Systemic therapy for advanced thymic epithelial tumors: a narrative review of current evidence and perspectives

Introduction

Thymic epithelial tumors (TETs) are a heterogeneous group of rare tumors arising from thymic epithelium, which plays an important role in the maturation of T lymphocytes. Thymomas typically retain organotypic features of the normal thymus and often follow a relatively indolent clinical course, whereas thymic carcinomas lack these features and instead exhibit overt cytologic atypia with more aggressive behavior (1). According to the 5^th edition of the World Health Organization (WHO) classification of thoracic tumors (1), tumors of the thymus are broadly categorized into thymoma, thymic carcinoma, and thymic neuroendocrine neoplasms. In this article, we use the term TETs to refer specifically to thymoma and thymic carcinoma and do not address thymic neuroendocrine neoplasms.

At initial presentation, the stage distribution differs between thymoma and thymic carcinoma. Although most patients with thymoma present with early-stage disease, a subset are diagnosed with stage III or IV disease (2). In contrast, thymic carcinoma is more often detected at an advanced or metastatic stage, with more than three-quarters of patients presenting with stage III or IV disease (2). Prognosis varies substantially according to stage and histologic subtype. In large retrospective studies, the 5-year survival rates for thymoma were approximately 70–90% for Masaoka stage III and 40–60% for stage IV, whereas those for thymic carcinoma were approximately 50–60% and 20–40% for stage III and IV, respectively (3-6). These data highlight that survival remains unsatisfactory in patients with advanced-stage disease, particularly those with thymic carcinoma, and they emphasize the need to optimize systemic treatment strategies for advanced TETs.

Although systemic therapy is commonly used for unresectable advanced or recurrent TETs, it is difficult to obtain sufficient evidence of systemic therapy for TETs because TETs are rare tumors. The current treatment strategy is formulated largely based on small-scale phase II trials or retrospective cohort studies. Cytotoxic anticancer agents are still the mainstream of systemic therapy for TETs; molecular-targeted drugs and immune checkpoint inhibitors (ICIs) have also demonstrated a certain degree of efficacy for TETs. Furthermore, recent clinical trials have shown that combining these drugs can produce better therapeutic effects.

In this narrative review, we summarize the current evidence on systemic therapies for advanced TETs, incorporating the most recent clinical trial data. Given that thymoma and thymic carcinoma differ in key clinicopathologic features yet are frequently pooled in clinical trials, we report outcomes separately by histologic type (thymoma vs. thymic carcinoma) where data are available. We also discuss practical considerations for treatment delivery and toxicity management in routine practice and outline future directions for advanced TETs. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-77/rc).

Methods

The current narrative review included prospective and retrospective original studies, meta-analyses, review articles, and case studies written in English and searched via PubMed and Google Scholar, considering all articles published up to November 2025. Ongoing and unpublished trials were additionally identified through ClinicalTrials.gov and the Japan Registry of Clinical Trials (Table 1). The terms used for literature search were “thymoma”, “thymic carcinoma”, “thymic cancer”, “thymic tumors”, “thymic epithelial tumors”, “chemotherapy”, “systemic treatment”, “immunotherapy”, and “targeted therapy”. The studies on neoadjuvant and postoperative adjuvant chemotherapy or concurrent combined chemoradiation therapy were excluded. We also excluded retrospective studies with fewer than 15 participants because small sample sizes limit the reliability and interpretability of outcome estimates. When trials enrolled both thymoma and thymic carcinoma, we extracted and reported treatment outcomes separately by histologic subtype where available. Therefore, sample sizes shown in the thymoma- and thymic carcinoma-specific sections and tables represent histology-specific subsets when studies enrolled mixed histologies, rather than the total trial accrual.

First-line systemic therapy for advanced thymoma

Several prospective phase II trials or retrospective cohort studies have reported first-line systemic therapy for stage III or IV advanced thymoma (Table 2, Figure 1). Although trials designed to deliver perioperative (neoadjuvant or adjuvant) chemotherapy or chemoradiation were excluded, surgery or radiotherapy was sometimes administered after first-line chemotherapy in advanced thymoma, which can confound time-to-event endpoints; progression-free survival (PFS) and overall survival (OS) should therefore be interpreted with caution.

Figure 1 Therapeutic efficacy of TETs. Results of selected clinical studies are shown by treatment line for thymoma and thymic carcinoma. The bubble size is proportional to the sample size of each study. The figure is descriptive and not intended for indirect comparisons across trials. It displays a selected subset of studies from Tables 2-5; studies with mixed treatment lines or mixed histologies without separable data, and very small cohorts were not plotted. ADOC, cisplatin + doxorubicin + vincristine + cyclophosphamide; CAP, cisplatin + doxorubicin + cyclophosphamide; CODE, cisplatin + vincristine + doxorubicin + etoposide; CP, carboplatin + paclitaxel; ICI, immune checkpoint inhibitor; ORR, overall response rate; PD-1, programmed death-1; PE, cisplatin + etoposide; PFS, progression-free survival; TET, thymic epithelial tumor; VIP, etoposide + ifosfamide + cisplatin.

Given the lack of head-to-head comparative trials and heterogeneity among study populations and designs, the available evidence is summarized descriptively and is not intended for indirect cross-trial comparisons or superiority claims.

Anthracycline-based regimens

In the first-line treatment of thymoma, anthracycline-based regimens are among the earliest reported and remain the mainstay of contemporary clinical practice. In retrospective series, the ADOC regimen (cisplatin + doxorubicin + vincristine + cyclophosphamide) achieved a notably high overall response rate (ORR) of 81–92% (7,8). Given its four-drug composition, the ADOC regimen necessitates careful toxicity management, including cardiotoxicity, gastrointestinal toxicity, and vincristine-associated peripheral neuropathy. The CAP regimen (cisplatin + doxorubicin + cyclophosphamide) omits vincristine from ADOC and may therefore reduce the risk of neuropathy. In the phase II study of CAP, a comparatively favorable efficacy profile was reported, with an ORR of 50%, a median duration of response of 11.8 months, and a median OS of 37.7 months (9). When interpreting the results of this CAP trial, it is important to note that many patients underwent resection after chemotherapy. The CODE regimen (cisplatin + vincristine + doxorubicin + etoposide) showed antitumor activity in disseminated thymoma, achieving an ORR of 59%. The reported median OS was over 6 years, which the investigators suggested may have been influenced by subsequent local therapy, particularly in stage IVa disease (10).

