Critical Next Step in Thymoma/Thymic Carcinoma Field Involves Examining Immunotherapies

Identifying the role of immunotherapy and immune-combinations in the treatment of thymic cancers, and uncovering the mechanisms behind paraneoplastic autoimmune disorders that most patients with thymomas have which are hindering them from being candidates for immunotherapy, are key areas of research in the thymic epithelial tumor field, according to Rohan Maniar, MD. In the meantime, multidisciplinary care remains crucial when treating patients with these rare cancers.

“[Improving the field] is about pushing the science. We oftentimes are taking the advances of other tumor types and trying to apply them to thymic tumors. Ultimately, it’s a rare tumor, and what advances the field is collaboration. We’re lucky to be part of a number of different organizations [at Indiana University] that work together to promote thymic tumor research and advances in thymic tumors,” Maniar said in an interview with OncLive®.

Data presented at the 2024 ESMO Congress from the phase 2 PECATI trial (NCT04710628) revealed that pembrolizumab (Keytruda) plus lenvatinib (Lenvima) could be a potential standard treatment in patients with pre-treated advanced B3-thymoma and thymic carcinoma as this patient population (n = 43) experienced a 5-month progression-free survival (PFS) rate of 88.4% (95% CI, 73%-95%).1 Additionally, the median PFS was 14.9 months (95% CI, 10.6-not available) and investigators added that the toxicity profile was manageable, but recommended close monitoring.

Notably, a phase 2 trial (NCT03463460) is ongoing at Indiana University as well as Moffitt Cancer Center and Ohio State’s Comprehensive Cancer Center evaluating pembrolizumab plus sunitinib (Sutent) in patients with refractory advanced thymic carcinomas.2 Other immune-based combination therapies are also under investigation, and Maniar and colleague Patrick J. Loehrer, MD, outlined future directions with ongoing research and knowledge gained from molecularly informed clinical trials in an article published in Cancers (Basel).3 The antibody-drug conjugate (ADC) sacituzumab govitecan-hziy (Trodelvy) is another agent under evaluation in a phase 2 study (NCT06248515); this trial is examining the drug in patients with advanced thymoma and thymic carcinoma who experienced disease progression after at least 1 prior therapy.4

In the interview, Maniar detailed considerations when treating patients with these rare cancers as well as notable ongoing research in the field. Maniar is an assistant professor of medicine and an associate member of the Experimental and Developmental Therapeutics research program at IU School of Medicine as well as a medical oncologist at Indiana University Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis.

OncLive: What are the current challenges in diagnosing thymoma and thymic carcinoma, and how do you approach diagnosis in clinical practice?

Maniar: Thymomas and thymic carcinomas fall under thymic epithelial tumors, which are very rare diseases, and based on the rarity it’s sometimes difficult to make the diagnosis when there are other competing diagnoses such as non–small cell lung cancer [NSCLC] and germ cell tumors. Typically, we expect the disease to be in the anterior mediastinum but often it can be oddly placed where it can look like a lung cancer. Ultimately, it’s a lot of experience amongst clinicians, pathologists, and radiologists that helps us pull that diagnosis together based on all the information.

The NCCN guidelines note all patients should be treated by a multidisciplinary team, what is most important to note about this for clinicians who don't have as much experience treating these patients?

It’s a matter of having that suspicion for a thymic epithelial tumor and then making sure that you’re talking with the radiologists, pathologists, and surgeons; we come together in a multidisciplinary fashion to review the case and make sure we’re not missing a possible thymic tumor diagnosis because the treatment can be very different from other solid tumors. We’re typically leveraging experience [of] the pathologist and radiologist [to] ensure that we’re making the right call. There are times where centers don’t have a lot of experience with thymic tumors and sending out the tissue to an outside pathologist [or] a high-volume center where they see a lot of patients with thymic tumors can be very helpful. You can leverage that experience to make the diagnosis.

At Indiana University we see a fair number of thymic tumors, probably one of the highest [amounts at a center] in the country. That’s a large result of Patrick J. Loehrer, MD, who has been seeing patients with thymic tumors for the past 40 years. We’ve become a referral center for a lot of second opinions as well as local catchment in terms of patients who have potential thymic tumors. A lot of the local doctors know that they can always refer to us to help make that diagnosis if needed.

How do you select a chemotherapy regimen for patients with thymoma and thymic carcinoma?

The selection for systemic treatment is largely based on the underlying histology. We work very closely with the pathologist to make sure we identify whether it’s a thymoma, thymic carcinoma, or sometimes a thymic neuroendocrine tumor, and then we make the decision on treatment based on the underlying histology. Certainly, there are a lot of times where there’s a bit of ambiguity in terms of the underlying diagnosis, and that comes with experience in terms of trying to understand what patients can tolerate [and] what regimen can cover all potential histologies. Then we look to the guidelines to help us [which] are based on clinical trial data [but] of course in a very rare tumor type the evidence for a lot of the treatments is limited because it’s a small number of patients. But we use the data that we do have to make the best and most informed decision we can.

