This multicenter, open-label phase 2 trial evaluated ivonescimab (a bispecific anti-PD-1/VEGF antibody, 20 or 30 mg/kg Q3W) combined with gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) for up to 8 cycles, then ivonescimab maintenance, in 30 treatment-naive adults with unresectable locally advanced or metastatic biliary tract cancer (BTC). A post-hoc proteomic analysis explored MAP2K7 as a resistance biomarker.
ORR was 66.7% (95% CI: 47.2–82.7; 1 CR + 19 PR), DCR was 100%, median PFS was 8.5 months (95% CI: 7.6–10.5), and median OS was 16.8 months (95% CI: 11.1–22.5). All patients had TRAEs; most common were anemia (83.3%), decreased neutrophil count (76.7%), decreased WBC (73.3%), and decreased platelets (73.3%). No treatment-related deaths occurred. MAP2K7 was upregulated in non-responders, and its knockdown enhanced ivonescimab-mediated T-cell activity in co-culture models.
- Single-arm design with only 30 patients (all enrolled in China, nearly all intrahepatic cholangiocarcinoma or gallbladder cancer), limiting generalizability and preventing causal inference. - No blinded independent central review of efficacy; response assessed by investigators only. - Proteomic and MAP2K7 biomarker analyses were post-hoc, non-prespecified, and unadjusted for multiplicity, making all biomarker findings hypothesis-generating only.
Ivonescimab plus gemcitabine/cisplatin showed an ORR of 66.7% and median OS of 16.8 months in advanced BTC—well above historical benchmarks with PD-1/L1 inhibitor plus chemotherapy—but these are single-arm phase 2 data requiring confirmation in an ongoing randomized phase 3 trial (NCT06591520) before practice change. Clinicians may note MAP2K7 expression as a potential future biomarker for patient selection, though it remains investigational.
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