Non-anthracycline-based regimens

Several non-anthracycline cisplatin-based regimens, such as PE (cisplatin + etoposide) and VIP (etoposide + ifosfamide + cisplatin), also showed activity in small phase II studies, with reported ORRs of 25–56% (13-15). Because these regimens omit anthracycline, they can avoid anthracycline-associated cardiotoxicity and may therefore be considered for patients with pre-existing cardiac disease or in older adults. For patients who are not candidates for cisplatin, carboplatin-paclitaxel has also been investigated as an alternative, with an ORR of 42.9% and a median PFS of 16.7 months (16).

Treatment selection for treatment-naïve thymoma

To date, no practice-changing prospective evidence has emerged to establish a new standard first-line systemic therapy for treatment-naïve advanced thymoma. Accordingly, the optimal first-line regimen remains uncertain. A pooled analysis of platinum-based chemotherapy for advanced thymoma and thymic carcinoma including 15 clinical trials and retrospective data reported a significantly higher ORR for platinum plus anthracycline-based chemotherapy than for platinum plus non-anthracycline-based chemotherapy in thymoma (69.4% vs. 37.8%, P<0.0001) (17). Although subject to interstudy heterogeneity and potential selection bias, these data may support platinum-anthracycline combinations as a reasonable default for first-line treatment of advanced thymoma. Consistent with this, the latest National Comprehensive Cancer Network (NCCN) guidelines list the CAP regimen as a preferred regimen, with other anthracycline- or platinum-based combinations (e.g., ADOC; PE/VIP in selected contexts) noted as reasonable alternatives (2). Given the frequency of thymoma-associated paraneoplastic autoimmune syndromes (e.g., myasthenia gravis, pure red cell aplasia, and Good’s syndrome), baseline clinical evaluation, including neuromuscular autoantibody testing such as anti-acetylcholine receptor (AChR) antibodies and assessments of reticulocyte counts and immunoglobulin levels, should be incorporated into treatment planning and monitoring when initiating systemic therapy. Paraneoplastic autoimmune syndromes may influence regimen selection and monitoring intensity, and therefore warrant individualized, multidisciplinary treatment planning. Among the commonly used platinum-based regimens, the main severe toxicities are hematologic (notably neutropenia/febrile neutropenia) and gastrointestinal adverse events, whereas anthracycline-containing regimens also warrant attention regarding cardiac toxicity. When toxicity is acceptable, a cisplatin–anthracycline regimen is considered first; however, its administration requires vigilant toxicity monitoring and proactive supportive care. In patients with pre-existing cardiac disease or in older patients, it is prudent to consider substitution with a non-anthracycline regimen or a carboplatin-based combination to mitigate treatment-related risk.

Second- and subsequent-line systemic therapy for advanced thymoma

In second- and subsequent-line treatments for advanced thymoma, prospective evidence remains limited (Table 3, Figure 1). Although first-line regimens for advanced thymoma predominantly consist of cytotoxic chemotherapy, second- and subsequent-line trials are more diverse and include not only cytotoxic agents but also targeted agents and ICIs, often in trials that pooled thymoma participants with thymic carcinoma participants.

The available evidence is summarized descriptively and is not intended for indirect cross-trial comparisons or superiority claims.

Cytotoxic agents for pretreated thymoma

Cytotoxic agents remain the mainstream for second- and subsequent-line treatments for advanced thymoma. However, the available evidence is limited to small, single-arm studies. Among single agents, pemetrexed and amrubicin showed modest response rates with median PFS of 8–12 months (19,20). Oral S-1 yielded a low ORR but a comparable median PFS, likely reflecting a high disease control rate (95%, 19 of 20) (21). Combination cytotoxic regimens have been evaluated in small phase II cohorts, with ORRs ranging from 33% to 40% and a median PFS of approximately 8–11 months across studies (12,18). There is also a small amount of prospective data available for ifosfamide (n=5), but the limited sample size leads to significant uncertainty (22).

Targeted agents, ICIs, and other agents for pretreated thymoma

Compared with thymic carcinoma, current evidence suggests that targeted agents have generally yielded low ORRs in thymoma. In multiple phase II studies of single-agent targeted therapies, ORRs ranged from 0% to 17% (23-25,27-29). Despite modest ORRs, median PFS exceeded one year with selected agents, including everolimus, palbociclib, and selinexor (25,27,29). In a single-center retrospective study, platinum-paclitaxel plus bevacizumab showed activity in previously treated thymoma, with an ORR of approximately 24% (26). Although ICIs have demonstrated antitumor activity for patients with previously treated thymoma (30-35), thymoma-specific evidence remains limited to very small patient subsets extracted from small trials enrolling mixed tumor types. Their clinical use is substantially limited by the high frequency of severe immune-related adverse events (irAEs), as detailed later (see the “Practical strategies for treatment delivery and toxicity management” section).

Treatment selection for pretreated thymoma

Determining the optimal second- or later-line systemic therapy for thymoma is challenging because the clinical efficacy of available regimens is generally limited. Targeted agents appear to show limited antitumor activity in thymoma relative to thymic carcinoma, and ICIs should generally be avoided outside clinical trials because of the high incidence of severe irAEs in thymoma. Consequently, cytotoxic chemotherapy remains the preferred default beyond the first-line therapy, with regimen selection individualized according to prior treatments and patient tolerability.

First-line systemic therapy for advanced thymic carcinoma

Cytotoxic chemotherapy remains a key component of first-line treatment for advanced thymic carcinoma, as in advanced thymoma. However, emerging prospective phase II evidence suggests that combination strategies incorporating anti-angiogenic agents or ICIs may improve outcomes in advanced thymic carcinoma (e.g., the RELEVENT and MARBLE trials), marking a shift in the systemic therapy landscape (Table 4, Figure 1).

The available evidence is summarized descriptively and is not intended for indirect cross-trial comparisons or superiority claims.

Cytotoxic agents for treatment-naïve thymic carcinoma

Evidence for first-line cytotoxic agents in advanced thymic carcinoma is largely limited to small cohorts, most commonly using platinum-based regimens. Carboplatin-paclitaxel is the most frequently reported platform, with ORRs of approximately 20–40% and a median PFS of 5–9 months across studies (16,39-41). Anthracycline-based cisplatin regimens have shown variable activity (ORR approximately 20–50%) in small cohorts (11,12,38), which appears less robust than the responses reported in thymoma (7-9). The VIP regimen was evaluated in a phase II trial that enrolled both thymoma and thymic carcinoma; thymic carcinoma-specific outcomes were available only for a very limited subset (n=4–8) (14,15). Carboplatin-paclitaxel may offer a more favorable safety profile, particularly regarding cardiac toxicity, while potentially maintaining an efficacy comparable to that of anthracycline-based regimens. As detailed below, recent first-line development has increasingly built on the carboplatin-paclitaxel regimen, incorporating molecular-targeted agents or ICIs in combination strategies.

