Phase 1 trial safety and efficacy of ragistomig, a bispecific antibody targeting PD-L1 and 4-1BB, in advanced solid tumors.
Authors: Falchook Gerald Steven , LoRusso Patricia , Goldman Jonathan W. , El-Khoueiry Anthony B. , Tolcher Anthony W. , Xing Yan , Henry Jason Timothy , Keam Bhumsuk , Kim Dong-Wan , Kim Tae-Yong , Kim Hye Ryun , Hong Min Hee , Kim Min Hwan , Lee Dae Ho , Lee SangMi , Jeon JuYeun , Hayslip John W. , Xu Cong , Garon Edward B. 
Published: June 2024

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Background: Activation of T cells in the tumor microenvironment by 4-1BB agonist antibodies is a promising approach to augment PD-(L)1 inhibitor efficacy. Ragistomig(ABL503/TJ-L14B) is a bispecific antibody combining PD-L1 antagonist with 4-1BB agonistic activity, designed to induce 4-1BB signaling only when bound to the PD-L1 tumor antigen on cancer cells, which may overcome resistance to PD-(L)1 inhibition and avoid hepatoxicity seen with traditional 4-1BB mAbs. Methods: ABL503 was investigated at doses ranging from 0.7 mg (flat dose) to 10 mg/kg (weight-based dose) IV every 2 weeks (Q2W) in patients with advanced or relapsed/refractory solid tumors, to assess safety, preliminary anti-tumor effect and pharmacokinetic (PK)/pharmacodynamic (Pd) activity. The BOIN design was utilized during dose escalation (regardless of CPS/TPS score). Additional patients were enrolled in dose expansion cohorts at 3 and 5 mg/kg (CPS/TPS>=1 required). Results: As of Jan 2024, the study enrolled 49 patients (30 dose escalation, 19 dose expansion). At least 1 treatment related adverse event (TRAE) occurred in 37 patients (75.5%); most common TRAE (≥ 10%, any grade/grade 3-4) were elevated AST (30.6%/18.4%), elevated ALT (26.5%/18.4%), rash (14.3%/4.1%), nausea (12.2%/0%), pyrexia (12.2%/2.0%) and fatigue (10.2%/0%). Dose limiting toxicities occurred in 5 patients and were observed at dose levels of 1, 5, and 10 mg/kg. All DLTs were recovered/recovering. MTD was not reached. Based on the safety, efficacy, PK and Pd analysis, the optimal dose was determined to be 5 mg/kg Q2W. Objective responses were observed in 6 out of 39 efficacy-evaluable patients, and all responses were observed at 3 and 5 mg/kg, including 1 complete response (CR) in a patient with ovarian cancer who received 6 prior lines of treatment and 5 partial responses (PRs) in patients with ovarian (n=1), melanoma (n=1), gastric (n=1), head and neck squamous cell (n=1), and esophageal cancer (n=1). Overall response rate (ORR) for all dose levels was 15.3%, and ORR at 5 mg/kg was 30% (3/10). Clinical benefit rate (CBR) for all dose levels was 61.5%, and CBR at 5 mg/kg was 80% (8/10). 66.7% of responders received prior PD-(L)1 inhibitors. One patient achieved sustained tumor regression over 6 months, even after treatment discontinuation. PK was dose proportional, and half-life was ~5 days. Dose-dependent increase of Pd marker s4-1BB was observed, demonstrating target engagement. Conclusions: ABL503 had a manageable safety profile and demonstrated promising anti-tumor activity, with objective responses in 6 out of 39 efficacy-evaluable patients across multiple tumor types in heavily pre-treated patients, including patients previously treated with checkpoint inhibitors. The data support continued development of ABL503 alone and in combination with other compounds, as a potential therapeutic option for patients with solid tumor cancers. Clinical trial information: NCT04762641 .