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Oncology
Malignant pleural mesothelioma (MPM) is a locally aggressive disease related to asbestos exposure with a median survival for untreated patients of 4–8 months. The growing research in the field of MPM has culminated in the approval of new therapies that improve patient survival. New combinations of immunotherapy with chemotherapy could further improve patient outcomes.
- malignant pleural mesothelioma
- immunotherapy
1. Introduction
Malignant pleural mesothelioma (MPM) is a rare, highly lethal cancer associated with asbestos exposure, with peak incidence expected in the 2020s in developed countries [1]. MPM can be classified according to histology from best to worst prognosis as epithelioid, biphasic, and sarcomatoid. The prognosis of patients with MPM is poor, with a median survival of 9–18 months.
For many years, chemotherapy based on platinum plus pemetrexed has been the standard treatment for patients with MPM, but recently, the combination of nivolumab and ipilimumab showed improvements in overall survival compared to chemotherapy [2,3]. After the first-line treatment, there are no other options for systemic treatment approved for MPM.
Genomic studies have shown that mesothelioma is mainly defined by the loss of function of tumor suppressor genes, with mutations in BAP1, CDKN2A, and NF2 being the most common alterations [4,5]. The chronic inflammatory response to asbestos creates a unique tumor environment composed primarily of immunosuppressive cells (regulatory T cells, macrophages, and myeloid-derived suppressor cells) [6]. MPM expresses multiple immune checkpoint inhibitors. VISTA expression in MPM is much higher compared to other tumors and is only expressed in tumors of the epithelioid subtype [5]. PD-L1 expression is positive in approximately 40% of patients [7,8,9,10]; it is more common in the non-epithelioid subtype and is associated with a worse prognosis [7,8,9,10,11].
2. Treatment
2.1. Surgery
Most patients with mesothelioma are not candidates for surgery due to the extent of the disease and comorbidities. The MARS study, which included 50 patients, demonstrated that extrapleural pneumonectomy was associated with severe complications and did not improve survival compared to patients who did not undergo surgery [12]. In 2023, the results of the MARS-2 study were presented, comparing the treatment of chemotherapy and pleuro-decortication versus chemotherapy without surgery [13]. The study found that survival was superior for patients who did not undergo surgery. However, this study has not yet been published, and the results should be interpreted with caution. More patients with tumors spreading to the lungs were included in the surgery arm. In addition, the preoperative staging of patients was not standardized, and there were no volumetry pre- and post-chemotherapy treatments for the evaluation of therapeutic response according to the modified RECIST criteria. These issues need to be rectified to establish the role of surgery in MPM.
2.2. First Line
Regarding systemic treatment, the standard treatment for almost two decades has been antifolate and platinum chemotherapy [2]. The pivotal EMPHACIS trial demonstrated that the combination of cisplatin and pemetrexed induces an increase in survival (OS) of 9.3 to 12.1 months compared to cisplatin alone. In the MAPS study, the addition of bevacizumab to chemotherapy with cisplatin and pemetrexed led to an increase in OS from 16.1 to 18.8 months and in progression-free survival (PFS) from 7.3 to 9.2 months [14]. However, bevacizumab is not approved by the FDA or EMA for treating MPM.
After almost two decades without new, relevant advances in first-line treatment for MPM, in May 2019, the FDA approved the NovoTTF therapy (alternating electric field therapy, TTFields) in combination with platinum pemetrexed [15]. The phase II STELLAR trial resulted in an OS of 18.2 months and a PFS of 7.6 months, with both results being favorable compared to historical cohorts.
The third regulatory approval of first-line treatments took place in 2020 with the combination of nivolumab plus ipilimumab (reviewed later) [3]. The results of this study have marked a change in the standard treatment of mesothelioma and opened the doors to new research studies on other immunotherapy molecules for use in the first line of treatment.
2.3. Second Line
There are currently no approved therapies for when patients progress to first-line platinum-based treatment. The most widely adopted treatment options include single-agent chemotherapy with vinorelbine or gemcitabine or retreatment with pemetrexed. These options are primarily based on retrospective or phase II studies reporting an overall response rate (ORR) of 0–19%, a disease control rate of 38–84%, and a PFS of 1.6–3.8 months, with an OS ranging from 2.5 to 12 months [16]. The results of the RAMES trial, the study with the largest number of second-line patients, have recently been published, comparing the combination of ramucirumab and gemcitabine versus gemcitabine and demonstrating an improvement in OS for the combination [17].
3. Immunotherapy
3.1. Second and Futher Lines
The first studies with anti-CTLA-4 yielded negative results. Tremelimumab was evaluated in the phase 2b DETERMINE study in a large cohort of patients versus a placebo and did not demonstrate an improvement in OS (7.7 and 7.3 months for patients treated with tremelimumab and the placebo, respectively) [18].