Targeted agents for treatment-naïve thymic carcinoma

While data on first-line targeted therapy in advanced thymic carcinoma remain limited, recent clinical development has increasingly focused on vascular endothelial growth factor receptor 2 (VEGFR2) blockade with ramucirumab. In the prospective, single-arm phase II RELEVENT trial (n=35), ramucirumab plus carboplatin-paclitaxel has shown promising activity, with an ORR of 57.6%, a median PFS of 18.1 months, and a median OS of 43.8 months (43). In SWOG S1701, a small randomized phase II trial that closed early because of slow accrual (n=20), the addition of ramucirumab to carboplatin-paclitaxel increased the ORR (88% vs. 40%, P=0.04), whereas PFS did not differ significantly [hazard ratio (HR) =0.51; P=0.13] (44); the interpretation is limited by the small sample size. Anti-angiogenic agents were generally manageable but required careful patient selection and vigilant monitoring for class-specific toxicities. In the RELEVENT trial, ramucirumab-related serious events included four cardiovascular events: two grade 3 acute myocardial infarctions, one grade 4 pulmonary embolism, and one grade 3 arterial hemorrhage (43). These safety signals warrant careful cardiovascular risk assessment, blood-pressure control, and surveillance for thromboembolism and bleeding during anti-VEGFR2 therapy.

ICIs for treatment-naïve advanced thymic carcinoma

As in other malignancies, ICI-chemotherapy combinations have been explored in advanced thymic carcinoma. In the prospective, multicenter, single-arm phase II MARBLE study (n=48), first-line carboplatin-paclitaxel plus atezolizumab achieved an ORR of 56.0% and a median PFS of 9.6 months; median OS was not reached at a median follow-up of 15.3 months (45). These prospective data support chemoimmunotherapy as an emerging first-line option for thymic carcinoma. In a separate real-world retrospective, non-randomized cohort study from China (n=107), platinum-taxane plus programmed death-1 (PD-1) inhibitor was associated with longer PFS than platinum-taxane alone (9.4 vs. 6.3 months; HR =0.37; P<0.001) (46). However, these findings should be interpreted cautiously given the retrospective, non-randomized design.

Treatment selection for treatment-naïve thymic carcinoma

In the absence of prospective comparative trials, the optimal first-line regimen for advanced thymic carcinoma has not been definitively established. In the pooled analysis of platinum-based chemotherapy across TETs, the ORR in thymic carcinoma was similar between platinum-anthracycline and platinum-non-anthracycline regimens (41.8% vs. 40.9%, P=0.91), in contrast to the superiority observed in thymoma (17). In the latest NCCN guidelines, anthracycline-containing regimens are not listed as preferred first-line options for thymic carcinoma but remain included as “Other Recommended” regimens, in part due to toxicity concerns (2). Among preferred first-line options, reflecting emerging phase II evidence, the guidelines list carboplatin-paclitaxel and carboplatin-paclitaxel plus ramucirumab as preferred options for treatment-naïve advanced thymic carcinoma (2,43). Chemoimmunotherapy combinations are expected to play an increasingly central role in first-line management of advanced thymic carcinoma. However, the combination therapy requires vigilant toxicity monitoring and proactive management, including baseline risk assessment, timely dose modifications, and coordinated supportive care to mitigate overlapping adverse events.

Second- and subsequent-line systemic therapy for advanced thymic carcinoma

For second- and later-line treatment for advanced thymic carcinoma, various agents, including targeted agents and ICIs, have been evaluated in recent years (Table 5, Figure 1).

Alongside cytotoxic chemotherapy, selected targeted agents and ICIs are recognized as subsequent-line options. More recently, trials evaluating combinations of molecular-targeted therapies with ICIs have also emerged. Practice-informing evidence for second-line and subsequent therapy in advanced thymic carcinoma is primarily derived from prospective phase II studies, which include NCCN-preferred regimens such as lenvatinib (REMORA trial), sunitinib, and pembrolizumab.

The available evidence is summarized descriptively and is not intended for indirect cross-trial comparisons or superiority claims.

Cytotoxic agents for pretreated thymic carcinoma

Prospective evidence for cytotoxic agents in previously treated thymic carcinoma is limited and is largely derived from small, single-arm studies (12,18-22,47). Single cytotoxic agents have generally shown modest activity (ORR 9–15%; median PFS 3–7 months) (19,20,22). Notably, oral S-1 has demonstrated comparatively favorable activity in Japanese phase II cohorts (ORR 25–30%; median OS 22–27 months) (21,47), although its availability is region dependent. Combination cytotoxic regimens have also been explored in small cohorts, but interpretation is constrained by sample size and clinical heterogeneity (12,18).

Targeted agents for pretreated thymic carcinoma

Several targeted agents have been evaluated in previously treated thymic carcinoma, with the most notable activity reported for anti-angiogenic multi-kinase inhibitors. In the multicenter, prospective phase II REMORA trial (n=42), lenvatinib achieved an ORR of 38% and a median PFS of 9.3 months (49), with long-term follow-up reporting a median OS of 28.3 months (50). Real-world retrospective studies are consistent with these findings and suggest clinical activity in routine practice (51,52). Sunitinib also showed antitumor activity in two phase II studies, with ORRs of 21–26% and a median PFS of approximately 7–9 months (23,24). Other targeted approaches, including IGF-1R blockade with cixutumumab and the XPO1 inhibitor selinexor, have shown limited activity (28,29).

ICIs for pretreated thymic carcinoma

ICIs have shown modest activity for pretreated thymic carcinoma in small, single-arm phase II studies. Pembrolizumab achieved ORRs of 19–23% with a median PFS of 4–6 months (30,53), whereas nivolumab yielded heterogeneous results (ORR 0% in PRIMER and 14% in NIVOTHYM trial) (35,54). Atezolizumab has also been evaluated, with modest activity in a phase II trial (56). Reported outcomes have varied across studies, but cross-trial comparisons are inherently limited and may be influenced by small sample sizes and differences in patient/tumor characteristics, including programmed death-ligand 1 (PD-L1) distribution. Regarding safety, although irAEs appear less frequent than in thymoma, myocarditis and other neuromuscular immune events remain key concerns with ICIs in thymic carcinoma.

