Ivonescimab Combination Improves Overall Survival in First-Line Advanced Biliary Tract Cancer

Ivonescimab (SMT112/AK112) plus chemotherapy demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit over durvalumab (Imfinzi; AstraZeneca) plus chemotherapy as first-line treatment for advanced biliary tract cancer (BTC), according to positive topline findings from the phase 3 HARMONi-GI1 trial (NCT06591520).^1,2

The findings represent the first known phase 3 results in advanced BTC showing OS superiority over an anti–PD-(L)1 agent combined with chemotherapy. Unlike studies that established immunotherapy by comparing it with chemotherapy alone, HARMONi-GI1 tested ivonescimab against an active immunotherapy-based standard of care.¹

HARMONi-GI1 Meets Primary and Secondary End Points

HARMONi-GI1, also known as AK112-309, is a randomized, double-blind, multicenter study conducted in China. The trial evaluated ivonescimab plus chemotherapy against durvalumab plus chemotherapy in patients with unresectable locally advanced or metastatic BTC who had not received prior systemic therapy for advanced disease. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1.^1,2

At a prespecified interim analysis assessed by an independent data monitoring committee, the ivonescimab regimen met the primary end point of OS and achieved statistically significant superiority over the durvalumab regimen. The study also met key secondary end points of progression-free survival and objective response rate.¹

Akeso and its partner Summit Therapeutics have not yet reported numerical efficacy findings, including median OS, hazard ratios, response rates, or subgroup results. Detailed safety data also remain unavailable. The companies plan to present the full findings at an upcoming medical congress and submit them for publication in a peer-reviewed journal.¹

Challenging an Established First-Line Standard

Durvalumab combined with gemcitabine and cisplatin became a first-line standard for advanced BTC following results from the phase 3 TOPAZ-1 trial. In TOPAZ-1, the addition of durvalumab to chemotherapy improved median OS to 12.8 months (95% CI, 11.1 to 14.0) compared with 11.5 months (95% CI, 10.1 to 12.5) with chemotherapy alone, corresponding to a hazard ratio for death of 0.74 (95% CI, 0.63-0.87).³

Longer follow-up reinforced the durability of the durvalumab benefit. At a median follow-up of 41.3 months, the 3-year OS rate was 14.6% with durvalumab plus chemotherapy compared with 6.9% with chemotherapy alone.⁴

Dual PD-1 and VEGF Blockade

Ivonescimab is a tetravalent bispecific antibody engineered to block programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF) within a single molecule. PD-1 inhibition is intended to restore antitumor immune activity, whereas VEGF inhibition targets angiogenesis and VEGF-associated immune suppression in the tumor microenvironment.⁵

The molecule uses cooperative binding, with the presence of VEGF increasing its binding avidity to PD-1. This design is intended to concentrate activity where PD-1 and VEGF are both expressed, although clinical outcomes and safety must ultimately establish whether the mechanism produces an advantage over existing combinations.⁵

Ivonescimab is approved in China for certain non–small cell lung cancer indications but remains investigational in the United States and Europe. HARMONi-GI1 is its first positive phase 3 readout outside lung cancer, extending the clinical development program into gastrointestinal malignancies.¹

For oncology pharmacists, complete safety findings will be particularly relevant because VEGF inhibition can introduce risks that differ from those associated with checkpoint inhibition alone. Rates of treatment interruption, discontinuation, immune-mediated adverse events, hypertension, bleeding, and proteinuria will help define the regimen’s monitoring and supportive-care requirements.

The HARMONi-GI1 findings establish an important proof of concept against an active first-line comparator. Full results will determine whether the survival advantage is accompanied by a manageable safety profile and whether ivonescimab can credibly challenge durvalumab-based treatment in advanced BTC.

REFERENCES

1. Ivonescimab plus chemotherapy demonstrates statistically significant overall survival benefit compared to durvalumab plus chemotherapy in first-line advanced biliary tract cancer in single-region trial conducted by Akeso in China. News release. Summit Therapeutics. Published August 25, 2026. Accessed August 27, 2026. https://smmttx.com/news/press-releases/news-details/2026/Ivonescimab-Plus-Chemotherapy-Demonstrates-Statistically-Significant-Overall-Survival-Benefit-Compared-to-Durvalumab-Plus-Chemotherapy-in-First-Line-Advanced-Biliary-Tract-Cancer-in-Single-Region-Trial-Conducted-by-Akeso-in-China/default.aspx

2. AK112 combined with chemotherapy versus durvalumab combined with chemotherapy in advanced biliary tract cancer. ClinicalTrials.gov Identifier: NCT06591520. Updated August 21, 2026. Accessed August 27, 2026. https://clinicaltrials.gov/study/NCT06591520?viewType=Card&cond=NCT06591520&rank=1

3. Oh DY, Ruth He A, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1(8):EVIDoa2200015. doi:10.1056/EVIDoa2200015

4. Oh DY, He AR, Qin S, et al. Durvalumab plus chemotherapy in advanced biliary tract cancer: 3-year overall survival update from the phase III TOPAZ-1 study. J Hepatol. 2025;83(5):1092-1101. doi:10.1016/j.jhep.2025.05.003

5. Zhong T, Zhang L, Huang Z, et al. Design of a fragment crystallizable-engineered tetravalent bispecific antibody targeting programmed cell death-1 and vascular endothelial growth factor with cooperative biological effects. iScience. 2024;28(3):111722. doi:10.1016/j.isci.2024.111722