Welcome, everybody. I am Marina Chaira Garrassino. I am a professor of Medicine at the University of Chicago. And I am the director of the thoracic oncology. Here with me is Professor Girard. He is a very well-known professor of oncology and we collaborated in the past for thymic malignancies and this is why he's here with me today. Do you want to do an introduction?

Sure, so very obviously happy to be here. We took the opportunity of the ASCO meeting to discuss together about thymic malignancies. These are rare tumors. Obviously, complex management because of the rarity of the disease and the need for a multidisciplinary teams dedicated to treating the patients.

Yes, and you are also the President of ITMIG which is the International Association of Thymic Malignancies. Can you say something about your Association?

Sure. So ITMIG is International Thymic Malignancy Interest. Group. This is an International Society created in 2010 with patients and physicians dedicated to the management of this disease. ITMIG is a common platform to discuss projects. We were able to participate to the staging revision of thymic tumors, to discuss the histopathological classifications of the disease.

We set up some conceptual definitions to report on this tumor. So a lot has been achieved so far. We have multiple committees discussing all the aspects of the management of the disease. That includes the neurological aspects, the pathology, radiology aspects of this disease.

Thymic malignancies are heterogeneous tumor, so there is a lot of complexity in the diagnosis and in defining the accurate strategy for treating the patients. We also have a database which is an international prospective database which is a very important resource to further explore how the patients are treated and what are the outcomes.

And this is why here at the University of Chicago we are starting now a big multidisciplinary tumor board. In the multidisciplinary tumor board, we have the surgeons. We have dedicated pathologists. And we have also the neurologists.

And this is why we know very well that is very difficult to treat these tumors. And you need to stay in places where there is enough competence and there is also the multidisciplinary tumor board. Can we just go through the different aspects? So why is so important to make the correct diagnosis of the thymic malignancies?

Well, the diagnosis of thymic malignancies is complex because of the multiple entities within thymic malignancies. You may have thymomas, thymic carcinomas. There are five clusters of thymomas. So this is a matter of its two pathological diagnoses, meaning, looking at the microscope, the biopsy from the tumor.

And here we showed in within the French network, that in about 30% of cases, there was a discrepancy between the initial pathological diagnosis and the final diagnosis made after revision with pathologists who are experts of this disease. So it's very important to make an accurate diagnosis. And we know that similar to what we have in other rare cancers, such as sarcomas. Histopathological review is a major step in making an accurate diagnosis for the patients.

Yeah, we published exactly in Italy also the same data. And there is a 40% of discordance between the diagnosis made in a center of excellence and diagnoses made in centers where they see less thymic malignancies. And this is important because we know very well that thymomas, for example, they have a different prognosis from the thymic carcinoma.

And within the thymomas, we have multiple differences again. And they have a potentially also different sensitivity to the chemotherapy and also to the surgery. So I think that this is a major problem. And I would suggest that all the patients who are diagnosed in centers where there is not this expertise to ask for a second look and the second opinion, at least for the pathology.

Moving to another important aspect of this kind of tumors, so I believe that the importance of the surgery is crucial for the control of the disease. We saw that there are incredible differences in centers who treat patients, who treat commonly patients with rare tumors and who are not so used to treat these kind of tumors. Can you comment something on that?

Yes, surgery is a mainstay of the treatment of patients with thymic tumors. And achieving a complete resection of the tumor is a most important factor that drives the outcomes. And whatever is the stage, whatever is the type of tumor, the main objective is to obtain resectable tumors, a complete resection.

And there are multiple ways to do surgery. In some small tumors, it will be possible to do robotic or minimally invasive. But in larger tumors, there will be a need for a more important approach to the tumor. But at the end, what is important is to get a complete resection. And there is a need to have a good planification of the surgical, of the surgery in those patients. And it is very important to have a good radiological assessment of these tumors. And this may include CT scans, MRIs before surgery is planned.

Oh, yeah, this is really important. And I think that the majority of patients diagnosed, they are in very early stages. So sometimes the resection for these patients is enough. But when the patients, they have no radical surgery, there are also other treatments that we can ask or we can propose to the patients.

It's very important to consider systemic treatments that may include chemotherapy as well as targeted agents for the management of patients with advanced disease or in the setting of recurrences. And here you have some complexity again because of the limited number of studies available in the literature because of the molecular complexity of thymomas and thymic carcinomas.

I personally recommend to do comprehensive genomic profiling in the setting of recurrent tumors because in some patients, we may identify alterations that will drive the use of targeted agents.

Yes and, another question is sometimes these patients, they have autoimmune diseases that are often not recognized. And they are important. The most important is clearly the myasthenia gravis, but there are many of them. So can you say something, both for the myasthenia gravis and also of the other autoimmune disorders?

For sure, so myasthenia gravis is associated with thymomas in about 30% of patients. And sometimes you have clinical signs so it's easy to diagnose. But sometimes it's only a biological disease without symptoms. And it's then very important to recognize this unfortunate myasthenias because at the time of surgery, the patient may develop symptoms. So it's very important to be prepared to do that and to have a systematic assessment for myasthenia as well as other autoimmune disorders.

