Safety and clinical activity of anti-programmed death-ligand 1 (PD-L1) antibody (ab) avelumab (MSB0010718C) in advanced thymic epithelial tumors (TETs).

Abstract

e20106 Background: Avelumab (MSB0010718C) is a fully human, IgG1 anti-PD-L1 ab under clinical development. We report safety and clinical activity in patients (pts) with relapsed TETs enrolled in a phase I trial (NCT01772004). Methods: Eligibility criteria: > 1 prior standard therapy, no prior immune checkpoint inhibitors, no prior autoimmune disease. Treatment: Avelumab 10-20 mg/kg iv q2 wks until progression or toxicity. Responses were assessed q6 wks by RECIST 1.1. Correlative studies: PD-1, PD-L1 IHC in tumor samples and peripheral blood immune subset analysis. Results: 8 pts were treated: 7 with thymoma (T) and 1 with thymic carcinoma (TC). Median age 53 yrs (39-76). 3 pts with T (2 B3, 1 B2/B3) received Avelumab 20 mg/kg; 4 T (1 B1, 3 B2) and 1 TC received 10 mg/kg. Responses: 2 (29%) pts with T had confirmed PR (1 at 20 mg/kg, 1 at 10 mg/kg), 2 (29%) unconfirmed PR, 2 (29%) SD and 1 (14%) PD; the TC pt had SD. 3 of 4 responses occurred after 1 dose. Treatment-related adverse events (AE, all grades) in > 15% pts were potential immune-related AEs (irAEs) in 5 (63%) pts and fatigue in 4 (50%) pts. Grade > 3 AEs were irAE (G3 in 3 (38%) pts; G4 in 2 (25%) pts) and hypokalemia (G4 in 1 (13%) pt). irAEs included 1 or more of: muscle weakness, myalgia, myositis, respiratory muscle insufficiency, hoarseness, paresthesia, dysphagia, dyspnea, diarrhea and elevated creatine kinase. With oral steroids irAEs resolved rapidly and completely in 3 pts and incompletely in 1 pt. irAEs gradually resolved with additional medications (IVIG, cyclosporine A) in 1 pt. All responders experienced irAEs (myositis in 3 pts, all after 1 dose of Avelumab and enteritis in 1 pt). Response was seen before or shortly after start of steroids in 3 pts suggesting response was related to Avelumab. Decreased CTLA4+ regulatory T cells and the ratio of granulocytic vs. monocytic myeloid-derived suppressor cells was seen post-treatment at the 20mg/kg dose. Conclusions: Avelumab is active in T with 4 of 7 pts having objective responses accompanied by development of irAEs that were generally reversible with oral steroids. Understanding the mechanism of irAEs and developing treatment strategies for this spectrum of toxicity is important. Clinical trial information: NCT01772004.