Phase II study of KN046 in patients with thymic carcinoma who failed immune checkpoint inhibitors.
Authors: Ma Barbara Ting-wen , Dai Victoria , Greenberg June , Ballman Karla V. , Li Li , Garcia Christine Ann , Scheff Ronald J. , Saxena Ashish , Giaccone Giuseppe 
Published: June 2022

TPS8607 Background: Thymic carcinomas are the most aggressive form of thymic epithelial tumors. They are often not operable and are more resistant to chemotherapy than thymomas. Thymic carcinoma is sensitive to pembrolizumab. However, most patients who respond to pembrolizumab eventually recur. Recently, molecules that combine PD(L)1 and CTLA-4 have been developed for solid tumor patients, with the hope that targeted therapy will be more effective than standard of care. KN046 is a bi-specific antibody against PD-L1 and CTLA-4 with a much higher affinity of the anti-PD-L1 portion and a weaker affinity for anti-CTLA-4, potentially leading to less autoimmune disorders and toxicities. We developed a Phase II study to test the hypothesis that dual PD-L1 and CTLA-4 inhibition with KN046 may represent a safe and tolerable option for patients with advanced thymic carcinoma who have progressed on prior treatment with immune checkpoint inhibitors. Methods: Key eligibility criteria include thymic carcinoma with progression after treatment with an immune checkpoint inhibitor with no limit to prior lines of therapy, adequate organ function and performance status. History of prior or current autoimmune disorders are not allowed and history of baseline positive anti-acetylcholine receptor (AChR) autoantibody are not allowed. KN046 will be administered intravenously at 5 mg/kg every 2 weeks until progression or excessive toxicity for up to 2 years. A cycle is defined as 2 treatments (28 days). The primary objective is to evaluate the antitumor activity of KN046 in patients with thymic carcinoma as measured by overall response rate defined by RECIST 1.1 criteria. The secondary objectives are to assess the safety and tolerability of KN046 including safety as measured by the number of adverse events (CTCAE 5.0), duration of response (RECIST 1.1) from first documented response to the date of first documented disease progression, progression-free survival, and overall survival. Exploratory objectives include the association of biomarkers (PD-L1 expression, tumor immune microenvironment determined by multiplex IHC, tumor mutational burden, T-cell inflamed gene expression profile) and clinical efficacy parameters. We will also characterize the safety laboratory results (AChR autoantibodies and creatinine kinase) and the occurrence of adverse events of interest. Simon’s two-stage design will be used. The null hypothesis that the true response rate is 5% will be tested against a one-sided alternative of target response rate ≥20%. In the first stage, 10 patients will be accrued. If there are no responses in the first stage, then the study will be stopped. Otherwise, 19 additional patients will be accrued for a total of 29 patients. The null hypothesis will be rejected if ≥4 responses are observed in 29 patients, with a type 1 error rate of 0.05 and power of 80%. The study was activated at Weill Cornell Medicine in December 2021. Clinical trial information: NCT04925947.