Subsequently, anti-PD-1 demonstrated promising results in phase II studies, but they were not confirmed in all phase III studies (Table 1). Pembrolizumab achieved a disease control rate of 72% in the phase Ib KEYNOTE-028 study [19]. Unfortunately, these good results were not confirmed in the randomized PROMISE-meso study that compared pembrolizumab with chemotherapy among patients who progressed to platinum and achieved a PFS of 2.5 months with pembrolizumab versus 3.4 months with chemotherapy [20].
Table 1. Summary of immunotherapy studies in MPM.
| Trial | Drug | N | PD-L1 Selected | Response Rate (%) | PFS (Months) | OS (Months) |
|---|---|---|---|---|---|---|
| Keynote028 | Pembrolizumab | 25 | Yes | 20 | 5.4 | 18 |
| Keynote158 | Pembrolizumab | 118 | No | 8 | 2.1 | 10 |
| PROMISE | Pembrolizumab | 73 | No | 22 | 2.5 | 10.7 |
| NivoMes | Nivolumab | 34 | No | 15 | 3.6 | 11.8 |
| Javelin | Avelumab | 53 | No | 8 | 4.1 | 10.7 |
| MERIT | Nivolumab | 34 | No | 29 | 6.1 | 17.3 |
| CONFIRM | Nivolumab | 332 | No | 11 | 3 | 9.2 |
| NIBITMESO | Durvalumab–Tremelumumab | 40 | No | 28 | 5.7 | 16.5 |
| INITIATE | Nivolumab–ipilimumab | 38 | No | 30 | 6.2 | 64% at 12 months |
| MAPS | Nivolumab–ipilimumab | 125 | No | 52 | 5.6 | 15.9 |
| CheckMate-743 | Nivolumab–ipilimumab | 303 | No | 40 | 6.8 | 18.1 |
| IND227 | Pembrolizuma–chemotherapy | 222 | No | 63 | 7.1 | 17.3 |
| DREAM | Durvalumab–chemotherapy | 54 | No | 61 | 6.9 | 18.4 |
| PrE0505 | Durvalumab–chemotherapy | 55 | No | 56.4 | 6.7 | 20.4 |
| JME-01 | Nivolumab–chemotherapy | 18 | No | 77 | 8 | 20.8 |
PFS: progression-free survival, OS: overall survival.
However, with nivolumab, an anti-PD-1 monoclonal antibody, the preliminary results of activity were confirmed in a phase III trial. The phase II NivoMes and MERIT studies demonstrated a response rate of 24–29% and OSs of 11.8 and 17.3 months [21,22]. Based on the results of this study, nivolumab was approved by the Japanese health authorities in August 2018 for patients who progress to chemotherapy. Subsequently, the phase III CONFIRM trial evaluated nivolumab versus a placebo in the second or third line [23]. Most patients had epithelioid histology (88%) and were PD-L1-negative (66%). The study met its primary objectives, with a median PFS of 3.0 months for nivolumab versus 1.8 months for the placebo and a median OS of 9.2 with nivolumab and 6.6 months with the placebo. The results of this study have not led to the approval of nivolumab in the second line of treatment.
Finally, avelumab, an anti-PD-L1 monoclonal antibody, was explored in a phase 1b study, achieving a response rate of 9%, a PFS of 4.1 months, and an OS of 10.7 months [24].
Regarding combinations of immunotherapy drugs, several studies have published the results of the combination of anti-PD-1 therapy with anti-CTLA-4. The NIBIT-MESO-1 study was a phase II, open-label, non-randomized trial involving patients with pleural or peritoneal mesothelioma in the second or third line that were administered tremelimumab in combination with durvalumab [25]. The study achieved a response rate of 28% with a duration of response of 16.6 months, a PFS of 5.7 months, and a median OS of 16.5 months. In a recent 4-year study update, it was reported that the combination of tremelimumab with durvalumab was associated with durable survival (20% at 36 months and 15% at 48 months) [26].
Two studies have explored the combination of nivolumab with ipilimumab for treating patients who relapse after the first line of treatment: the INITIATE study and the MAPS-2 [27,28]. The studies reported a response rate of around 30%, a PFS of 6 months, and an OS of 15.9 months.
3.2. Immunotherapy in First Line
CheckMate-743 is an open-label, randomized, phase III study comparing first-line treatment with nivolumab plus ipilimumab versus chemotherapy for patients with previously untreated unresectable MPM with an ECOG score of 1 or less [3]. A total of 605 patients were included, who were randomized 1:1 to receive nivolumab at a dose of 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks for two years versus chemotherapy with platinum and pemetrexed. The results of the study were positive, demonstrating a 4-month survival advantage for the immunotherapy combination (18.1 vs. 14.1 months). The 3-year survival rate was 23.2% for immunotherapy versus 15.4% for chemotherapy [29]. The median PFS was 6.8 months with nivolumab plus ipilimumab versus 7.2 months with chemotherapy, and there was no difference in the response rate (40% and 43% for immunotherapy and chemotherapy).
