A phase 1b/2 study of AK130 (TIGIT/TGF-β bispecific fusion protein) combined with ivonescimab in advanced biliary tract cancer (BTC).

Abstract

4142 Background: Chemotherapy (chemo) combined with or without PD-(L)1 inhibition is the standard first-line treatment for advanced BTC. After first-line treatment fails, patients (pts) lacking targetable genetic alterations (FGFR2, IDH1, or HER2 etc.) have limited options. For the majority, chemo (FOLFOX as the preferred regimen) is the default but suboptimal option. To date, the therapeutic potential of multi-target ICIs and anti-angiogenesis combination in the post-line regimen of BTC remains unexplored and constitutes a significant clinical demand. Additionally, early preclinical and clinical evidences support the combination blockade of TIGIT, TGF-β and PD-(L)1 plus anti-VEGF therapy in several solid tumors. AK130 is a TIGIT/TGF-β bispecific fusion protein. Ivonescimab, the first approved PD-1/VEGF bispecific antibody, has demonstrated promising efficacy in solid tumors, including BTC. Here, we aim to evaluate the efficacy and safety of AK130 plus ivonescimab in post-line BTC and the primary results from phase 1b is reported. Methods: This was an open-label, multi-center phase 1b/2 study. Pts who had progressed on prior chemo combined with or without a PD-(L)1 inhibitor were enrolled and treated with AK130 and ivonescimab. Phase 1b included dose escalation and expansion parts. In the escalation part, escalating doses of AK130 (10, 30, 45 mg/kg Q3W) were administered using a "3+3+3" design, with ivonescimab at 20 mg/kg Q3W (previously approved dose by NMPA). Dose-limiting toxicities (DLTs) were assessed. Based on safety profile, the expansion proceeded at selected doses, with up to 15 evaluable pts per dose. The primary endpoint of phase 1b was the incidence of AEs and DLTs. The secondary endpoint was ORR. Results: As of Jan 2026, a total of 23 pts was enrolled. 12 pts were enrolled in dose escalation across 3 dose levels (10, 30, 45 mg/kg AK130 Q3W; n = 3, 3, 6). No DLTs were observed, and no maximum tolerated dose (MTD) was established. All pts in the 10 mg/kg and 30 mg/kg groups experienced stable disease (SD). The 45mg/kg group was further expanded to 17 pts, including 15 pts that progressed on prior PD-(L)1 inhibition plus chemo.15 pts from 45mg/kg group were efficacy-evaluable with an ORR of 20.0% (3/15) and a DCR of 73.3% (11/15). 87.5% of the SD pts (7/8) reached shrinkage from baseline. 40.0% pts (6/15) had only one time evaluation and are continuing to be followed. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 39.1% (9/23) pts. The most common TRAEs were anemia and atopic dermatitis, each reported in 2 pts (8.7%). AK130 45 mg/kg Q3W is planned as the recommended phase 2 dose (RP2D), whose safety and efficacy will be further evaluated in phase 2. Conclusions: AK130 plus ivonescimab demonstrated potential anti-tumor activity with a manageable safety profile as a post-line option for advanced BTC, supporting its further development in this setting. Clinical trial information: NCT06938321 .