ELCC 2021 | Mesothelioma: how will novel immunotherapies impact surgery?

This year, at the IASLC, I’ll be presenting about surgery in the immunotherapy era. Traditionally, there are three known operations for mesothelioma, as defined by the IASLC. There’s a big operation called extra-pleural pneumonectomy, a medium operation called pleurectomy decortication, and a small operation called partial pleurectomy. When I say big, medium and smaller I refer to the extent of surgical disease, not the magnitude to the patient, rather the actual amount of tissue intended for removal.

The United Kingdom is the only country in the world that has undertaken a clinical trial in all three groups of surgical resection. In 2011, Tom Treasure and colleagues published on extra-pleural pneumonectomy, an operation which removes the lung, the lining of the lung, the diaphragm and the lining of the heart. In addition, they have trimodality treatment. So, you have chemotherapy and radiotherapy and demonstrated that there was no survival advantage. In fact, survival was worse with extra-pleural pneumonectomy. Since then, around the world, that study has received a degree of unfair criticism, but for better or for worse, the operation is hardly ever performed now around the world.

There is a small operation called partial pleurectomy, and that removes a section or proportion of the tissue or disease to prevent fluid from re-accumulating. Robert Rintoul and colleagues did the MesoVATS trial in the UK, suggesting that there was no survival advantage either.

So, that leaves the whole world with just one operation left, which is called pleurectomy/decortication that removes just the lining of the lung, the lining of the chest wall, the diaphragm if it’s involved and the lining of the heart if it’s involved. That leaves the standard of care for surgery for mesothelioma.

The question is where does this go in terms of the immuno-oncology era? Prior to the publication of CheckMate-743, there was no yardstick for surgery. As long as any benefit could be demonstrated, it could be considered as an option for treatment. CheckMate-473 changed the whole landscape and scenario in that they’ve reported a 24% improvement in survival above that of cisplatin and pemetrexed.

I’m the chief investigator for MARS 2. It’s a study that investigates surgery within the cisplatin, pemetrexed chemotherapy regimen. Initially, we start to define a 30% benefit from MARS 2 which, fortunately, falls really nicely in line with the 24% reported by CheckMate-743. If MARS 2 is a positive study, it puts surgery as an equal or better footing to immunotherapy in mesothelioma and surgeons and all of us around the world and patients will celebrate.

On the other hand, if MARS 2 is negative and negative, meaning that it does not achieve a 30% improvement in survival, or maybe not at all, then that really reframes the role of surgery for mesothelioma. It is a last option available. The one that’s all used to date. And if it does not beat immunotherapy, then all thoracic oncologists and mesothelioma experts around the world will really need to think long and hard if and where surgery fits in in the management of mesothelioma.

So, I think, the MARS 2 study, despite having suffered through two waves of COVID pandemic has successfully recruited and completed in November 2020, randomizing 335 out of the intended 328 patient accrual, and the results will be available in two years. That’s where I see how the immunotherapy era has framed the last remaining operation for mesothelioma.