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The treatment landscape for malignant pleural mesothelioma (MPM) has historically been a pretty barren one, as it is a , with an of only 3.05 cases per 100,000 people, according to the CDC.

As a result, the pace of research on the underpinnings of MPM, as well as potential treatments, has been slow, noted Anne S. Tsao, MD, MBA, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

But ground has been gained in the last few years. For instance, genomic studies have revealed that "BAP1 is the most frequently mutated gene in mesothelioma and is also affected by copy-number alterations," the team explained. "BAP1 alterations can be somatic or germline, and the BAP1 hereditary cancer syndrome predisposes patients to mesothelioma, uveal melanoma, and other malignancies."

As for treatments, multiple trials have "reshaped the standard-of-care landscape," the authors stated in a review on the latest in MPM treatment options.

"Mesothelioma therapy is now dependent on the histologic subtype, given the differences in survival to treatments. Recent trials have clearly demonstrated the role of immunotherapy in malignant pleural mesothelioma treatment with improved survival," the authors added.

Two trials in particular, 2019's and 2021's (for which Tsao was a co-investigator) were convincing enough for the FDA to green-light two approvals for immunotherapy in MPM -- respectively, the in combination with pemetrexed plus platinum-based chemotherapy as first-line treatment of unresectable, locally advanced or metastatic MPM; and nivolumab (Opdivo) plus ipilimumab (Yervoy) as of unresectable MPM.

In terms of other therapies, "most CAR-T trials that have included patients with mesothelioma have targeted the tumor-associated antigen mesothelin that is broadly expressed by epithelioid variants of mesothelioma," Tsao and co-authors wrote, although they noted that most CAR-T cell treatment studies in the disease have "demonstrated limited efficacy with poor infiltration of tumors, limited persistence of the CAR-T cells, and in some cases, anaphylactic reactions."

Raffit Hassan, MD, a senior investigator in the Thoracic and GI Malignancies Branch at the National Cancer Institute Center for Cancer Research (NCI/CCR) in Bethesda, Maryland, offered insights on the immunotherapy development pathway in MPM, including findings from the CheckMate 743 trial, and what's on the horizon with mesothelin-based treatment in a 2021 YouTube hosted by the Eskişehir Osmangazi University ESOGÜ Lung and Pleural Cancers Application and Research Center (Esogu Apkam) in Odunpazari, Turkey:

How would you describe mesothelioma?

Hassan: Mesothelioma is a tumor that arises from sites that are lined by mesothelial cells; so it arises from the mesothelial lining of the pleura ... the pleural mesothelioma, as well as from the peritoneum, and very occasionally from the lining of the heart of the tunica vaginalis. But the most common form of mesothelioma is pleural mesothelioma, as well as peritoneum mesothelioma.

Asbestos is the primary cause of mesothelioma, and patients with Hodgkin's disease and [non-Hodgkin lymphoma who have] received radiation are also at increased risk of developing mesothelioma. And more recently, germ line mutations in BAP1 predispose patients to mesothelioma.

MPM is an aggressive disease with poor prognosis. Most of the patients present with advanced disease and are not candidates for resection. For a long time, the only FDA-approved therapy for this disease was chemotherapy with pemetrexed plus cisplatin -- that was approved in 2004 [based on] the by [Nicholas J. Vogelzang, MD] and colleagues. [In the study], the median overall survival [OS] of patients who got pemetrexed plus cisplatin was 12.1 months, whereas with cisplatin alone it was 9.3 months. And for a long time, this was the only standard therapy for this disease.

So has there been progress since 2004? Although it's a rare disease, mesothelioma has been an area of active clinical investigation and there are multiple phase II and phase III trials that have been done in this disease. But most of these studies have been negative. However, there are some promising therapies that have emerged over the last 2 or 3 years.

What has been the path for immunotherapy in MPM?

Hassan: One of the first clinical trials of immune checkpoint in mesothelioma was the anti-CTLA-4 antibody as second- or third-line treatment for unresectable malignant mesothelioma. Patients either received tremelimumab or they received placebo [and] there's no difference in overall survival [OS] for tremelimumab versus placebo, so this was a negative study showing that tremelimumab by itself had no benefit in patients with advanced mesothelioma.