In the setting of advanced disease, some patients may be considered for immunotherapy, immune checkpoint inhibitors. This is now part of clinical trials. But there are also some recommendations in refractory treatment to use, immune checkpoint inhibitors, especially for thymic carcinomas. And again, here it's very important to have an accurate assessment for autoimmune disorders and a close monitoring of the patients.

Yeah, this is why here, at the University of Chicago, we created an important collaboration also with Dr. Sullivan and with the neurology team because this patient must be accurately followed also with the neurological part and also for the immunological part. So what do you think? So you know that for rare disease, to have a new drugs is very difficult. Do you see something that is coming in the space of the thymomas and that can be important, also thymic carcinomas, that is promising for the future?

Well, we see many phase II studies with new agents. I believe that we need to have some strong rationale before moving to clinical trials with targeted agents. And so this is why we need to have more patients who benefit from comprehensive genomic profiling the setting of advanced disease.

There are some clinical trials ongoing in thymic malignancies, some with new agents, some with combination of immune checkpoint inhibitors with chemotherapy. We have also one randomized clinical trial that is ongoing, at least in France, but hopefully in the future in other countries, which is autorhythmic, a clinical trial that is assessing the value of post-operative radiotherapy after complete resection of thymoma.

This is a major question in the field. After surgery for thymic tumors, it has been historically standard to deliver radiotherapy. But at the end, we need to actually assess with a modern techniques of radiation delivery, the real value of this strategy.

Yeah, this is a very important topic because the majority, luckily, the majority of these patients, they will survive after the surgery. And so you give some radiation to patients who will survive for a long time and potentially they can develop also some problems after some years from the radiation. So congratulations on this aspect.

So all the patients coming to our clinic are asking about the role of the immunotherapy. Clearly, they saw the immunotherapy everywhere in other tumors. And so when we start with the chemotherapy, sometimes they are disappointed because they want to have immunotherapy. What is the exact role of the immunotherapy in 2022?

Well, there are still some clinical trials ongoing in thymoma [INAUDIBLE] and thymic carcinomas. EU FTC, [INAUDIBLE] time study with nivolumab plus ipilimumab that we saw during this ASCO meeting, a trial in progress with a very specific antibody targeting PD-1 and CTLA-4. So trials are ongoing. This is the first one.

The other point is that we have some evidence of efficacy of immune checkpoint inhibitors, especially pembrolizumab for patients with advanced refractory thymic carcinoma. So an immunotherapy with pembrolizumab, that's been part of the NCCN recommendation in this setting.

I am very cautious with the use of immunotherapy in patients with thymic malignancies overall. Thymomas are a contraindication for the use of immunotherapy because of the high risk of severe immuno-related adverse events. It has been published multiple times in the literature.

But for patients with thymic carcinomas, we probably here have of an opportunity of treating the patients with immune checkpoint inhibitors. This requires close monitoring for the occurrence of immune-related adverse events, because these patients may develop myocarditis, myositis, which can be anticipated with this close clinical and biological monitoring.

OK. So trying to wrap up what we said and tell me if I'm doing correctly. So I suggested for all the patients in the world to remain in centers where there is a multidisciplinary tumor board on board for the thymic malignancies. Here at the University of Chicago, I am the medical oncologist for this part.

We have Jessica Donington for the thoracic part. And we have a big department of pathology expert in this field. And on top of that, we have also the neurologists and also the immunologist. What it is really important is to understand if the patient is resectable or not. And if the patient is resectable, the surgery is always the best thing to do, again, in centers where there are high volume of thymic malignancies.

For the post-operative part, it is very debatable what to do as you said. Also the radiation therapy is now a very crucial point of discussion with the multidisciplinary tumor board. And the use of the adjuvant chemotherapy and the radiation are based on the presence of the residual tumor and also on the subtype and also on the fact that if this is a thymoma or if this is a thymic carcinoma.

And for more advanced situations, we have the possibility to start with the chemotherapy. And after the chemotherapy, we can continuously evaluate again the surgery during the time of the treatment. What it is really important in 2022 is to join the patient advocacies and for us as doctors to join the international associations because this is the way how we communicate the science, how we can share ideas, how we can create protocols for the patients. And so this is why here, you are the President of ITMIG and we wanted you to have you in this discussion today.

Yes, I believe it's very important to discuss all the patient at the multidisciplinary tumor board. There are also two models that are organized within ITMIG for complex cases. So very important to have this networking of specialists of thymic malignancies because in some complex situation, it's very important to discuss between colleagues, having several surgeons, several medical oncology, several ideation oncologists and pathologists discussing together the cases.

So ITMIG is a common platform. Patients are involved within ITMIG. There are multiple resources on the website, so please visit ITMIG.org. We have an annual meeting, again, making physicians and patients joining together and discussing the scientific news and the actual management of this disease.

And finally, also, the role of the researcher. This is a rare tumor, so we have to join forces all together to collect all together data. So if the patients are asked to sign the informed consent for their data, this is really important for them. And this is very important for all the patients in the future. So thank you really for joining this discussion. I hope that this will be important for our patients and happy to answer all the questions.