Discovering Research Advances in Mesothelioma With Samuel Kareff, MD, MPH, and Estela Rodriguez, MD, MPH

In this Fellows Forum interview, Dr. Samuel Kareff speaks with Dr. Estela Rodriguez, Clinical Research Lead of the Thoracic Site Disease Group at the University of Miami Sylvester Comprehensive Cancer Center, about recent research advances in mesothelioma, the emerging roles of immunotherapy and biomarker testing, and the importance of ensuring access to care for patients with this rare disease. 

Samuel Kareff, MD, MPH: Hello, and welcome to this episode of the Oncology Data Advisors Fellows Forum. Today, I’m humbled to be joined by Dr. Estela Rodriguez here at the University of Miami Sylvester Comprehensive Cancer Center, where she serves as the Clinical Research Lead of the Thoracic Site Disease Group, as well as the Associate Director for Diversity, Equity, and Inclusion (DEI) at the Cancer Center. Welcome, Dr. Rodriguez.

Estela Rodriguez, MD, MPH: Thank you for the invitation.

Dr. Kareff: For today’s episode, we’re going to be talking about a relatively rare type of lung cancer called mesothelioma. Let’s go ahead and jump right on into it. Dr. Rodriguez, what is mesothelioma, and why is it so difficult to treat?

Dr. Rodriguez: Mesothelioma is a disease that starts in the lining of the lung, and it’s not very common. We know it’s mostly associated with asbestos exposure, and it can take many years before people present after the exposure. It is a rare disease, so people don’t have a lot of experience in treating it.The usual way it presents is with either chest pain or pleural fluid, and it sometimes takes a long time for patients to present to their doctors with symptoms.

Also, because it’s so rare—there are around 3,000 new cases diagnosed every year—not every center will have experience in diagnosing mesothelioma from cytology. There are patients who have had pleural fluids drained, and mesothelial cells have been identified, but they haven’t been recognized as having mesothelioma. There’s pleural mesothelioma, and there’s also peritoneal mesothelioma. Most patients will present with pleural mesothelioma since it’s caused by airborne exposure, but we do have about 25% of patients who have peritoneal mesothelioma.

Dr. Kareff: It sounds like the rarity and the difficulty in diagnosis make it such a unique tumor, and like you said, a lot of folks will go to specialized centers for this treatment, which makes it interesting in some ways. Along that line, I was wondering, what is one therapy advance for mesothelioma that has made the biggest impact during your career in oncology?

Dr. Rodriguez: We’ve known for a long time that these patients need to be managed in multispecialty teams because surgery and radiation need to be offered, but surgery and radiation only go so far. I think the biggest advance that we have seen in the last five to 10 years has been the advent of immunotherapy, which has really revolutionized the way we have treated many cancers, including mesothelioma.

We have data for the FDA-approved combination of ipilimumab and nivolumab in the first-line setting for patients with metastatic pleural mesothelioma. That is based on the CheckMate 743 trial, which is a large international trial that randomized patients to upfront platinum-based chemotherapy with pemetrexed for six cycles, compared with patients who received the immunotherapy combination of ipilimumab/nivolumab upfront. What we learned from this was that immunotherapy worked, and we were able to see responses better than those with chemotherapy upfront. There was a median overall survival improvement in the treatment arm with immunotherapy of 18 months versus 14 months for chemotherapy.

We also learned that it made a difference if patients had epithelial or sarcomatoid mesothelioma. The group that benefited the most from immunotherapy upfront was the sarcomatoid group. We have known forever that sarcomatoid has been the most aggressive mesothelioma to treat. In the past, patients haven’t done well with surgery, and they don’t do well with chemotherapy. Immunotherapy is the one treatment that we never had before for patients with either mixed epithelial sarcomatoid or sarcomatoid alone.

I think in some ways, when you look at the data from that trial, what the immunotherapy really did is bring up the sarcomatoid group to the same level as the epithelial group. For that reason, some experts still use chemotherapy in epithelial mesothelioma because we can get responses to chemotherapy, but for sarcomatoid, we favor the immunotherapy upfront.

Dr. Kareff: Wow, so we’ll just add this to the long laundry list of malignancies that benefit from the use of immunotherapy. Mesothelioma does, for sure. Are there any other research advances in mesothelioma you’d like to highlight?

Dr. Rodriguez: Now that we’ve opened the door for immunotherapy to be an option, I think there are two major areas of potential discovery. One is how to really harness the immune system to optimize responses on patients who have already responded to immunotherapy. We have trials ongoing with chimeric antigen receptor (CAR) T-cell therapy. Unfortunately, the initial CAR T trials that are driven against the mesothelin protein, which is expressed in mesothelioma, are leading to a lot of toxicity in the lungs. We have yet to find the right CAR T target, but I do think that all the research in that area is going to hopefully take us to a better salvage long-term immunotherapy option for patients.

