinical Trials investigating Immunotherapy in MPM.
Name |
Trial ID |
IO Agent |
Phase |
No. pts |
Treatment Arms |
Result/ Status |
Endpoint |
Relapsed/Recurrent MPM |
MESOT-TREM-2008 [18] |
NCT01649024. |
Tremelimumab |
II |
25 |
Tremelimumab (15 mg/kg every 90 days) |
Negative |
ORR |
MESOT-TREM-2008 [19] |
NCT01655888. |
Tremelimumab |
II |
29 |
Tremelimumab (10 mg/kg every 4 weeks) |
Negative |
ORR |
DETERMINE [20] |
NCT01843374. |
Tremelimumab |
IIB |
571 |
Temelimumab (10 mg/kg) vs. placebo |
Negative |
OS |
KEYNOTE-028 [21] |
NCT02054806 |
Pembrolizumab |
I |
25 |
Pembrolizumab (10 mg/kg q14) |
/ |
ORR |
KEYNOTE-158 [22] |
NCT02628067 |
Pembrolizumab |
II |
118 |
Pembrolizumab 200 mg q21 up to 35 cycles |
Negative |
ORR |
PROMISE-Meso [23] |
NCT02991482 |
Pembrolizumab |
III |
114 |
Pembrolizumab vs. CHT |
Negative |
PFS |
JAVELIN Solid Tumor [24] |
NCT01772004 |
Avelumab |
IB |
53 |
Avelumab (10 mg/kg q14) |
Negative |
ORR |
NivoMes [25] |
NCT02497508 |
Nivolumab |
II |
38 |
Nivolumab (3 mg/kg q14) |
Positive |
DCR |
MERIT [26] |
JapicCTI163247 |
Nivolumab |
II |
34 |
Nivolumab (3 mg/kg q14) |
Positive |
ORR |
CONFIRM [27] |
NCT03048474 |
Nivolumab |
III |
332 |
Nivolumab (240 mg q14) |
Positive |
PFS/OS |
NCT03075527 [28] |
NCT03075527 |
Tremelimumab + Durvalumab |
II |
19 |
Trem + Durv (4 Cycles) − Durv |
Negative |
ORR |
NIBIT-Meso-1 [29] |
NCT02588131 |
Tremelimumab + Durvalumab |
II |
40 |
Trem + Durv (4 Cycles) − Durv |
Positive |
ORR |
MAPS2/IFCT1501 [30] |
NCT02716272 |
Ipilimumab + Nivolumab |
II |
125 |
Nivolumab +/− Ipilimumab |
Positive |
12W DCR |
INITIATE [31] |
NCT03048474 |
Ipilimumab + Nivolumab |
II |
35 |
Nivolumab + Ipilimumab |
Positive |
12W DCR |
Upfront treatment |
Checkmate 743 [32] |
NCT02899299 |
Ipilimumab + Nivolumab |
III |
92 |
CDDP + PEM vs. IPI + NIVO |
Positive |
OS |
IND-227 |
NCT02784171 |
Pembrolizumab |
II-III |
520 |
CDDP + PEM +/− PEMBRO |
Active, not recruiting |
PFS/OS |
PrE505 [33] |
NCT02899195 |
Durvalumab |
II |
55 |
CDDP + PEM + DURVA |
Positive |
OS |
DREAM [34] |
ACTRN 12616001170415 |
Durvalumab |
II |
54 |
CDDP + PEM + DURVA |
Positive |
PFS |
DREAM3R |
NCT04334759 |
Durvalumab |
III |
480 |
CDDP + PEM +/− DURVA |
Recruiting |
OS |
ETOP BEAT-meso trial |
NCT03762018 |
Atezolizumab |
III |
320 |
CBDCA + PEM + BEVA +/− ATEZO |
Recruiting |
PFS, OS |