Cancers of the thymus, a small organ located in the mediastinum above the heart, are uncommon and understudied. Recent developments, including research led by Giuseppe Giaccone, PhD, MD, at Weill Cornell Medicine, however, have shined a light on a malignancy that only affects about 400 Americans annually.

“The thymus is…the place where the immune cells are formed,” said Giaccone, professor of medicine and associate director of clinical research at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “It’s a very important organ, in particular, at the beginning of life. Later in life, this organ evolves and becomes essentially fat tissue so it’s not that important anymore. But in early life, it is an essential organ. If you don’t have the thymus, then you don't have immunity.”

Primary thymic epithelial tumors are a heterogenous collection of malignancies that differ in both appearance and biological behavior. The World Health Organization categorizes thymic epithelial cancers as type A, AB, B1, B2, and B3 thymomas collectively and thymic carcinoma.

According to the American Society of Clinical Oncology, nearly all patients with type A disease live at least 15 years after diagnosis.

 In contrast, patients with thymic carcinomas, the most aggressive subtype, are often not curable by surgery. The 5-year overall survival rate is 62% for patients with diagnosed with thymic neuroendocrine tumors and 52% for those with thymic carcinoma.

Giaccone, who specializes in thymic cancers, said that no biomarkers are available for these cancers. “There are sometimes tumors that produce some tumor markers that you can find in the blood, but that’s pretty rare,” he said. “You can find [them] sometimes in carcinomas that produce tumor markers that are common in other carcinomas, but that’s pretty uncommon.”

Surgery is the primary treatment option, and radiation and chemotherapy are options for those with recurring disease or with localized disease that is not amenable to surgery. No FDA-approved treatments for thymic cancers exist. However, angiogenesis inhibitors are effective, Giaccone said, and immunotherapy is an option for thymic carcinomas.

Giaccone and colleagues published data from a single-arm phase 2 trial investigating pembrolizumab [Keytruda] for patients with thymic carcinoma in 2018. Patients (N = 41) received 200 mg of pembrolizumab every 3 weeks for up to 2 years. Forty patients were evaluable for efficacy.

At a median follow-up of 20 months (interquartile range [IQR], 14-26), the overall response rate (ORR) was 22.5% (95% CI, 10.8%-38.5%) with 1 complete response (3%) and 8 partial responses (20%). The most common grade 3/4 adverse events (AEs) were increased aspartate aminotransferase and alanine aminotransferase in 5 (13%) patients apiece.

“None of these are curative though,” he said. “Once you pass the step of surgery that is curative, all the rest is palliative. We really need better treatments that would prolong lives in a more significant way.”

Progress in thymic carcinomas is evident in the form of checkpoint inhibitors. In October 2022, investigators published data from the phase 2 CAVEATT trial, showing that the combination of avelumab (Bavencio) and axitinib (Inlyta) demonstrated encouraging response rates and progression-free survival (PFS) in pretreated patients with advanced type B3 thymoma and thymic carcinoma.

Thirty-two patients enrolled from April 22, 2019 to June 30, 2021. Twenty-seven had been diagnosed with thymic carcinoma, 3 with type B3 thymoma, and 2 with mixed type B3 thymoma and thymic carcinoma.

 Twenty-five (78%) patients died by the February 1, 2022, data cutoff. Four (13%) patients remained on treatment.

The ORR was 34% (90% CI, 21%-50%). All 11 responders had a partial response and 18 (56%) had stable disease. At a median follow-up of 22.4 months (IQR, 12.3-24.3), the median PFS was 7.5 months (90% CI, 3.7-10.0). The 6-month PFS rate was 61.3% (90% CI, 45.3%-73.9%).

Fourteen (43%) patients underwent surgery prior to enrollment and most patients had extensive metastatic disease. The median number of prior lines of therapy was 2 (IQR, 1-2) and 13 (41%) patients had received prior treatment with an antiangiogenic drug.

“In many other solid tumors, combining immunotherapy and angiogenesis inhibitors has been shown to produce at least additive effects,” said Giaccone, who was a coauthor on the study. “It’s a relatively small sample size still, so it will have to be confirmed. But, in general, these 2 treatment modalities go well together, so the response rate is higher. The toxicity seems to be acceptable. What we’ll need is maybe a longer follow-up to see how prolonged the response is in patients treated with this combination.”

Giaccone, along with Yongfeng He, PhD, recently identified a common mutation found in thymic epithelial tumors that they hope could result in targeted therapies for these malignancies.