Avelumab [Bavencio] is an anti-PD-L1 antibody, and we evaluated it in a phase Ib trial called the trial. [We showed that], out of the 53 patients, nine patients had an objective partial response, and the response was seen irrespective of the tumor PD-L1 expression, so there was some hint of activity with about 10% of the patients having a partial response.

And [KEYNOTE-028] was an important study of [Keytruda]. This was the single-arm study and the response rate was about 20%, and some of the responses appeared durable. These studies showed proof of principle that anti-PD-1 or anti-PD-L1 antibodies had activity in patients with advanced mesothelioma, so a non-chemotherapy regimen did lead to objective tumor response.

What about the CheckMate 743 trial?

Hassan: A major advance in mesothelioma has been the trial of first-line nivolumab, which is an anti-PD-1 antibody, plus ipilimumab, which is an anti-CTLA-4 antibody [versus chemotherapy] in unresectable MPM.

The overall response rate [in the trial] in the immunotherapy arm was 40% with 2% complete response, whereas the overall response rate in the chemotherapy arm was 42% -- so very similar response. However, the duration of response was significantly better in the immunotherapy arm. At 12 months, 47% of the patients had ongoing response, compared with 26% in the chemotherapy arm. So the median duration of response in the immunotherapy arm was 11 months compared to 6.7 months in the chemotherapy arm -- clearly, although the response rate was the same, the duration of response was much better in the immunotherapy arm.

The median OS for all the patients was 18.1 months in the immunotherapy arm compared to 14 months in the chemotherapy arm, and the difference was statistically significant with a P value of 0.020, so clearly, the immunotherapy arm resulted in increased OS.

But what is significant is when [the investigators] looked at OS by histology. In the group of patients with epithelioid histology ... in the immunotherapy arm, the median OS was 18 months versus 16.5 months in the chemotherapy arm with a hazard ratio of 0.86.

What is really very impressive is the OS in patients with sarcomatoid mesothelioma. We all know that sarcomatoid mesothelioma is an aggressive cancer and chemotherapy has very little benefit. So this was a pretty dramatic difference: the median OS in the non-epithelioid or the sarcomatoid histology was 18 months compared with 8 months in the chemotherapy arm -- more than double the median OS with a hazard ratio of 0.46.

In terms of adverse events [AEs], the AEs in the immunotherapy arm were as expected with the most common side effects pruritus, rash, hypothyroidism, and increased lipase. And most of these side effects were grade 1 or grade 2. We also had some grade 3 side effects such as diarrhea, increased lipase. And with the chemotherapy arm, the side effects were as expected, with bone marrow suppression being most common.

The CheckMate 743 trial really is defining the standard of care for these patients. Immunotherapy has made a significant impact in this disease and it is now a standard of care for newly diagnosed patients, and there are other trials going on comparing immunotherapy with chemotherapy or other agents.

What about mesothelin-targeted therapies?

Hassan: Mesothelin is a cell-surface glycoprotein. It is made as a precursor protein of 71kDa, which is attached to the cell membrane by GPI [glycosylphosphatidylinositol] anchor, and it is processed by the protease furin into a shed fragment called MPF, or megakaryocyte potentiating factor, and a membrane-bound fragment that we call mesothelin.

So the therapies that we are developing [at the NCI/CCR Hassan lab] are targeting this molecule, which is attached to the cell membrane. The most important thing is that expression of mesothelin in normal human tissues is limited only to the mesothelial cells lining the pleural peritoneum and pericardium, and that's what makes it a good target for immunotherapy because there is no expression on important organs such as heart, lung, brain, or kidneys.

The normal biologic function of mesothelin is not known, but we and others have shown that mesothelin binds MUC16 and may play a role in tumor metastasis. Mesothelin is highly expressed in many solid tumors; almost 100% of mesothelioma epithelial type express mesothelin ... There are a number of mesothelin-targeted therapies that are currently in clinical trials, [and] these include immunotoxins, for example ; antibody drug conjugates, such as ; radioimmunotherapy using ; ; as well as using chimeric antigen receptor T cells or TRuCs.

Read the study here and expert commentary about the clinical implications here.