Genomic co-alterations and immune-related adverse events shape outcomes of thymic malignancies treated with immune checkpoint inhibitors

Thymic carcinoma, thymoma, and thymic neuroendocrine tumors are rare malignancies with limited treatment options in advanced stages. Immune checkpoint inhibitors (ICIs) have shown preliminary activity in thymic tumors, although their clinical benefit and toxicity profile remain incompletely defined. We retrospectively analyzed patients with thymic tumors treated with ICIs at MD Anderson Cancer Center from 2010 to 2024. Clinical characteristics, molecular profiles, treatment details, immune-related adverse events (irAEs), and survival outcomes were collected. The primary objective was ICI safety. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Cox regression identified predictors of survival. Forty-two patients were analyzed (median age, 59 years; 55% male), comprising 29 thymic carcinomas, 8 thymomas, and 5 neuroendocrine tumors. ICIs were administered as monotherapy (55%) or combinations (45%), most commonly anti-PD-1 agents (86%). IrAEs occurred in 60% overall and in all patients with thymoma. Grade ≥3 irAEs developed in 19%, including one treatment-related death from pneumonitis. Common irAEs included fatigue, rash, and musculoskeletal symptoms. Notable neuromuscular syndromes included concurrent myasthenia gravis and myocarditis in thymoma. Among 37 RECIST-evaluable patients, ORR was 21%, and DCR was 78%. Median PFS was 6.5 months, and median OS was 9.1 months. Any-grade irAEs were associated with reduced mortality risk (HR, 0.30). TP53 mutations and lung metastases predicted worse OS, whereas CDKN2A alterations correlated with improved OS. ICIs demonstrated preliminary activity in thymic tumors but were associated with substantial toxicity, especially in thymoma. Biomarker-driven patient selection and vigilant irAE monitoring are needed.