Along with their colleagues, Giaccone and He genetically engineered mice to harbor the 

 L424H mutation, which is the most common mutation found in thymic epithelial tumor cells. The mutation resulted in abnormal development of the thymus in young animals and thymic tumors in aging animals.

The mouse tumors shared many molecular characteristics with type B1 and B2 human thymic tumors.

He, an instructor of cancer biology in medicine at Weill Cornell, added that investigators demonstrated that this single-point mutation in thymic epithelial cells can induce thymic tumors. 

 L424H is a transcription factor so it therefore is unlikely to be a therapeutic target, but this discovery may be the first step in developing a treatment.

“One way to treat these types of patients is to identify the downstream genes, or the genes that can be regulated by this mutation. Those genes might be a potential target in the future,” He explained. “However, further investigation needs to be performed in order to understand which gene regulated by this mutation can be targeted.

“Alternatively, there is a strategy called synthetic lethality, which means you cannot have 2 specific genes mutated in the same cell. If so, the cell will undergo apoptosis. So, we are thinking, [if we can identify] synthetic lethal targets for 

2I mutation then we can try to target the mutation better synthetically.”

American Cancer Society. Key statistics about thymus cancers. January 25, 2021. Accessed October 14, 2022. https://bit.ly/3MAd7oF

Suster S, Moran CA. Thymoma classification: current status and future trends. 

. 2006;125(4):542-554. doi:10.1309/CAV8-RNU5-TKNA-CKNC

Cancer.net. Thymoma and thymic carcinoma: stages and classification. February 2021. Accessed October 14, 2022. https://bit.ly/3s0rcCb

Bakhos CT, Salami AC, Kaiser LR, Petrov RV, Abbas AE. Thymic neuroendocrine tumors and thymic carcinoma: demographics, treatment, and survival. 

 (Phila). 2020;15(5):468-474. doi:10.1177/1556984520949287

Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. 

. 2018;19(3):347-355. doi:10.1016/S1470-2045(18)30062-7

Conforti F, Zucali PA, Pala L, et al. Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial. 

. 2022;23(10):1287-1296. doi:10.1016/S1470-2045(22)00542-3

He Y, Kim IK, Bian J, et al. A knock-in mouse model of thymoma with the 

. Published online August 30, 2022. doi:10.1016/j.jtho.2022.08.008

Articles

Recent developments in cancers of the thymus, a small organ located in the mediastinum above the heart, have shined a light on a malignancy that only affects about 400 Americans annually.

A Newly Identified Genetic Mutation May Be Key to Developing Thymic Cancer Treatment

Thymic Cancers

Giuseppe Giaccone, MD, PhD, is a professor of medicine and associate director of clinical research at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York, New York.

As is the case with many rare cancers, investigators struggle to find funding to research thymic cancers. On one level, Giaccone understands that there will be less funding available when compared with a malignancy such as breast cancer. However, for patients with thymic cancer, this reach is absolutely vital.

The Department of Defense and small foundations make some funding available. However, Giaccone would like to see the federal government take a more proactive role in making money available for this resarch. 

Videos

Giuseppe Giaccone, MD, PhD, highlights the difficulties with funding for research focused on rare cancers. 

Dr. Giaconne on the Lack of Funding for Rare Cancers Research

Yongfeng He, PhD, is an instructor of cancer biology in medicine at Weill Cornell Medicine in New York, New York.

He, along with Giuseppe Gianccone, MD, PhD, professor of medicine and associate director of clinical research at the Sandra and Edward Meyer Cancer Center at Weill Cornell, discovered that the presence of the 

 L424H mutation in thymic epithelial cells induced thymic tumors in mouse models. The mouse tumors shared many molecular characteristics with type B1 and B2 human thymic tumors.

 L424H is a transcription factor so it is unlikely to be a therapeutic target. However, this discovery may be the first step in developing a systemic treatment for patients with thymic cancers.

Yongfeng He, PhD, discusses how the presence of the GTF2I L424H mutation in thymic epithelial cells induced thymic tumors in mouse models.

Dr. He Discusses Potential Therapeutic Uses for GTF2I L424+ Thymic Cancers

Giuseppe Giaconne, MD, PhD, is professor of medicine and associate director of clinical research at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, in New York, New York.

Cancers of the thymus, a small organ located in the mediastinum above the heart, affect 400 to 600 Americans annually. Giaconne said the disease can be difficult to classify histologically, so the actual incidence is unclear.

He added that the rareness of the disease means that few pathologists have experience detecting thymic cancer. As such, only major cancer centers have good experience classifying these maligancies.

Giuseppe Giaconne, MD, PhD, discusses why thymic cancers can be difficult to classify histologically, so the actual incidence is unclear.