Combination with targeted agents and ICIs for pretreated thymic carcinoma

Combination strategies integrating targeted agents with ICIs have also been evaluated in pretreated advanced thymic carcinoma. In the phase II PECATI study (31), lenvatinib plus pembrolizumab met its primary endpoint (5-month PFS rate of 88.4%) and achieved a median PFS of 11.1 months with an ORR of 22.2% in the thymic carcinoma subgroup. In the phase II CAVEATT trial (33), axitinib plus avelumab yielded an ORR of 33% with a median OS of 26.6 months. Early-phase evaluation of nivolumab plus the anti-angiogenic tyrosine kinase inhibitor (TKI) vorolanib has also been reported in refractory thoracic tumors, including thymic carcinoma, but evidence remains limited (57). Across these regimens, toxicity reflects both VEGFR-inhibitor effects and immune-related events, requiring heightened vigilance; dose modifications and supportive care are essential (see the “Practical strategies for treatment delivery and toxicity management” section).

Treatment selection for pretreated thymic carcinoma

Given the limited, mostly single-arm evidence base in pretreated thymic carcinoma, treatment selection should be individualized based on prior therapy, clinical status, and toxicity risk. More recent data support lenvatinib as one of the more active options in pretreated advanced disease, and ICIs have demonstrated clinical activity in selected patients. In line with these developments, the latest NCCN guidelines list lenvatinib and pembrolizumab among preferred agents for second- or later-line therapy (2). In the future, combination strategies that incorporate molecular-targeted agents may be poised to assume a more prominent role beyond the first-line.

Practical strategies for treatment delivery and toxicity management

Treat-to-tolerability strategies for lenvatinib

Lenvatinib is a key targeted option for previously treated thymic carcinoma. In the REMORA phase II study (n=42), all patients had at least one dose reduction of lenvatinib due to adverse events, most commonly hypertension, proteinuria, and hand-foot syndrome. Although 9.5% of patients discontinued treatment due to adverse events, no treatment-related deaths were reported (49). A subsequent long-term follow-up and exploratory analysis showed that a higher relative dose intensity (RDI) at 8 weeks, defined as ≥75% RDI, was significantly associated with improved OS compared to RDI <75% (median OS, 38.5 vs. 17.3 months; HR =0.46; P=0.0406) (50). In addition, patients who maintained their lenvatinib dose during the first 8 weeks had a significantly higher ORR than those who required dose reduction (75.0% vs. 29.4%, P=0.0379) (50). These exploratory findings suggest that maintaining adequate early treatment intensity is associated with more favorable outcomes in this setting. This supports the need for careful monitoring and prompt management of adverse events during the initial weeks to preserve dose intensity.

Nevertheless, even with careful management of adverse events, many patients require dose reduction or treatment interruptions because of cumulative toxicities. In this context, alternative dosing approaches aimed at preserving treatment exposure while reducing toxicity have been explored for other tumor types. In unresectable hepatocellular carcinoma, a retrospective study reported that weekends-off administration of lenvatinib (5-day-on/2-day-off administration) reduced toxicities and improved tolerability, contributed to a longer treatment duration and prolonged OS (58). Furthermore, in a post-hoc analysis of the prospective COLLECT study in thyroid cancer (59), planned drug holidays of lenvatinib were associated with significantly improved OS and other clinical outcomes compared with continuous daily administration. In that study, planned drug holidays were utilized as a strategy to avoid severe or intolerable toxicities.

These findings suggest that thoughtfully implemented drug-holiday strategies may help mitigate toxicity while preserving clinically meaningful dose intensity. However, the supporting evidence remains limited and derives from other tumor types. Data on thymic carcinoma are scarce, with only a few published reports describing the use of a drug-holiday approach for toxicity management (60,61). For now, such approaches should be considered an exploratory option for selected patients when standard dose reductions and brief interruptions fail to provide adequate toxicity control.

ICI–related neuromuscular and cardiac toxicities

ICIs show antitumor activity in thymoma and thymic carcinoma. However, unlike in many other solid tumors, their use in TETs is characterized by a distinctive pattern of irAEs, with neuromuscular and cardiac toxicities emerging as major concerns, especially in thymoma. Across recent prospective ICI-based trials in TETs (30,31,33,45,53,54,56), the incidence of grade ≥3 irAEs ranged from approximately 30% to 70% in thymoma and 5% to 15% in thymic carcinoma. Severe neuromuscular or cardiac irAEs were observed in approximately 30–40% of patients with thymoma but in up to 8% of those with thymic carcinoma. Despite this high burden of severe irAEs, treatment-related deaths were uncommon in those trials. However, these estimates (including mortality) are based on small patient cohorts, especially for thymoma, and should be interpreted with caution. Nevertheless, multiple fatal cases of overlapping myocarditis, myositis, and myasthenia gravis have been reported in case series, particularly in thymoma, underscoring the potential for catastrophic toxicity when these irAEs occur. A large review of 244 reported cases of ICI-related myocarditis found that concomitant myositis or myasthenia gravis was present in nearly half of patients (62). Additionally, a systematic review documented 60 cases of ICI-related myocarditis with overlapping myositis or myasthenia gravis across multiple tumor types, including TETs; in that cohort, the overlap manifestation typically developed after a median of one ICI dose and carried an in-hospital mortality rate of around 60% (63).

Although thymic carcinoma shows a lower incidence of severe irAEs than thymoma, this difference is consistent with the well-recognized tendency of thymoma to be complicated by autoimmune diseases such as myasthenia gravis (64). Nevertheless, even in thymic carcinoma, the risk of ICI-related myotoxicities appears substantially higher than in other solid tumors; in a French nationwide study, the 6-month cumulative incidence of ICI-related myotoxicities reached 7.1% in thymic carcinoma, compared with an incidence of 0.9% across all tumor types (65). Taken together, these data illustrate that while the relative risk differs between thymoma and thymic carcinoma, both entities warrant particular caution when treated with ICIs. As indicated in the current NCCN guidelines (2), anti-PD-1/PD-L1 therapy is not recommended for thymoma. For thymic carcinoma, pembrolizumab is listed as a preferred regimen, with the caveat that PD-1/PD-L1 blockade in this entity may be associated with a higher incidence of irAEs.

