George Naumov, COO at RS Oncology, summarizes a few of the recent advancements in malignant pleural mesothelioma treatment and discusses how localized administration could offer additional treatment benefits.
Malignant mesothelioma with pleural effusion, also called malignant pleural mesothelioma (MPM), is a type of cancer that primarily affects the mesothelial cells that line the protective membranes (pleura) surrounding the lungs, abdomen, and other organs. These abnormal cells cause irritation and increased fluid production in the pleural space (pleural effusion), causing chest pain, shortness of breast, and persistent cough.
MPM is most commonly caused by asbestos exposure and, unfortunately, often diagnosed at an advanced stage where treatment options are severely limited. The average age at diagnosis is 75 years old, also making treatment that much more complicated. Prognosis is largely dependent on the disease subtype (epithelioid, sarcomatoid, or biphasic), but the average life expectancy overall is typically less than two years.
While surgery and radiotherapy are potential treatment options, most patients are too far advanced for these to be effective. As such, chemotherapy had traditionally been the prescribed regimen. The FDA-approved combination of permetrexed with cisplatin has been the standard-of-care chemotherapy, but this typically only extends survival by a few months (12.1 months combination vs. 9.3 months for cisplatin alone, as observed in the Phase III EMPHACIS study used for FDA approval).
In addition to chemotherapy, most patients will also have a catheter placed to periodically drain the pleural fluid. Doctors might also perform talc pleurodesis, in which a talc slurry is introduced via the catheter to induce inflammation and scaring to the pleural lining. This in turn reduces the amount of space that fluid can accumulate and, while not curative, helps to manage symptoms and discomfort.
Looking Beyond Chemotherapy
Our understanding of cancer biology has grown immensely, especially over the past decade. The rise of advanced next-generation sequencing and proteomic technologies have given us a more holistic understanding of tumor biomarker signatures, gene expression profiles, and the tumor microenvironment. From this new knowledge has come new, innovative ways to treat MPM beyond traditional chemotherapies such as cisplatin.
Small molecule inhibitors
Like in any other cancer cell, MPM cells ramp up certain molecular signaling pathways to ensure their survival. Multi-omic approaches have given us a glimpse as to which proteins and functions are up- and down-regulated, and in turn we are developing small molecule inhibitors that interrogate those pathways to kill cancer cells.
One such pathway that has caught our personal interest is the mitochondrial antioxidant pathway. Because of their aggressive and uncontrolled growth, mesothelioma cells must kick their redox-responsive signaling pathways into overdrive to dispose of harmful reactive oxygen species (ROS), such as peroxides. Our lead therapeutic candidate, RSO-021, irreversibly binds to and inhibits one such enzyme in this pathway, mitochondrial peroxiredoxin 3 (PRX3), resulting in ROS accumulation and apoptotic cell death. Preclinical data have been promising thus far, and currently RSO-021 is being evaluated in a Phase 1/2 trial (MITOPE; NCT05278975) in patients with malignant pleural effusion, including those with MPM.
Other drug developers are evaluating compounds that target other pathways, either alone or in combination with other therapies. Researchers at the University of Chicago, for example, currently have an ongoing Phase 2 trial evaluating Lynparza (olaparib), a PARP inhibitor that targets poly ADP ribose polymerase, in patients with homologous recombination deficient (HRD) malignant mesothelioma (NCT04515836). There is another ongoing Phase 2 trial sponsored by the Netherlands Cancer Institute evaluating the combination of Keytruda (pembrolizumab) with Lenvima (Lenvatinib), a multikinase inhibitor that targets VEGFR1, VEGFR2, and VEGFR3, in MPM patients (PEMMELA; NCT04287829). And this is just the very tip of the iceberg in terms of ongoing trials and preclinical research.
Immunotherapy
Rather than treating cancer cells directly with drugs, immunotherapy works by rallying the body’s immune response against the tumor. Immunotherapies generally work best against “hot” tumors – those that are inflammatory in nature. Data suggest that MPM is not only inflammatory but has also has a rich T cell microenvironment, suggesting that immunotherapy might be a feasible option to treat this disease.
After a therapeutic dry spell, a landmark milestone for MPM came in 2020 with the FDA approval of Opdivo (nivolumab) in combination with Yervoy (ipilimumab) as the new first-line treatment for MPM – 16 years following the approval of permetrexed and cisplatin combination chemotherapy. Further, this was also the first immunotherapy combination approved for this disease. The approval was based on the Phase 3 CheckMate 743 study, a randomized, open-label trial in 605 patients with previously untreated, unresectable MPM. Patients who received Opdivo in combination with Yervoy survived a median of 18.1 months while patients who underwent chemotherapy survived a median of 14.1 months. Although the median difference was only a few months, it was still an achievement very much worth celebrating for such a difficult disease. Further, it fueled a continuing interest in evaluating other immunotherapies.
