A phase II trial of ivonescimab for previously treated thymic carcinoma UCLA L-11

Background: Thymic carcinoma (TC) is a rare and aggressive thymic epithelial tumor (TET), accounting for approximately 20% of thymic neoplasms. TC is often more invasive and less responsive to standard therapy than other TETs, with a 5-year survival rate of 30-50% in the advanced/metastatic setting. Effective treatment remains limited following progression with platinum-based chemotherapy. Programmed Death-(Ligand) 1 (PD-(L)1) inhibition demonstrates modest activity in recurrent TC, with an objective response rate (ORR) of 19.5-22.5% with manageable toxicities [Cho, Clin Oncol . 2019; Giaccone, J Thorac Oncol. 2021]. Moreover, vascular epithelial growth factor (VEGF) inhibition with sunitinib or lenvatinib achieved ORRs of 26-38% in second line therapy and beyond (Thomas, Lancet Oncol. 2015; Sato, Lancet Oncol. 2020). Combination of lenvatinib and pembrolizumab as second line therapy and beyond has shown an ORR of 22.5%, with a median duration of response of 8.2 months (Remon, Lancet Oncol. 2025 ). Ivonescimab is a humanized bispecific monoclonal antibody targeting both PD-1 and VEGF and shows favorable safety and efficacy in non-small cell lung cancer. In light of the known benefit of VEGF and PD-(L)1 blockade in TC, this study aims to evaluate the safety and efficacy of ivonescimab in patients with previously treated TC. Methods: This study is a multi-center, open-label, single-arm Phase II trial enrolling adults with histologically or cytologically confirmed unresectable/metastatic TC whose disease has progressed following systemic therapy. Key inclusion criteria include one-prior line of treatment, ECOG performance status ≤1, and adequate organ function. Exclusion criteria include prior treatment with PD-(L)1 inhibitors, positive paraneoplastic serologies, or autoimmune disease requiring active systemic therapy. Ivonescimab is administered intravenously on D1 of a 21-day cycle until disease progression, unacceptable toxicity, withdrawal, or loss of follow up. The primary endpoints are investigator confirmed ORR via RECIST 1.1 and safety/tolerability of ivonescimab. Secondary endpoints include progression-free survival, duration of response, time to response, and overall survival. Exploratory analyses will evaluate correlation of antitumor activity with tissue and blood-based biomarkers, such as PD-L1 expression and circulating tumor DNA (ctDNA). The study uses a Simon's two stage design: in stage 1, 15 patients will be enrolled. The study will be stopped if ≥ 5 treatment-related serious adverse events or if ≤1 patient achieves an objective response within the first three months of treatment. Otherwise, an additional 10 patients will be enrolled in stage 2. The design has 80% power with a 5% Type I error to detect an ORR of 30% over the null hypothesis of 10%. The study is currently enrolling patients. Clinical trial information: NCT06980077