CHIMERA: A Phase II Study of Neoadjuvant Pembrolizumab in Combination With Cisplatin or Carboplatin and Pemetrexed Followed by Surgery and Adjuvant Pembrolizumab in Resectable Pleural Mesothelioma

: Pleural mesothelioma (PM) is a rare asbestos-related malignancy characterized by complex diagnosis and poor prognosis, with survival strongly influenced by histological subtype and eligibility for a multimodality approach, reserved for highly selected patients. While platinum-pemetrexed chemotherapy or the combination of ipilimumab plus nivolumab represent standard first-line options for unresectable disease, pembrolizumab combined with platinum-pemetrexed has demonstrated improved survival in advanced PM (IND227/Keynote483 trial). In resectable PM, multimodality treatment including surgery and chemotherapy remains preferred, yet pathological complete response (pCR) rates remain low at approximately 5%, and the role of perioperative immunotherapy is still poorly defined. CHIMERA is a prospective, open-label, multicenter phase II single-arm trial evaluating neoadjuvant pembrolizumab combined with platinum-pemetrexed chemotherapy followed by surgery and adjuvant pembrolizumab in patients with treatment-naïve, resectable stage I-IIIA epithelioid or biphasic PM. Patients receive three cycles of neoadjuvant pembrolizumab plus cisplatin or carboplatin and pemetrexed every three weeks, followed by centralized pleurectomy/decortication or extended pleurectomy/decortication in two high-volume referral centers, and subsequently 14 cycles of adjuvant pembrolizumab. The primary endpoint is pCR, with secondary endpoints including major pathological response, objective response rate, event-free survival, overall survival, treatment feasibility, and safety; translational tissue- and blood-based biomarker analyses are planned. The study is powered to detect an increase in pCR from 5% to 18%, requiring 40 patients to account for potential dropouts. By focusing on pathological efficacy within a standardized multimodality framework, CHIMERA aims to clarify the role of perioperative chemo-immunotherapy and to improve outcomes for patients with resectable PM.