In terms of toxicity, grade 3–4 adverse events were experienced by 31% of patients treated with immunotherapy and 32% of patients treated with chemotherapy. However, for patients who discontinued immunotherapy due to toxicity, survival was not affected, reaching a median OS of 25.4 months from randomization.
The magnitude of the survival benefit with nivolumab plus ipilimumab was greater for patients whose PD-L1 expression was ≥1%, but it should be noted that PD-L1 expression was not a stratification factor in this study.
In a prespecified histology-based exploratory analysis, subgroups of patients with epithelioid histology had an OS of 18.7 months with immunotherapy versus 16.2 months with chemotherapy (HR 0.85). However, in the subgroup of patients with non-epithelioid histology, the differences were greater, with an OS of 18.1 months versus 8.8 months for immunotherapy versus chemotherapy, respectively (HR 0.46). Although the benefit of immunotherapy seems greater with respect to non-epithelioid tumors, after adjusting for treatment, it was observed that the OSs of the patients treated with immunotherapy in the group of epithelioid and non-epithelioid tumors were similar (with median OSs of 18.7 months and 18.1 months for the epithelioid and non-epithelioid patients). It is postulated that non-epithelioid tumors have a worse prognosis and are less sensitive to chemotherapy treatment.
An exploratory biomarker analysis included a four-gene gene expression signature (CD8A, STAT1, LAG3, and CD27), TMB (tumor mutation burden), and the pulmonary immune prognostic index (LIPI) measured according to LDH levels and neutrophil/lymphocyte ratios (NLR) in peripheral blood [29]. A positive correlation was detected in patients with high inflammatory gene signature expression with a survival benefit from immunotherapy (21.8 months for patients with a high inflammatory signature versus 16.8 months for patients with low scores). Of the other two markers studied, neither the TMB nor the LIPI score were predictive of survival.
Regarding the analysis of quality of life, immunotherapy imparted an improvement in symptoms accompanied by the maintenance of general condition and a reduction in the risk of definitive deterioration of symptoms related to the disease during treatment [30].
The results of this study led to the approval by regulatory agencies (FDA and EMA) of the combination of nivolumab plus ipilimumab as a first-line treatment for unresectable MPM.
3.3. Combination of Immunotherapy with Chemotherapy
Prior to the publication of the CheckMate-743 study, the results of two phase II studies that analyzed the effectiveness of the combination of immunotherapy with durvalumab added to the first line of chemotherapy were presented [31,32]. The DREAM study included 54 patients who received durvalumab in combination with cisplatin and pemetrexed for a total of six cycles followed by durvalumab until the completion of one year or progression [31]. The trial exceeded its prespecified objective, attaining a 6-month PFS rate of 57%. The median PFS was 7 months, and OS was 18.4 months. In a post hoc analysis, responses were observed in all histological types, and no significant association was detected between PD-L1 expression and PFS. The same treatment scheme was used in the PrE0505 study, finding a response rate of 56.4% and a PFS of 6.7 months [32]. The median OS of 20.4 months was significantly longer than that of the historical control. Regarding analysis according to histology, patients with epithelioid tumors had a higher response rate than patients with non-epithelioid tumors (65.9% versus 28.6%, p = 0.03). Based on these results, a randomized phase III study (DREAM3R) was conducted to compare whether there are survival differences with the addition of durvalumab to standard platinum treatment, the results of which are pending.
The third study of combination chemotherapy plus immunotherapy in the first line is the phase 2 JME-01 study [33]. This was a single-arm treatment study combining cisplatin with pemetrexed and nivolumab for 4–6 cycles, followed by a maintenance phase with nivolumab until progression or reaching unacceptable toxicity levels. The objective response rate was 77%, including responses for all histologies, with a duration of response of 6.7 months, a PFS of 8 months, and an OS of 20.8 months.
During the year 2023, the results of the first phase III study of chemotherapy with immunotherapy in the first line were presented [34]. The IND.227 study was a phase 2–3 study that evaluated the addition of pembrolizumab to chemotherapy. In phase II, the trial did not demonstrate differences in PFS (6.7 and 6.8 months), but it did reveal differences in OS (19.8 versus 8.9 months for combination and chemotherapy respectively) [35]. Despite not meeting the primary endpoint of PFS, numerically superior survival data for the combination with pembrolizumab led to the completion of enrollment. In phase III, 440 patients were included and stratified by histology. The study demonstrated improved OS for the chemo-immunotherapy combination, with a median OS of 17.3 months versus 16.1 months in favor of the pembrolizumab group. Three-year survival was 25% vs. 17% for immunotherapy. However, as in the CheckMate-743 study, no differences were observed in PFS (7.1 months in both treatment groups), and a greater survival benefit was observed for patients with non-epithelioid histology (with an OS of 12.3 versus 8.1 months in favor of pembrolizumab for non-epithelioid tumors and 19.8 vs. 18.2 months for epithelioid tumors). No significant differences were observed according to the level of PD-L1 expression.
This entry is adapted from the peer-reviewed paper 10.3390/cancers15245787
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