Given these substantial and early-onset risks, careful pretreatment evaluation is essential. Baseline assessment should include a careful history of overt or subclinical autoimmune disease and a focused neuromuscular examination. Moreover, baseline neuromuscular autoantibody screening (e.g., AChR antibodies) should be considered, particularly in patients with thymoma or when suggestive clinical findings are present. Cardiac evaluation should include a 12-lead electrocardiogram (ECG), and measurements of troponin and creatine kinase; baseline echocardiography is reasonable for patients with pre-existing cardiovascular disease or other high-risk features. Given that ICI-related myocarditis and myotoxicities typically manifest early, often within the first one or two cycles, close clinical reviews during the initial 4–6 weeks are crucial. For higher-risk patients, serial monitoring of cardiac biomarkers and ECG is essential, together with clear education for patients and caregivers to ensure prompt reporting of new cardiopulmonary or neuromuscular symptoms such as dyspnea, chest pain, ptosis, or limb weakness. At the first sign of myocarditis or neuromuscular-cardiac overlap, ICIs should be withheld, and the patient should be urgently hospitalized for a comprehensive multidisciplinary evaluation. Current cardio-oncology position statements (66) recommend the prompt initiation of high-dose corticosteroids (intravenous methylprednisolone, 500 to 1,000 mg per day) for severe ICI-related myocarditis, in parallel with ongoing diagnostic evaluation and clinical stabilization. They also advise early escalation to additional immunosuppression for steroid-refractory disease, or an upfront combination including abatacept, anti-thymocyte globulin, or intravenous immunoglobulin and plasma exchange for severe myocarditis or triple M syndrome (myocarditis-myositis-myasthenia). Permanent discontinuation of ICIs is recommended for any case of myocarditis grade 2 or greater.

In clinical practice, ICIs should generally be avoided for thymoma outside clinical trials, except in highly selected patients after careful risk–benefit discussion and informed consent. In contrast, they are an accepted treatment option in previously treated thymic carcinoma, and emerging phase II evidence (e.g. the MARBLE trial) also supports first-line combination strategies; however, careful patient selection and vigilant safety monitoring remain critical.

Future perspectives for advanced TETs

In recent years, many clinical trials have been conducted to explore new systemic treatment approaches for advanced TETs. As summarized in Table 6, most studies are evaluating cytotoxic chemotherapy regimens, multitarget kinase inhibition, antibody-drug conjugates (such as agents targeting TROP-2), and combinations with ICIs in small phase II settings. These studies are expected to inform future treatment options, although their ultimate impact on standard care will depend on forthcoming results.

Alongside these therapeutic advancements, biomarker research has become increasingly important for refining patient selection and risk stratification for immunotherapy in TETs (Table S1). Although PD-L1 has been investigated as a potential biomarker in TETs, reported positivity shows substantial inter-study variation. This variability is partly due to differences in antibodies/assays, scoring systems, and intratumoral heterogeneity (71). Notably, given that thymic epithelial cells can naturally express PD-L1 as part of central tolerance programs, PD-L1 expression in TETs should be interpreted with caution. Consequently, PD-L1 alone may be insufficient as a predictive biomarker for ICI benefit (72,73). Furthermore, thymoma and thymic carcinoma are immunologically distinct; thymoma can maintain a thymus-like, immature thymocyte-rich environment, whereas thymic carcinoma more frequently exhibits a myeloid-skewed, immunosuppressive microenvironment (74,75). Recent genomic profiling of thymic carcinoma has highlighted recurrent alterations in key tumor suppressor genes and oncogenes (TP53, CDKN2A, CYLD, KIT) and several epigenetic regulators (TET2, SETD2, BAP1, and ASXL1). This analysis also confirmed that the tumor mutational burden is generally low, and microsatellite instability is rare. In particular, CYLD mutations have been proposed as a candidate biomarker for predicting response to ICIs (76), but the available data remain exploratory and require validation. Regarding toxicity, data from small thymoma cohorts and the broader literature on neuroimmune-related adverse events indicate that pre-existing autoantibodies, human leukocyte antigen (HLA) class I alleles, and baseline immune profiles may influence the risk of severe neuromuscular and cardiac toxicities (77,78). However, these potential biomarkers remain exploratory and largely unvalidated in thymic carcinoma. Looking ahead, composite biomarkers that integrate these genomic alterations with tumor- and host-immune features will be needed to better capture the likelihood of benefit and the risk of life-threatening immune-related toxicity in advanced TETs.

Because TETs are rare, generating high-level evidence from large randomized phase III trials is challenging. Dedicated national and international infrastructure has therefore become crucial for building evidence. In France, the RYTHMIC network operates as a nationwide prospective program that includes multidisciplinary tumor board discussions and data collection (79,80). The International Thymic Malignancy Interest Group (ITMIG) and its collaborative databases have also demonstrated the feasibility of large-scale, coordinated, global data pooling (81). Integrating future systemic therapy trials and translational research into these platforms is crucial for effective validation of new treatment strategies and biomarkers for TETs.

Artificial intelligence (AI) is emerging as a key tool to address the diagnostic and prognostic complexity of TETs, mainly through imaging- and pathology-based biomarkers. A recent systematic review identified 65 AI-based studies on TETs (82). Across these and other studies, computed tomography (CT)-based radiomics and deep learning models can assist in tumor characterization and WHO risk classification (83,84), and digital pathology approaches using deep learning and registry-based prediction models can support histologic subtyping and survival prediction (85-87). However, most existing models have been developed retrospectively, in single-center cohorts, and outside the framework of prospective therapeutic trials. Future research should focus on prospective, multi-institutional validation of AI-derived imaging and pathology signatures and their integration into trials of systemic therapy for advanced TETs. The international INTHYM study (NCT06301945) is currently ongoing to develop and validate AI-based tools for histologic assessment and recurrence risk prediction in TETs. Any AI-based biomarker entering clinical decision-making should meet emerging methodological standards, such as the European Society for Medical Oncology (ESMO) Basic Requirements for AI-based Biomarkers in Oncology (EBAI) (88).