There are still a lot of trials looking at vaccines, and I think what we haven’t fully discovered yet, but we are getting on the way there, is biomarker testing, which is something that has really changed the management of non–small cell lung cancer, where we have 10 biomarker-driven treatments. For patients with mesothelioma, we don’t have a biomarker-driven treatment, but there are cases where you have methylthioadenosine phosphorylase (MTAP) loss and other epigenetic changes in mesothelioma that may be able to be targeted with some of the agents that are coming up a tumor-agnostic way.

Even though we don’t see a lot of mesothelioma, when you do encounter a patient and you want to have all the options, especially for younger patients, I think doing next-generation sequencing (NGS) testing is critical. We also note about a familial syndrome of BAP1 loss that may also trigger mesothelioma. Genetics is going to be part of the future of treatment of mesothelioma. We’re not there yet, so we have to collect more data.

Dr. Kareff: I certainly dream of the day where we can use CAR therapies as well as broad-based NGS testing to help us most efficiently treat our patients with mesothelioma. Dr. Rodriguez, before we conclude today, is there anything else you’d like to highlight related to the treatment or care of mesothelioma?

Dr. Rodriguez: Our group at the university has done work in this space about understanding access to care and how it impacts survival in mesothelioma. Together, we published an analysis of the National Cancer Database (NCDB) looking at patients with stage I, II, or III mesothelioma—which are patients who could potentially have surgery—and trying to understand which patients did better and what impacted their survival. What we learned is that if you’re African American, you’re twice as likely to do worse, for many reasons, but partly because of a higher likelihood of lack of access to treatment. For those patients who were able to travel farther, meaning to specialty centers with expert surgeons and multidisciplinary teams, those patients also had an advantage in terms of survival.

I think even in rare diseases like mesothelioma, access makes the biggest difference in terms of hopefully getting patients to a curative-intent treatment, because there are patients who do survive mesothelioma with appropriate treatment. I think the confusing part is that you need to have a lot of patient selection. We recently learned from the Mesothelioma and Radical Surgery (MARS) study, which compared chemotherapy versus surgery, that if you take all-comers and look at survival, especially in the UK system in England where most of these patients were treated, you don’t see a big difference.

What we and our experts have shown is that patient selection and timely referral to surgeons does matter. We don’t think surgery is not an option; we just think that proper access to surgery at the appropriate time may have an impact. We need patients to have access and be seen by multidisciplinary teams.

Dr. Kareff: I think this just adds to the case that social determinants of health are critical in treating patients with cancer, and it’s up to us to help advocate to expand access in efficacious and equitable ways. I’m glad we at least saw that there are some potential avenues towards doing so for patients with mesothelioma in that project.

Dr. Rodriguez: I will also add that, globally, mesothelioma is bigger than the United States, and there are still a lot of countries that don’t have asbestos bans in terms of exposure to risk factors of mesothelioma. So, we still need to advocate for risk prevention and laws that prohibit asbestos exposure.

Dr. Kareff: Absolutely. In fact, a lot of the international organizations that deal with lung cancer are advocating for such bans, and we hope to see those go through in the near future. Excellent. Dr. Rodriguez, thank you so much for joining us on this very special edition of the Oncology Data Advisor Fellows Forum. We’ll see you all next time. Take care.

Dr. Rodriguez: Thank you.

About Dr. Kareff and Dr. Rodriguez

Samuel Kareff, MD, MPH, is a Medical Oncologist and a Hematology-Oncology Fellow at the University of Miami’s Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital in Florida. He has special research interests in health advocacy, public policy, and the development of cancer therapies.

Estela Rodriguez, MD, MPH, is Clinical Research Lead of the Thoracic Site Disease Group and the Associate Director for DEI, and Associate Director of Community Outreach for Thoracic Oncology at the University of Miami Sylvester Comprehensive Cancer Center. Dr. Rodriguez specializes in the treatment of thoracic malignancies, including lung cancer and mesothelioma. She is passionate about mentorship and empowering patients to take charge of their health care.

For More Information

Peters S, Scherpereel A, Cornelissen R, et al (2022). First line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Ann Oncol, 33(5):488-499. DOI:10.1016/j.annonc.2022.01.074

Alnajar A, Kareff SA, Razi SS, et al (2023). Disparities in survival due to social determinants of health and access to treatment in US patients with operable malignant pleural mesothelioma. JAMA Netw Open, 6(3):e234261. DOI:10.1001/jamanetworkopen.2023.4261

Transcript edited for clarity. Any views expressed above are the speakers’own and do not necessarily reflect those of Oncology Data Advisor. 

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