Perioperative Pembrolizumab for Locally Advanced Thymic Epithelial Tumors: A Single-Arm, Phase 2 Trial

Introduction: Complete surgical resection remains the only potentially curative option for thymic epithelial tumors (TETs). We hypothesized that adding perioperative pembrolizumab to standard therapy may improve response, resectability, and disease-free survival (DFS). Methods: In this single-arm, prospective phase 2 trial, patients with potentially resectable TETs (Masaoka-Koga stages III–IV) received neoadjuvant docetaxel (75 mg/m²), cisplatin (75 mg/m²), and pembrolizumab (200 mg) every 3 weeks for 3 cycles, followed by surgery and maintenance pembrolizumab for 2 years. R1/R2-resected patients received adjuvant radiotherapy concomitant with pembrolizumab. The primary end point was a major pathologic response (MPR). Results: From March 2020 to January 2025, 40 untreated patients were recruited, including those with WHO B3 thymoma (n = 7, 17.5%) or thymic carcinoma (n = 29, 72.5%). Most were diagnosed with stage IV disease (n = 31, 77.5%). The median follow-up duration was 27.5 months (95% confidence interval [CI]: 22.0–39.2), and 28 patients (70.0%) underwent surgical resection. Among the patients who received surgery, MPR and pathologic complete response were observed in 13 (46.4%) and five (17.9%) patients, respectively. Notably, all cases of MPR and pathologic complete response occurred exclusively in patients with thymic carcinoma, not in those with thymoma. The 1-year DFS rate was 91.0% (95% CI: 79.9–100.0), and the median DFS was 49.3 months (95% CI: 25.3–not reached) from the time point of surgery. Most of the adverse events were grade 1 or 2 (n = 21, 52.5%), with nine (22.5%) grade 3 and five (12.5%) grade 4. Two patients with thymoma died from myocarditis. Conclusions: Perioperative pembrolizumab demonstrated promising rates of MPR, R0 resection, and long-term DFS in stage III to IV TETs.