While results with other immunotherapy regimens have been variable in MPM, many early-phase studies have shown some promise for additional immune checkpoint blockade. There are also numerous studies ongoing, such as this NCI-sponsored Phase 1/2 study evaluating Keytruda (pembrolizumab) alone and in combination with anetumab ravtansine in MPM (NCT03126630). Others are also evaluating the combination of immunotherapy plus chemotherapy rather than immunotherapy alone. Rondon et al recently wrote an informative review article summarizing this and a number of other ongoing immunotherapy clinic trials against MPM.
While promising, it’s important to note that immunotherapy is not always the right choice for patients, as there are significant side-effects that can significantly lower quality of life. Going forward, identifying additional treatment options that work alone or in combination with immunotherapy will be critical.
Cell Therapy
Cell therapies have caught considerable interest from drug developers, especially after seeing the success of CAR T-cell therapies for hematologic cancers. Solid tumors have been notoriously trickier to treat with cell therapy in comparison, and MPM is no exception. While there has not yet been an approved cell therapy for MPM, preclinical data have been promising, and there are numerous clinical trials in progress.
Part of the challenge of cell therapy is finding a suitable target that is selectively expressed on tumor cells. In the case of MPM, mesothelin has been one such target of interest, as it’s been shown to be broadly overexpressed on malignant tumor cells. An ongoing Phase 1/2 study conducted by Memorial Sloan Kettering (NCT02414269) published preliminary results in 2021 showing that intrapleural administration of 0.3M-60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T-cells were detected in peripheral blood for >100 days in 39% of patients. 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for ≥6 months in 8 patients; 2 exhibited complete metabolic response on PET scan.
There are numerous additional studies also in progress. Memorial Sloan Kettering, for example, is performing an additional Phase 1 study to evaluate the safety of autologous mesothelin-targeted CAR T-cells in combination with cyclophosphamide chemotherapy in mesothelioma patients (NCT04577326). Another trial, a Phase 1/2 sponsored by TCR2 Therapeutics, is evaluating an autologous CAR T-cell therapy consisting of two synthetic constructs – a single-domain antibody targeting mesothelin, and a PD-1:CD28 switch receptor designed to elicit a costimulatory signal upon PD-L1 engagement on the cancer cell (NCT05451849).
Beyond T-cell therapy, others are exploring other types of immune cells. The Amphera-sponsored DENdritic Cell Immunotherapy for Mesothelioma (DENIM; NCT03610360) study is a randomized Phase 2/3 trial evaluating the administration of dendritic cells encapsulated with allogenic tumor cell lysate plus best supportive care (BSC) vs those receiving BSC alone.
Localized Administration – Giving Next-Generation Therapies a Potential Added Boost
Cancer therapies can either be administered systemically or locally at the specific site of the tumor. When possible, localized therapy (also called “locoregional” therapy) is the ideal treatment regimen because it allows for direct contact between the drug therapy and the tumor(s). This results in an increased concentration of drug in the local environment, which may have the added advantage of reducing off-target side effects associated with drugs entering the bloodstream.
The decision to administer treatments systemically vs locally is largely influenced by the type of cancer. Melanomas, for example, are a prime candidate for localized treatment because the primary tumor is easily visible on a patient’s skin, making it easy to inject. Other solid tumors, however, require deep radiology or surgical expertise to gain access to the tumor, which is burdensome to the patient and can be risky.
In the case of MPM, patients could immensely benefit from a localized treatment approach because they often will already have a catheter port in place to drain the pleural fluid. This is a unique situation that warrants an opportunity for further study, not only with small molecule drugs but also with immunotherapies and perhaps even cell therapies. Indeed, this is exactly the strategy we at RS Oncology are taking with our MITOPE clinical trial.
A Hopeful Future
Mesothelioma in general has been an incredibly tough nut to crack in terms of finding effective treatments, and MPM is no exception. There has been significant progress in the field, but also immense frustration as many approaches haven’t quite panned out. Nonetheless, we and others are dedicated to this mission and refuse to back down. While asbestos use has been banned in many countries across the world, including the United States, we’re still seeing the lingering effects from decades ago as those who were exposed continue to age.
As newer therapies are being evaluated, we encourage drug developers and oncologists to explore the option for localized therapy, as this is a unique opportunity that many other solid tumor cancers do not have. And, of course, we will continue to move forward with our own MITOPE study and will share results when available.