Immune Checkpoint Inhibitors Improve Treatment Outcomes in Malignant Pleural Mesothelioma

Corey Langer, MD, Director of Thoracic Oncology, Abramson Cancer Center, Hospital of the University of Pennsylvania, provides an overview on the potential for immune checkpoint inhibitors for the treatment of malignant pleural mesothelioma, a topic he presented at the virtual 2022 Great Debates & Updates in Lung Cancers meeting.

In his presentation, Dr Langer touched on the history of the therapeutic landscape of malignant pleural mesothelioma and discussed the latest research regarding the exciting ways immune checkpoint inhibitors have improved survival outcomes in the treatment of malignant pleural mesothelioma in comparison to previously established treatments.

Transcript:

Hello, I'm Corey Langer, I'm the Director of Thoracic Oncology at the Abramson Cancer Center in University of Pennsylvania, in Philadelphia. And the end of August, I had the privilege of co-chairing the Great Debates & Updates in Lung Cancers meeting virtually with my colleague, Eddie Garon from L.A. During that meeting, I spoke specifically on malignant plural mesothelioma. Now mesothelioma is a relatively uncommon malignancy, about 3000 to 4000 cases a year in the United States. Back in the 1980s and 1990s, my mentors thought this was a disease that would disappear, because asbestos was no longer being mined and it was no longer used as a fire retardant, but unfortunately that does not seem to be the case. It's still in the environment.

Sadly, the destruction of the World Trade Center probably released a huge amount of asbestos particles into the air in Southern Manhattan and in adjacent boroughs. The latency period from exposure to manifestation of mesothelioma can be anywhere from 40 to 60 years, so the effects of asbestos, even though it may not be mined primarily anymore, will still be felt in all of our professional lifetimes.

Historically, mesothelioma was a very refractory tumor. It was resistant to a standard treatment. That all changed around the turn of the millennia. In 2003, Nick Vogelsang and colleagues, presented the results of a landmark paper looking at platinum chemotherapy alone or platinum chemotherapy combined with pemetrexed. That trial irreversibly altered the therapeutic landscape for mesothelioma. We now had a standard regimen that was at least a 3- or 4-month improvement in median survival, clear improvement in progression-free survival and overall response rates, now topping 40%. There was also an improvement in quality of life and pulmonary function. For the next 15 years or so pemetrexed with appropriate vitamin support, folic acid and B12, combined with platinum chemotherapy, generally cisplatin, but also carboplatin, had been our standard of care.

In the late 2010s there was a study from France that looked at the combination of bevacizumab with platinum chemotherapy and pemetrexed, and that too translated into a survival advantage of about 2-and-a-half to 3-month improvement in median survival going from about 16 months to 18-and-a-half months. And again, over time at 3, 4, and 5 years, a steady persistent improvement in therapeutic outcome.

The therapeutic landscape is once more changed irrevocably with immunotherapy. The CheckMate 743 trial directly compared combinatorial immunotherapy, ipilimumab, and nivolumab together versus the standard platinum-pemetrexed combination, and showed a major improvement in survival about a 4-and-a-half-month improvement in median survival that survival advantage persists over time. Now at 2 and 3 years, we don't have more mature follow up.

That advantage was generated by the population that was no doubt, least sensitive to standard chemotherapy. These are individuals with sarcormatoid or mixed sarcormatoid histology, PD-L1 positivity, and by and large, somewhat younger patients. In the sarcormatoid group, the median survival more than doubled from 8 to 18-plus months. And the epithelioid population may be not quite the same advantage that we were seeing in the sarcormatoid population.

At this point, our therapeutic approaches have sort of bifurcated. For those with the sarcormatoid or mixed histology, PD-L1 positivity, we're generally favoring, at least off-protocol, the ipilimumab/nivolumab combination for older individuals, pure epithelioid histology PD-L1 negative, generally favoring a platinum combination, of course if they're past 75 or 80, it's generally a carbo-platinum combination with pemetrexed, as opposed to cisplatin.

More recently, there have been efforts to combine immunotherapy with chemotherapy. Pat Forde from John Hopkins led a PrECOG effort doing exactly that with median survival now exceeding 20 months, and that has laid the groundwork from ongoing randomized phase three called the DREAM3R Trial, basically looking at chemotherapy, either pembrolizumab-platinum plus-or-minus durvolumab in that setting. We are seeing a lot of research now in a relatively rare malignancy where hope really did not exist at all. But today, we are seeing folks with the malignant plural mesothelium fare far better than they had previously.

Source:

Langer, C. Impact of CPIs on Malignant Pleural Mesothelioma. Presented at: Great Debates & Updates in Lung Cancers. Aug 24-26, 2022. Virtual.