Ivonescimab Combo Improves Survival in Advanced Biliary Tract Cancer

First-line ivonescimab (AK112) plus gemcitabine/cisplatin chemotherapy significantly prolonged overall survival (OS) compared with durvalumab (Imfinzi) plus the same chemotherapy backbone in patients with advanced biliary tract cancer (BTC), according to results from the phase 3 HARMONi-GI1 trial (NCT06591520) presented at the 2026 European Society for Medical Oncology (ESMO) Congress.¹

What were the survival and response outcomes?

At a median follow-up of 14.3 months in this preplanned interim analysis, the median OS was 14.9 months (95% CI, 12.9-not estimable [NE]) with ivonescimab/chemotherapy vs 12.1 months (95% CI, 11.0-13.4) with durvalumab/chemotherapy (stratified HR, 0.75; 95% CI, 0.61-0.92; one-sided P = .0031). Ivonescimab/chemotherapy reduced the risk of death by 25% vs durvalumab/chemotherapy, with 12-month OS rates of 59.7% vs 50.7% and 18-month OS rates of 44.0% vs 32.5%.

The median progression-free survival (PFS) was 8.4 months (95% CI, 7.5-9.3) with ivonescimab/chemotherapy vs 5.8 months (95% CI, 5.6-7.2) with durvalumab/chemotherapy (stratified HR, 0.61; 95% CI, 0.51-0.72; one-sided P <.0001), with 6-month PFS rates of 68.7% vs 49.3%. The objective response rate (ORR) was 53.8% (95% CI, 48.4-59.2) vs 32.5% (95% CI, 27.5-37.7; P <.0001), and the disease control rate was 91.5% (95% CI, 88.0%-94.2%) vs 77.8% (95% CI, 73.0%-82.1%).

“Ivonescimab plus chemotherapy significantly improved [OS], [PFS], and [ORR] in advanced [BTC] as first-line treatment compared with durvalumab plus chemotherapy,” said presenter Jian Zhou, MD, PhD, of Zhongshan Hospital in Shanghai, China.

The OS and PFS benefits were consistent across prespecified subgroups, including by primary tumor location (intrahepatic, extrahepatic, and gallbladder).

How did the trial account for subsequent therapy?

The rate of subsequent anti-tumor therapy was 14.1 percentage points higher in the durvalumab/chemotherapy arm (45.9%) than in the ivonescimab/chemotherapy arm (31.8%), including higher use of targeted therapy (25.1% vs 14.4%) and immunotherapy (21.1% vs 14.4%), a difference the investigators noted provides context for interpreting the OS results.

What was the safety profile?

Ivonescimab/chemotherapy demonstrated a manageable safety profile with longer treatment exposure (median, 7.8 months vs 5.7 months with durvalumab/chemotherapy). Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurred in 82.0% of patients in the ivonescimab arm and 72.3% in the durvalumab arm, serious TEAEs were similar (43.4% vs 43.7%), and TEAEs leading to death occurred in 11 patients (3.2%) vs 13 patients (3.8%). The most common TEAEs of any grade and of grade 3/4 were hematologic, and no new safety signals were identified.

The incidence of immune-related AEs of any grade (26.3% vs 22.1%) and grade 3 or higher (4.1% in both arms) was similar between the arms, with no immune-related deaths. Most AEs potentially associated with VEGF inhibition were low-grade proteinuria and hypertension, with a manageable bleeding risk and no increase in grade 3 or higher hemorrhage.

“The safety profile was manageable, with no unexpected [AEs], low rate of discontinuation, no increase in grade 3 or 4 hemorrhage, and no increase in immune-related [AEs],” Zhou said.

What is the trial design, and what are the implications?

HARMONi-GI1 is a randomized, controlled, double-blinded phase 3 trial conducted in China that enrolled 682 patients with locally advanced or metastatic BTC that was initially unresectable or recurrent after curative surgery, with no prior systemic therapy and an ECOG performance status of 0 or 1. Patients were randomly assigned 1:1 to ivonescimab at 20 mg/kg every 3 weeks (n = 340) or durvalumab at 1500 mg every 3 weeks (n = 342), each combined with gemcitabine and cisplatin for up to 8 cycles, followed by maintenance therapy.

The primary end point was OS, and key secondary end points were PFS and ORR, tested in a prespecified hierarchy. Ivonescimab is a first-in-class PD-1/VEGF dual-target bispecific antibody that has been approved in China for 3 lung cancer indications since 2024, and it holds a priority review designation in China for first-line BTC.

“HARMONi-GI1 is the first phase 3 trial in [BTC] to show statistically significant and clinically meaningful improvement in [OS] over durvalumab plus chemotherapy in [a] Chinese population,” Zhou said, concluding that the results “support ivonescimab plus chemo as a new standard of care for first-line BTC.”

Reference

Zhou J, Zheng T, Fan J, et al. Ivonescimab plus chemotherapy versus durvalumab plus chemotherapy as first-line treatment for advanced biliary tract cancer: a randomized, controlled, double-blinded, phase 3 trial (HARMONi-GI1). Presented at: European Society for Medical Oncology (ESMO) Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA8.