Conclusions

Systemic treatment for advanced TETs continues to include cytotoxic chemotherapy as a major component. Accumulating evidence suggests clinically meaningful activity of targeted agents and ICIs in selected patients and supports the ongoing development of combination strategies. The emergence of novel agents, such as antibody-drug conjugates and bispecific T-cell engagers, as well as the integration of immunotherapy and targeted therapy, is expected to expand treatment options. Prospective collaborative trials with rigorous safety monitoring and biomarker-based patient selection are needed to define optimal treatment strategies and maximize clinical outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-77/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-77/prf

Funding: This study was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Nos. 23K15187 and 25K19461 to T.S.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-77/coif). T.S. reports support from JSPS KAKENHI (Nos. 23K15187 and 25K19461). The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. WHO Classification of Tumours Editorial Board. Thoracic Tumours. WHO Classification of Tumours. 5th ed. International Agency for Research on Cancer; 2021.
2. Riely GJ, Wood DE, Loo BW, et al. Thymomas and Thymic Carcinomas, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology. J Natl Compr Canc Netw 2025;23:255-69. [Crossref] [PubMed]
3. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;76:878-84; discussion 884-5. [Crossref] [PubMed]
4. Mariano C, Ionescu DN, Cheung WY, et al. Thymoma: a population-based study of the management and outcomes for the province of British Columbia. J Thorac Oncol 2013;8:109-17. [Crossref] [PubMed]
5. Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg 2015;149:95-100, 101.e1-2.
6. Ye C, Bao M, Li H, et al. Surgery in Masaoka stage IV thymic carcinoma: a propensity-matched study based on the SEER database. J Thorac Dis 2020;12:659-71. [Crossref] [PubMed]
7. Fornasiero A, Daniele O, Ghiotto C, et al. Chemotherapy for invasive thymoma. A 13-year experience. Cancer 1991;68:30-3.
8. Berruti A, Borasio P, Gerbino A, et al. Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience. Br J Cancer 1999;81:841-5. [Crossref] [PubMed]
9. Loehrer PJ Sr, Kim K, Aisner SC, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 1994;12:1164-8.
10. Kunitoh H, Tamura T, Shibata T, et al. A phase-II trial of dose-dense chemotherapy in patients with disseminated thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9605). Br J Cancer 2009;101:1549-54. [Crossref] [PubMed]
11. Thomas A, Rajan A, Szabo E, et al. A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study. Clin Cancer Res 2014;20:5392-402. [Crossref] [PubMed]
12. Inoue A, Sugawara S, Harada M, et al. Phase II study of Amrubicin combined with carboplatin for thymic carcinoma and invasive thymoma: North Japan Lung Cancer group study 0803. J Thorac Oncol 2014;9:1805-9. [Crossref] [PubMed]
13. Giaccone G, Ardizzoni A, Kirkpatrick A, et al. Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1996;14:814-20.
14. Loehrer PJ Sr, Jiroutek M, Aisner S, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 2001;91:2010-5.
15. Grassin F, Paleiron N, André M, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma. A French experience. J Thorac Oncol 2010;5:893-7.
16. Lemma GL, Lee JW, Aisner SC, et al. Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma. J Clin Oncol 2011;29:2060-5. [Crossref] [PubMed]
17. Okuma Y, Saito M, Hosomi Y, et al. Key components of chemotherapy for thymic malignancies: a systematic review and pooled analysis for anthracycline-, carboplatin- or cisplatin-based chemotherapy. J Cancer Res Clin Oncol 2015;141:323-31. [Crossref] [PubMed]
18. Palmieri G, Buonerba C, Ottaviano M, et al. Capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase II trial. Future Oncol 2014;10:2141-7. [Crossref] [PubMed]
19. Gbolahan OB, Porter RF, Salter JT, et al. A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma. J Thorac Oncol 2018;13:1940-8. [Crossref] [PubMed]
20. Hellyer JA, Gubens MA, Cunanan KM, et al. Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies. Lung Cancer 2019;137:71-5. [Crossref] [PubMed]
21. Tsukita Y, Inoue A, Sugawara S, et al. Phase II study of S-1 in patients with previously-treated invasive thymoma and thymic carcinoma: North Japan lung cancer study group trial 1203. Lung Cancer 2020;139:89-93. [Crossref] [PubMed]
22. Conforti F, Pala L, Vivanet G, et al. High-dose continuous-infusion ifosfamide in advanced thymic epithelial Tumors: A TYME network study. Lung Cancer 2023;176:98-102. [Crossref] [PubMed]
23. Thomas A, Rajan A, Berman A, et al. Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet Oncol 2015;16:177-86. [Crossref] [PubMed]
24. Proto C, Manglaviti S, Lo Russo G, et al. STYLE (NCT03449173): A Phase 2 Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines. J Thorac Oncol 2023;18:1070-81. [Crossref] [PubMed]
25. Zucali PA, De Pas T, Palmieri G, et al. Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy. J Clin Oncol 2018;36:342-9. [Crossref] [PubMed]
26. Wang CL, Gao LT, Lyu CX, et al. Bevacizumab in combination with paclitaxel and platinum for previously treated advanced thymic epithelial tumors. Med Oncol 2022;39:25. [Crossref] [PubMed]
27. Jung HA, Kim M, Kim HS, et al. A Phase 2 Study of Palbociclib for Recurrent or Refractory Advanced Thymic Epithelial Tumors (KCSG LU17-21). J Thorac Oncol 2023;18:223-31. [Crossref] [PubMed]
28. Rajan A, Carter CA, Berman A, et al. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. Lancet Oncol 2014;15:191-200. [Crossref] [PubMed]
29. Kim C, Aggarwal V, Daugaard G, et al. Parallel Phase II Clinical Trials of Selinexor in Patients With Advanced Thymoma and Thymic Carcinoma. JTO Clin Res Rep 2025;6:100848. [Crossref] [PubMed]
