Endometrial cancer is one of the most common gynecologic malignancies, with its global incidence on the rise. In recent years, immunotherapy combined with chemotherapy has emerged as a promising strategy, demonstrating significant benefits in prolonging survival and maintaining durable responses in patients with advanced or recurrent endometrial cancer. However, as the use of immuno-chemotherapy becomes more widespread, concerns surrounding its safety profile have also come to the forefront.

At the 2025 Annual Meeting of the National Comprehensive Cancer Network (NCCN), held from March 28 to 30 in Orlando, USA, a meta-analysis on the incidence of adverse events associated with immunotherapy combined with chemotherapy for advanced or recurrent endometrial cancer was featured as a poster presentation. Oncology Frontier had the privilege of speaking with Professor Jihong Liu from Sun Yat-sen University Cancer Center for her expert commentary on this important study.

Meta-Analysis of Randomized Controlled Trials (RCTs) to Evaluate the Incidence of Venous Thromboembolism (VTE) and Immune-Related Adverse Events (iRAEs) in Patients with Primary Advanced or Recurrent Endometrial Cancer Treated with Immunochemotherapy

INTRODUCTION:

Immunochemotherapy, combining immune checkpoint inhibitors (ICIs) with platinum-based chemotherapy, has demonstrated improved survival and durable treatment responses for patients with primary advanced or recurrent endometrial cancer (EC). While enhancing treatment efficacy, immunochemotherapy also raises concerns about adverse events, specifically hypothyroidism, rash/dermatitis, and venous thromboembolism (VTE). This meta-analysis evaluates the incidence and relative risk of iRAEs(hypothyroidism and rash/dermatitis) and VTE in patients with primary advanced or recurrent EC treated with immunochemotherapy compared to chemotherapy alone.

METHOD:

Literature Search:

We conducted a comprehensive literature search using Medline, Embase, and Cochrane databases from inception through August 10th, 2024.

Eligibility Criteria:

Eligible studies included Phase II/III RCTs utilizing immunochemotherapy in primary advanced or recurrent EC reporting hypothyroidism, rash/dermatitis, and VTE (deep vein thrombosis and/or pulmonary embolism) events.

Data Extraction:

Data extraction was independently conducted by two authors; discrepancies were resolved by a third reviewer.

Study Outcome Measures:

The primary endpoint of our meta-analysis was the incidence of hypothyroidism, rash/dermatitis, and VTE (deep vein thrombosis and/or pulmonary embolism) events.

Data Synthesis and Analysis. The primary meta-analytic approach was a random effects model using the Mantel-Haenszel (MH) method. This method was used to calculate the estimated pooled risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI). Heterogeneity among the studies was assessed using the I2 statistic and Cochran’s Q-statistic. A p-value of less than 0.05 was considered statistically significant.

RESULTS:

Search Results:

A total of 2624 patients from four Phase III RCTs (AtTEnd, NRG-GY018, RUBY, DUO-E) and one phase II RCT (MITO END-3) were eligible for evaluation of hypothyroidism, rash/dermatitis, and VTE, events.

Characteristics of the Studies:

All five trials compared immunotherapy combined with chemotherapy versus placebo plus chemotherapy in primary advanced or recurrent EC.

Meta-Analysis Results:

The incidence of hypothyroidism was 12.53% in the immunochemotherapy arm vs 3.61% in the control arm (RR 3.27; 95% CI: 2.34-4.57; P < 0.00001). The incidence of rash/dermatitis was 12.07% in the immunochemotherapy arm vs 6.85% in the control arm (RR 1.80; 95% CI: 1.39-2.33; P < 0.00001). The incidence of VTE was not statistically significant. 3.56% in the immunochemotherapy arm vs 2.07% in the control arm (RR 1.60; 95% CI: 0.97-2.64; P= 0.07).

CONCLUSIONS:

Patients with primary advanced or recurrent endometrial cancer treated with immunochemotherapy had a significantly higher incidence of hypothyroidism and rash/dermatitis compared to chemotherapy alone, emphasizing the need for proactive monitoring and management of these immune-related adverse events. While the incidence of venous thromboembolism was higher in the immunochemotherapy group, the difference was not statistically significant, suggesting further studies are needed to confirm this trend. The findings underscore the importance of balancing the therapeutic benefits of immunochemotherapy with its potential risks, reinforcing the need for personalized treatment strategies and vigilant adverse event management to optimize patient outcomes.

Professor Jihong Liu：In the context of multidisciplinary cancer therapy, evaluating the safety profile of immunotherapy-chemotherapy combinations is of high clinical relevance. However, this meta-analysis has certain limitations, as it centers primarily on the incidence of adverse events as its core research endpoint.

From a pharmacological standpoint, it is well understood that adding immunotherapy or other anticancer agents to a chemotherapy backbone naturally increases toxicity. This phenomenon is expected and widely recognized in clinical practice. For example, the observed differences in hypothyroidism and skin toxicities stem largely from this additive effect, making the findings somewhat limited in terms of clinical innovation.

Nevertheless, the study offers a valuable safety alert for clinicians. It reinforces the need to establish robust monitoring systems and contingency protocols when implementing combination regimens, ensuring that patients benefit from treatment advances while minimizing harm.

Department of Gynecologic Oncology, Sun Yat-sen University Cancer Center Professor, Chief Physician, Doctoral Supervisor, Lead Expert

• Chair, Gynecologic Tumor Committee, Chinese Anti-Cancer Association
• Deputy Chair, Gynecologic Oncology Branch (CSGO), Chinese Medical Association (serving on the 1st and 5th committees)
• Deputy Chair, Expert Committee on Cervical Cancer Prevention and Control, National Cancer Center/National Clinical Research Center for Cancer
• Deputy Chair, Cervical Cancer Prevention and Screening Group, Cancer Epidemiology Branch, Chinese Society of Cancer Control and Prevention (CSCCP)
• Standing Member, Gynecologic Physicians Branch, Chinese Medical Doctor Association
• Deputy Chair, Gynecologic Oncology Branch, Guangdong Medical Association; Chair, Youth Committee
• Member, Gynecologic Oncology Group, Gynecologic Oncology Branch, Guangdong Anti-Cancer Association
• Chair, Gynecologic Oncology and Reproductive Tumors Committee, Southern Oncology Research Alliance