Phase I Study of the Anti-Btla Antibody Tifcemalimab As a Single Agent or in Combination with Toripalimab in Relapsed/Refractory Lymphomas

Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Using Peripheral Blood Mononuclear Cell (PBMC) derived from cancer patients, co-blockade of the BTLA and PD-1 pathways improved antigen specific T cell response compared to either blockade alone. Tifcemalimab (also known as icatolimab, JS004 or TAB004) is a humanized IgG4 monoclonal antibody with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand Herpesvirus Entry Mediator (HVEM). In this first-in-human study, we report the preliminary safety and anti-tumor activity of tifcemalimab as a single agent or in combination with toripalimab (anti-PD-1) in patients with relapsed/refractory (R/R) lymphoma.

Methods: Eligible patients with R/R lymphoma were enrolled in this open-label, multicenter study (NCT04477772). Tifcemalimab was administered as a monotherapy at escalating doses of 1, 3 and 10 mg/kg intravenously Q3W, followed by 3 mg/kg and 200 mg monotherapy dose expansion until disease progression or intolerable toxicity. During combination dose escalation, patients received ascending doses of tifcemalimab (100mg and 200mg) plus toripalimab (240mg). Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, and efficacy.

Results: By the cutoff date of July 21, 2022, a total of 48 patients were enrolled, including 25 in the monotherapy and 23 in the combination subgroup. The lymphoma subtypes included 28 Hodgkin's lymphoma (HL) and 20 non-Hodgkin's lymphoma. The median age was 43.5 (range 19-70) years with 33 (68.8%) male patients. The median prior line of therapy was 4 with 32 (66.7%) progressed upon prior anti-PD-1/L1 therapy. By the cutoff date, the median follow-up was 31.3 weeks. No DLT was observed in either monotherapy or combination dose escalation. Forty-one (83.3%) patients experienced treatment emergent adverse events (TEAEs), 9 (18.8%) of whom experienced grade 3 or above TEAEs. The most common TEAEs were fever (27.1%) and anemia (25.0%). Five treatment-related adverse events led to the discontinuation of the study drug. Ten (40.0%) and 13(56.5%) patients experienced immune related AEs in the monotherapy and combination subgroups, respectively, but all were grade 1 or 2. Among 22 evaluable patients receiving monotherapy, 1 PR (follicular lymphoma) and 7 SD were observed per Lugano criteria. Among all evaluable HL patients receiving the combination regimen (n=12), 1 CR, 4 PR (ORR 41.7%) and 5 SD (DCR 83.3%) were observed. Among them, 11 (91.7%) and 7 (58.3%) patients were refractory to prior anti-PD-1/L1 or anti-CD30 therapy, respectively. The clinical efficacy is durable as all responses are ongoing by the cutoff date, with the duration of response ranges from 2+ to 8+ months. Preliminary data showed a trend of correlation between high HVEM expression and clinical response.

Conclusions: Tifcemalimab alone or in combination with toripalimab were well tolerated in all doses evaluated. The combination showed encouraging preliminary clinical efficacy in patients with R/R HL refractory to anti-PD-1/L1 and/or anti-CD30.

Pan:Shanghai Junshi Biosciences: Current Employment. Liu:Shanghai Junshi Biosciences: Current Employment. Ran:Shanghai Junshi Biosciences: Current Employment. Feng:TopAlliance Biosciences: Current Employment; Shanghai Junshi Biosciences: Current Employment. Yao:TopAlliance Biosciences: Current Employment; Shanghai Junshi Biosciences: Current Employment. Keegan:TopAlliance Biosciences: Current Employment. Zou:Shanghai Junshi Biosciences: Current Employment.