30. Cho J, Kim HS, Ku BM, et al. Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol 2019;37:2162-70. [Crossref] [PubMed]
31. Remon J, Bironzo P, Girard N, et al. Lenvatinib plus pembrolizumab in pretreated metastatic B3 thymoma and thymic carcinoma (PECATI): a single-arm, phase 2 trial. Lancet Oncol 2025;26:1215-26. [Crossref] [PubMed]
32. Rajan A, Heery CR, Thomas A, et al. Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma. J Immunother Cancer 2019;7:269. [Crossref] [PubMed]
33. 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. Lancet Oncol 2022;23:1287-96. [Crossref] [PubMed]
34. Tabernero J, Andre F, Blay JY, et al. Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers. ESMO Open 2022;7:100419. [Crossref] [PubMed]
35. Girard N, Ponce Aix S, Cedres S, et al. Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: results from the EORTC-ETOP NIVOTHYM phase II trial. ESMO Open 2023;8:101576. [Crossref] [PubMed]
36. Palmieri G, Montella L, Martignetti A, et al. Somatostatin analogs and prednisone in advanced refractory thymic tumors. Cancer 2002;94:1414-20. [Crossref] [PubMed]
37. Loehrer PJ Sr, Wang W, Johnson DH, et al. Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group Phase II Trial. J Clin Oncol 2004;22:293-9. [Crossref] [PubMed]
38. Agatsuma T, Koizumi T, Kanda S, et al. Combination chemotherapy with doxorubicin, vincristine, cyclophosphamide, and platinum compounds for advanced thymic carcinoma. J Thorac Oncol 2011;6:2130-4. [Crossref] [PubMed]
39. Furugen M, Sekine I, Tsuta K, et al. Combination chemotherapy with carboplatin and paclitaxel for advanced thymic cancer. Jpn J Clin Oncol 2011;41:1013-6. [Crossref] [PubMed]
40. Hirai F, Yamanaka T, Taguchi K, et al. A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L. Ann Oncol 2015;26:363-8. [Crossref] [PubMed]
41. Xu JP, Hao XZ, Zhang XR, et al. Efficacy and safety of the combination of paclitaxel and platinum in advanced thymic carcinoma. Thorac Cancer 2016;7:222-5. [Crossref] [PubMed]
42. Fukuda A, Okuma Y, Hakozaki T, et al. Cisplatin and Irinotecan as First-Line Chemotherapy for Previously Untreated Metastatic Thymic Carcinoma: Updated Analysis. Front Oncol 2021;11:779700. [Crossref] [PubMed]
43. Proto C, Ganzinelli M, Manglaviti S, et al. Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671). Ann Oncol 2024;35:817-26. [Crossref] [PubMed]
44. Tsao AS, Hsieh MH, Koczywas M, et al. S1701, A Randomized Phase 2 Trial of Carboplatin-Paclitaxel With and Without Ramucirumab in Patients With Locally Advanced, Recurrent, or Metastatic Thymic Carcinoma. JTO Clin Res Rep 2024;5:100738. [Crossref] [PubMed]
45. Shukuya T, Asao T, Goto Y, et al. Activity and safety of atezolizumab plus carboplatin and paclitaxel in patients with advanced or recurrent thymic carcinoma (MARBLE): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2025;26:331-42. [Crossref] [PubMed]
46. Liu M, Zhao J, Liu Z, et al. Efficacy and Safety of First-Line Anti-PD-1 Antibody Combined With Taxane-Platinum Versus Taxane-Platinum Alone in Metastatic Thymic Carcinoma: A Real-World Retrospective Study. Clin Lung Cancer 2025;26:e547-e559.e4.
47. Okuma Y, Goto Y, Ohyanagi F, et al. Phase II trial of S-1 treatment as palliative-intent chemotherapy for previously treated advanced thymic carcinoma. Cancer Med 2020;9:7418-27. [Crossref] [PubMed]
48. Remon J, Girard N, Mazieres J, et al. Sunitinib in patients with advanced thymic malignancies: Cohort from the French RYTHMIC network. Lung Cancer 2016;97:99-104. [Crossref] [PubMed]
49. Sato J, Satouchi M, Itoh S, et al. Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial. Lancet Oncol 2020;21:843-50. [Crossref] [PubMed]
50. Niho S, Sato J, Satouchi M, et al. Long-term follow-up and exploratory analysis of lenvatinib in patients with metastatic or recurrent thymic carcinoma: Results from the multicenter, phase 2 REMORA trial. Lung Cancer 2024;191:107557. [Crossref] [PubMed]
51. Miyamoto S, Tsukaguchi A, Kuhara H, et al. Real-World Efficacy and Safety of Lenvatinib in Advanced or Recurrent Thymic Carcinoma: A Multicenter Retrospective Study in Japan. Thorac Cancer 2025;16:e70047. [Crossref] [PubMed]
52. Takagi K, Saito G, Tanaka H, et al. Lenvatinib for patients with previously treated advanced thymic carcinoma in real-world settings. ESMO Open 2025;10:105301. [Crossref] [PubMed]
53. Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 2018;19:347-55. [Crossref] [PubMed]
54. Katsuya Y, Horinouchi H, Seto T, et al. Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study. Eur J Cancer 2019;113:78-86. [Crossref] [PubMed]
55. Wang W, Lin G, Hao Y, et al. Treatment outcomes and prognosis of immune checkpoint inhibitors therapy in patients with advanced thymic carcinoma: A multicentre retrospective study. Eur J Cancer 2022;174:21-30. [Crossref] [PubMed]
56. Lu S, Ma X, Liu L, et al. Efficacy and Safety of Atezolizumab in Chinese Patients With Advanced Thymic Carcinoma: A Multicenter, Single-Arm Phase 2 Study. Clin Lung Cancer 2025;26:244-252.e2. [Crossref] [PubMed]
57. Beckermann KE, Bestvina CM, El Osta B, et al. A Phase 1/2 Study to Evaluate the Safety and Activity of Nivolumab in Combination With Vorolanib, a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor, in Patients With Refractory Thoracic Tumors. JTO Clin Res Rep 2024;5:100619. [Crossref] [PubMed]
58. Iwamoto H, Suzuki H, Shimose S, et al. Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability toward Adverse Events. Cancers (Basel) 2020;12:1010. [Crossref] [PubMed]
59. Tahara M, Takami H, Ito Y, et al. A Prospective Cohort Study Exploring the Effect of Lenvatinib Planned Drug Holidays in Treatment of Differentiated Thyroid Cancer. Thyroid 2024;34:566-74. [Crossref] [PubMed]
60. Sunaga N, Miura Y, Sakurai R, et al. Sustained antitumor response to lenvatinib with weekend-off and alternate-day administration in chemotherapy-refractory thymic carcinoma: a case report. Anticancer Drugs 2023;34:605-8. [Crossref] [PubMed]
