Ivonescimab Plus Chemotherapy Represents a New SOC in First-Line Biliary Tract Cancer

Ivonescimab (SMT112; AK112) plus chemotherapy improved overall survival (OS) compared with durvalumab (Imfinzi) plus the same chemotherapy as first-line treatment for patients with advanced biliary tract cancer, according to findings from the phase 3 HARMONi-GI1 trial (NCT06591520) presented at the 2026 ESMO Congress.¹

At a median follow-up of 14.3 months, the median OS was 14.9 months (95% CI, 12.9-not evaluable) in the ivonescimab arm (n = 340) vs 12.1 months (95% CI, 11.0-13.4) in the durvalumab arm (n = 342; HR, 0.75; 95% CI, 0.61-0.92; 1-sided P = .0031). The 12-month OS rates in the ivonescimab and durvaumab arms were 59.7% vs 50.7%, respectively, and the 18-month OS rates were 44.0% vs 32.5%.

Ivonescimab plus chemotherapy also improved both key secondary end points. The median progression-free survival (PFS) was 8.4 months (95% CI, 7.5-9.3) with ivonescimab vs 5.8 months (95% CI, 5.6-7.2) with durvalumab (HR, 0.61; 95% CI, 0.51-0.72; 1-sided P < .0001). Respective 6- and 9-month PFS rates in the ivonescimab arm were 68.7% and 49.3% compared with 49.3% and 31.7% in the durvalumab arm.

Moreover, the objective response rate (ORR) was 53.8% (95% CI, 48.4%-59.2%) vs 32.5% (95% CI, 27.5%-37.7%), respectively (P < .0001).

Presenting the data during the Presidential Symposium, Zhou said the findings support ivonescimab plus chemotherapy as a new standard of care for patients with previously untreated advanced BTC.

"HARMONi-GI1 is the first phase 3 trial in biliary tract cancer to show statistically significant and clinically meaningful improvement in OS over [durvalumab] plus chemotherapy in [the] Chinese population. HARMONi-GI1 supports ivonescimab plus chemotherapy as a new standard of care for first-line biliary tract cancer," said Jian Zhou, MD, PhD, in a presentation of the data.

Zhou is the President of Zhongshan Hospital in Shanghai, China.

How was the phase 3 HARMONi-GI1 trial of ivonescimab in advanced BTC designed?

The randomized, double-blind trial, enrolled patients with locally advanced or metastatic biliary tract cancer who were initially unresectable or recurrent after receiving curative thearpy. Patients also needed to have received no prior systemic therapy and have a ECOG performance status of 0 or 1.

Patients were randomly assigned to ivonescimab at 20 mg/kg or durvalumab at 1500 mg every 3 weeks, each with gemcitabine 1000 mg/m² and cisplatin 25 mg/m² on days 1 and 8 every 3 weeks for up to 8 cycles, followed by blinded maintenance. Randomization was stratified by disease status and primary tumor location.

OS served as the trial’s primary end point, whereas PFS and ORR were key secondary end points for the trial.

How did ivonescimab plus chemotherapy perform across HARMONi-GI1 subgroups in advanced BTC?

Point estimates for OS favored ivonescimab plus chemotherapy across prespecified subgroups. By primary tumor location, the OS hazard ratio (HR) was 0.63 (95% CI, 0.48-0.83) for those with intrahepatic cholangiocarcinoma (ivonescimab, n = 198; durvalumab, n = 196), 0.94 (95% CI, 0.57-1.55) for those with extrahepatic cholangiocarcinoma (n = 65; n = 66), and 0.95 (95% CI, 0.63-1.42) for gallbladder cancer (n = 77; n = 80). PFS HRs by primary tumor location broke down as 0.56 (95% CI, 0.45-70) for those with intrahepatic cholangiocarcinoma, 0.71 (95% CI, 0.47-1.08) for extrahepatic cholangiocarcinoma, and 0.66 (95% CI, 0.47-0.94) for those with gallbladder cancer.

ORRs with ivonescimab vs durvalumab were 54.0% vs 30.1% in the intrahepatic subgroup, 47.7% vs 36.4% in the extrahepatic subgroup, and 58.4% vs 35.0% in the gallbladder subgroup. The disease control rate was 91.5% (95% CI, 88.0%-94.2%) vs 77.8% (95% CI, 73.0%-82.1%) overall.

Notably, subsequent antitumor therapy was received by 31.8% in the ivonescimab arm vs 45.9% in the durvalumab arm.

What was the safety profile of ivonescimab plus chemotherapy vs durvalumab in HARMONi-GI1?

In the safety population (n = 339 per arm), the median duration of exposure was 7.8 months (range, 0.4-19.9) with ivonescimab vs 5.7 months (range, 0.2-19.8_ with durvalumab.

All patients in the ivonescimab arm experienced any-grade treatment-emergent adverse effects (TEAEs) whereas 98.8% did in the durvalumab arm. Grade 3/4 TEAEs occurred at rates of 82.0% vs 72.3% of patients, respectively, and serious TEAEs occurred in 43.4% vs 43.7%. TEAEs led to discontinuation of ivonescimab or durvalumab in 3.5% vs 5.6% of patients and to death in 3.2% vs 3.8%. Hematologic toxicities were the most common TEAEs, including grade 3 or 4 decreased neutrophil count in 54.6% vs 41.3% of patients.

Immune-related adverse effects (irAEs) of any grade occurred in 26.3% vs 22.1% of patients; grade 3 or higher irAEs occurred in 4.1% of each arm, and no irAEs were fatal. Among toxicities potentially associated with VEGF inhibition, proteinuria occurred in 32.2% vs 11.8% of patients, hypertension in 15.0% vs 2.4%, and hemorrhage in 9.7% vs 6.5%.

What are the next steps for ivonescimab in first-line biliary tract cancer?

Ivonescimab will be further evaluated in first-line BTC in the phase 2/3 EA2251 trial (NCT07765433), which the ECOG-ACRIN Cancer Research Group is conducting in the United States.³ The study will compare ivonescimab plus chemotherapy with pembrolizumab (Keytruda) or durvalumab plus chemotherapy, with OS as the primary end point.

Disclosures: Zhou reported receiving research funding from AstraZeneca, MSD, Roche, Pfizer, Junshi, Innovent, BGNE, Eisai, EDDING, Hengrui, Oricell, ChiaTaiTianQing, Fosun, Qilu, Gilead, Akeso-Sino, SciClone, Zelgen, and Singlera; and serving on advisory boards for AstraZeneca, MSD, and Pfizer.

References

1. 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: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA8.
2. Summit Therapeutics. Summit Therapeutics and ECOG-ACRIN Cancer Research Group enter into phase II/III clinical trial collaboration to evaluate ivonescimab in first-line biliary tract cancer. News release. October 21, 2026. Accessed October 25, 2026. https://s206.q4cdn.com/652410165/files/doc_news/Summit-Therapeutics-and-ECOG-ACRIN-Cancer-Research-Group-Enter-into-Phase-II--III-Clinical-Trial-Collaboration-to-Evaluate-Ivonescima-BOQ2L.pdf