Fundamentals of Mesothelioma

Suresh Ramalingam, MD: Mesothelioma is a rare disease, but certainly we see enough of them in our clinical practice, and it is important for us to have a conversation about some recent developments that will guide management. Christine, at your institution, you have a long track record of developing novel approaches to treat mesothelioma. Tell us about the standard of care and how we got here.

Christine Bestvina, MD: The real staple of treatment for mesothelioma has been cisplatin. We built off of cisplatin with a trial back in 2003, which added pemetrexed to cisplatin in a randomized fashion and did demonstrate an improvement of overall survival at that time of 9 to 12 months with the addition of pemetrexed. We continued to try to build on this combination therapy and finally, with the MAPS study, the addition of bevacizumab demonstrated an addition of 3 months of overall survival.

However, for these patients it was still disappointing based off what histology the patients had. There are 2 main buckets of mesothelioma patients, the epithelioid and the nonepithelioid patients, and we’ve just struggled to have any great treatment options for these nonepithelioid patients, and it seems to have to do with chemotherapy resistance.

Suresh Ramalingam, MD: Thank you. When mesothelioma is diagnosed, the first question always is, is this surgically resectable or not? Steve, what are some things that would help make that determination?

Stephen Liu, MD: That’s something we need to discuss with an experienced surgical team. Fortunately, I sit down with my surgeons and go through things. We’ve moved a bit away from more radical surgeries, like extrapleural pneumonectomy, and look more at localized, pleural-stripping surgeries. There are some who think that mesothelioma is not a curable disease, even those who present who are surgical candidates. I would agree that relapse rates are very high. Avoiding very morbid procedures is appropriate. This is a cancer where regardless of stage, systemic treatment is important.

Suresh Ramalingam, MD: Thank you. When we have a patient with mesothelioma, Christine mentioned the median survival with systemic chemotherapy at this time is about 12 to 13 months. We’ve also seen qualitative improvements in those studies where a patient’s respiratory function improves with systemic chemotherapy. Is there a role for maintenance pemetrexed? You’ve given patients 6 cycles of cisplatin-pemetrexed. A recent study suggested perhaps not so. How do you approach that situation, Martin? You get the 6 cycles of chemotherapy, then what’s your next step with these patients?

Martin Dietrich, MD, PhD: Fortunately, we don’t have that many of them to say that. This is a segment of the country where mesothelioma is not as common, but we have a lot of patients from New York with asbestosis preload who are developing mesothelioma. We typically do not consider the addition of maintenance therapy, partly because of the toxicity, the cumulative toxicity of cisplatin. We see declining kidney function as a concern, also for the maintenance dosing of pemetrexed. I’m not 100% certain about the addition of bevacizumab. There seems to be some improvement in the MAPS study, but it’s not FDA approved, so it’s a little more challenging. It’s in the NCCN [National Comprehensive Cancer Network] Guidelines but not necessarily as the defined standard of care, and this is reflected in this treatment.

It’s a very difficult-to-treat disease. There is no early intervention. There’s no real surgery, which makes this ESMO [European Society for Medical Oncology Congress] presentation of the introduction of immunotherapy in the first-line setting so interesting. We’ve seen the CheckMate743 trial as a phase 3 randomized trial comparing cisplatin-pemetrexed against the combination of ipilimumab-nivolumab, in the same dosing regimen like we’ve seen in CheckMate 227 with nivolumab every 2 weeks and ipilimumab given every 6 weeks at the low dose of 1 mg/kg body weight. They were interesting to be separated into epithelioid and nonepithelioid subtypes, and there clearly seemed to be a preferential effect in what we thought to be the more challenging-to-treat subtype, which was the nonepithelioid type, and a very equivalent performance of ipilimumab-nivolumab in the epithelioid subtype.

With regard to expectations for mesothelioma, it’s surprising. Most of the single-agent immunotherapy trials have either been abandoned or reported out negative. It’s interesting to see that we have responses here with ipilimumab in the first-line setting, particularly in the PD-L1–positive subset of patients. PD-L1 may be a prognostic marker to be looked at, to guide a discussion; maybe not to select treatment but to guide a discussion. In my opinion, this is a practice-changing part for sure against cisplatin-pemetrexed in the nonepithelioid type, but I don’t have a good reason in the absence of referential considerations with comorbidities to not use it as a standard of care in the epithelioid subtype either. The efficacy and outcome are the same. The adverse effects are typically milder than cisplatin-pemetrexed, and there is a population of long-term responders. We don’t know why they occur, but they certainly do, and it’s something we really don’t see much in the chemotherapy-treated arm.

Suresh Ramalingam, MD: Firas, how much of that enthusiasm do you share for the ipilimumab-nivolumab regimen in mesothelioma?

Firas Badin, MD: I agree with Martin. This practice is changing to have a chemotherapy-free regimen in such aggressive disease, difficult disease to treat, with such a big survival advantage with nivolumab-ipilimumab. Here is another time where this combination, PD-1 plus anti-CTLA4 combination, showing survival advantage regardless of different histology of this disease and regardless of PD-L1 status. That’s exciting, especially if you have somebody with nonepithelioid histology where chemotherapy historically does very poorly, this is a wonderful option. In the epithelioid histology, where you’re trying to avoid chemotherapy in somebody who is older, this is also a wonderful option. I wonder if we can adopt the 9LA approach with 2 cycles of maybe cisplatin–Alimta [pemetrexed], plus nivolumab, plus ipilimumab, and then you go to maintenance. I would also love to see something like that come into this disease. It’s not a common disease. I don’t see a lot of it. The biggest challenge for us in the community, whether you do or don’t have a skilled surgeon, having a surgeon turn down by 1 CT [cardiothoracic] surgeon who does maybe a few surgeries of mesothelioma a year. I don’t think it’s a fair answer to give the answer about surgery vs no surgery from somebody who is experienced, who does tons of those procedures, before you move along with palliative treatment. But this offers hope. Survival rate was fantastic, more than 40%, and I’m excited about it.

Suresh Ramalingam, MD: Great. When we talk about this regimen, the next obvious question would be, what is the role of PD-L1 expression? Is there a reason to check PD-L1 expression in mesothelioma patients if you are thinking of ipilimumab-nivolumab? Christine, can you talk a little about that?

Christine Bestvina, MD: In this trial, they did show what the rates of overall survival were for patients who were PD-L1 negative as well as patients who were PD-L1 positive or had PD-L1 expression. The benefit in this trial did seem to be better for patients who had PD-L1 expression, with a hazard ratio of 0.69. However, for patients who are PD-L1 negative, ipilimumab-nivolumab did not appear to be inferior to chemotherapy, which is also important to know.

Transcript Edited for Clarity