61. Nakamura T, Yoshida T, Masuda K, et al. Genetic Characteristics of Disease Flare After Lenvatinib Discontinuation in Patients With Thymic Carcinoma: A Brief Report. JTO Clin Res Rep 2025;6:100872. [Crossref] [PubMed]
62. Zotova L. Immune Checkpoint Inhibitors-Related Myocarditis: A Review of Reported Clinical Cases. Diagnostics (Basel) 2023;13:1243. [Crossref] [PubMed]
63. Pathak R, Katel A, Massarelli E, et al. Immune Checkpoint Inhibitor-Induced Myocarditis with Myositis/Myasthenia Gravis Overlap Syndrome: A Systematic Review of Cases. Oncologist 2021;26:1052-61. [Crossref] [PubMed]
64. Blum TG, Misch D, Kollmeier J, et al. Autoimmune disorders and paraneoplastic syndromes in thymoma. J Thorac Dis 2020;12:7571-90. [Crossref] [PubMed]
65. Salem JE, Ajrouche A, Rozes A, et al. Incidence and risk factors of immune checkpoint inhibitor myocardial and muscle toxicity: a French nationwide study. Eur Heart J 2026;47:1014-30. [Crossref] [PubMed]
66. Herrmann J, Barac A, Carver J, et al. Immune Checkpoint Inhibitor-Associated Cardiovascular Toxic Effects: International Cardio-Oncology Society Position Statement. JAMA Oncol 2026;12:90-9. [Crossref] [PubMed]
67. Hayashi F, Matsuo M, Takemoto S, et al. A phase II clinical trial on the efficacy and safety of carboplatin plus nab-paclitaxel in chemotherapy-naive advanced or recurrent thymic epithelial tumors: protocol of Nab-TET. J Thorac Dis 2025;17:7343-51. [Crossref] [PubMed]
68. McAdams M, Swift S, Donahue RN, et al. Preliminary efficacy, safety, and immunomodulatory effects of PT-112 from a phase 2 proof of concept study in patients (pts) with thymic epithelial tumors (TETs). J Clin Oncol 2023;41:e20647.
69. Ahn MJ, Park S, Cho EK, et al. LBA105 A phase II, open-label, single-arm, multi-center study of rivoceranib in patients with metastatic thymic epithelial tumor, KCSG LU23-09 (THRIVE). Ann Oncol 2025;36:S1762.
70. Okuma Y, Nomura S, Sakakibara-Konishi J, et al. Artemis: A Multicenter, Open-Label, Single-Arm, Phase II Study to Evaluate the Efficacy and Safety of First-Line Carboplatin/Paclitaxel/Lenvatinib/Pembrolizumab Combination for Previously Untreated Advanced or Recurrent Thymic Carcinomas. Clin Lung Cancer 2024;25:389-94. [Crossref] [PubMed]
71. Ao YQ, Gao J, Wang S, et al. Immunotherapy of thymic epithelial tumors: molecular understandings and clinical perspectives. Mol Cancer 2023;22:70. [Crossref] [PubMed]
72. Caruso B, Weeder BR, Thompson RF, et al. PD-1 Limits IL-2 Production and Thymic Regulatory T Cell Development. Immunohorizons 2024;8:281-94. [Crossref] [PubMed]
73. Parmar K, Rajan A. Immune aberrations in thymic epithelial tumors. Mediastinum 2025;9:34. [Crossref] [PubMed]
74. Xin Z, Lin M, Hao Z, et al. The immune landscape of human thymic epithelial tumors. Nat Commun 2022;13:5463. [Crossref] [PubMed]
75. Shimamura SS, Shukuya T, Yamashita M, et al. Comparative analysis of the tumor immune microenvironment between thymoma and thymic carcinoma. Lung Cancer 2025;209:108785. [Crossref] [PubMed]
76. Takata S. Genomic insights into molecular profiling of thymic carcinoma: a narrative review. Mediastinum 2024;8:39. [Crossref] [PubMed]
77. Mammen AL, Rajan A, Pak K, et al. Pre-existing antiacetylcholine receptor autoantibodies and B cell lymphopaenia are associated with the development of myositis in patients with thymoma treated with avelumab, an immune checkpoint inhibitor targeting programmed death-ligand 1. Ann Rheum Dis 2019;78:150-2. [Crossref] [PubMed]
78. Vogrig A, Dentoni M, Florean I, et al. Prediction, prevention, and precision treatment of immune checkpoint inhibitor neurological toxicity using autoantibodies, cytokines, and microbiota. Front Immunol 2025;16:1548897. [Crossref] [PubMed]
79. Basse C, Thureau S, Bota S, et al. Multidisciplinary Tumor Board Decision Making for Postoperative Radiotherapy in Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort. J Thorac Oncol 2017;12:1715-22. [Crossref] [PubMed]
80. Molina TJ, Bluthgen MV, Chalabreysse L, et al. Impact of expert pathologic review of thymic epithelial tumours on diagnosis and management in a real-life setting: A RYTHMIC study. Eur J Cancer 2021;143:158-67. [Crossref] [PubMed]
81. Huang J, Ahmad U, Antonicelli A, et al. Development of the international thymic malignancy interest group international database: an unprecedented resource for the study of a rare group of tumors. J Thorac Oncol 2014;9:1573-8. [Crossref] [PubMed]
82. Esteve Domínguez AS, Dimmers M, Mulders TA, et al. Artificial intelligence for diagnosis and prognosis of thymic epithelial tumors: a systematic review. Mediastinum 2025;9:27. [Crossref] [PubMed]
83. Xia H, Yu J, Nie K, et al. CT radiomics and human-machine hybrid system for differentiating mediastinal lymphomas from thymic epithelial tumors. Cancer Imaging 2024;24:163. [Crossref] [PubMed]
84. Feng XL, Wang SZ, Chen HH, et al. Optimizing the radiomics-machine-learning model based on non-contrast enhanced CT for the simplified risk categorization of thymic epithelial tumors: A large cohort retrospective study. Lung Cancer 2022;166:150-60. [Crossref] [PubMed]
85. Xu H, Lin X, Wu J, et al. Machine learning for predicting the prognosis of patients with thymoma and thymic carcinoma. J Thorac Dis 2025;17:824-35. [Crossref] [PubMed]
86. Zhang H, Chen H, Qin J, et al. MC-ViT: Multi-path cross-scale vision transformer for thymoma histopathology whole slide image typing. Front Oncol 2022;12:925903. [Crossref] [PubMed]
87. Wang C, Du X, Yan X, et al. Weakly supervised learning in thymoma histopathology classification: an interpretable approach. Front Med (Lausanne) 2024;11:1501875. [Crossref] [PubMed]
88. Aldea M, Salto-Tellez M, Marra A, et al. ESMO basic requirements for AI-based biomarkers in oncology (EBAI). Ann Oncol 2026;37:414-30. [Crossref] [PubMed]