What recent research on thymoma and thymic carcinomas is important to highlight?

I also treat [patients with] NSCLC, small cell lung cancer, and other thoracic malignancies that are much more common, [and] we tend to look at the advances that we see in those disease states and try to apply them to thymic tumors as well. One of the recent advances in lung cancer treatment has been immunotherapy, and we’re actively trying to see where immunotherapy fits with thymic tumors. With thymomas, patients can often have paraneoplastic autoimmune disorders which would increase the risk for toxicity, so we don’t use immunotherapy in that histology.

But for thymic carcinomas, there have been a number of studies that have looked at immunotherapy including in patients who have had a durable response to immune checkpoint blockade. We’re always looking for avenues [to] advance that. A number of combinatorial strategies with multi-kinase inhibitors are being evaluated, or have been evaluated already, and we’ve seen some promising response rates with that as well as a manageable safety profile.We’re in that same boat as everyone else trying to use advances in molecular characterization, targeted therapies, and immunotherapies, but we’re trying to apply it to a much smaller population of patients with the goal of having better outcomes for them.

What notable research is ongoing in this space?

There are a couple of studies looking at ADCs [such as] sacituzumab govitecan which is a TROP2-targeted agent. The Indiana University group as well as others have [published research] showing significant expression levels [of TROP2] in thymic tumors, and that’s the rationale for exploring that drug in the clinical space. There are also a number of studies that are looking at the combination of immunotherapy with multi-kinase inhibitors. In the US, we [are examining] pembrolizumab plus sunitinib in an ongoing [phase 2] study to see if the combination of the 2 drugs improves outcomes compared with the drugs individually and to see if there’s synergy. There’s a lot of exciting science that’s being done along with these trials to try to understand how the drugs we’re giving impact the tumor, the tumor microenvironment, and all the things that go into how tumorigenesis develops [and] how tumors evolve and escape our treatments.

Fundamentally we’re also trying to understand the basis of how thymic tumors develop, and in particular, for thymomas [we are] trying to understand how paraneoplastic autoimmune disorders develop. There’s a lot of very rich science using multiomic technologies, advances in spatial transcriptomics, [and] single-cell analysis. We’re trying to get a better grasp of culprit cells with autoimmune disorders and how they’re a unique characteristic of thymomas. We hope that by having a better understanding of the paraneoplastic autoimmune disorders we’ll be able to open the door to understanding how immune-related adverse events can develop, particularly as there’s a significant heterogeneity in what those immune-related adverse effects can look like. Thymomas are an example of where the immune system can be very deranged and dysregulated. Therefore, this may be an opportunity for us to understand those culprit immune cells and ultimately address them in a way [where] patients who would otherwise not be candidates for immunotherapy can become candidates for immunotherapy.

Is there anything else you’d like to add on the thymic cancer field?

It’s an exceedingly rare tumor. A lot of patients can sometimes feel left behind with all the other advances that are occurring in lung cancer and other [cancers such as] myeloma and breast cancer; we see a lot of announcements every year about new advances in therapies, and unfortunately for thymic tumors [although] we’ve seen advances, they’re not at quite the same rate as we’ve seen in the other cancer types. The goal is to try to parallel those rates and try to advance the science so that we’re not leaving patients with this very rare tumor behind. The way we’re doing it is through collaboration, and we’re doing a good job of bringing a lot of scientists from across the world together to answer some of these very difficult questions.

References

1. Remon Masip J, Bironzo P, Girard N, et al. PECATI: a phase II trial to evaluate the efficacy and safety of lenvatinib in combination with pembrolizumab in pretreated advanced B3-thymoma and thymic carcinoma. Ann Oncol. 2024;35(suppl 2):1270. doi:10.1016/j.annonc.2024.08.2326
2. Pembrolizumab and sunitinib malate in treating participants with refractory metastatic or unresectable thymic cancer. ClinicalTrials.gov. Updated November 4, 2024. Accessed February 19, 2025. https://clinicaltrials.gov/study/NCT03463460
3. Maniar R, Loehrer PJ Sr. What have we learned from molecularly informed clinical trials on thymomas and thymic carcinomas-current status and future directions? Cancers (Basel). 2024;16(2):416. doi:10.3390/cancers16020416
4. A phase II trial of sacituzumab govitecan in patients with advanced thymic epithelial tumors. ClinicalTrials.gov. Updated November 27, 2024. Accessed February 19, 2025. https://clinicaltrials.gov/study/NCT06248515