Ivonescimab plus gemcitabine and cisplatin as first-line therapy for advanced biliary tract cancer: A multicenter,...

Patients with advanced biliary tract cancers (aBTC) are in urgent need of additional treatment options. We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy in patients with aBTC.

In this multicenter, open-label, phase II study, 30 patients with treatment-naive unresectable locally advanced or metastatic BTC received ivonescimab (20 mg/kg or 30 mg/kg) combined with gemcitabine (1,000 mg/m²) and cisplatin (25 mg/m²) every 3 weeks for up to eight cycles, followed by ivonescimab maintenance. The primary endpoint was the investigator-assessed objective response rate and safety. Pretreatment tumor specimens available from the trial were subjected to a post hoc exploratory proteomic analysis. The correlation between MAP2K7 levels and ivonescimab efficacy was assessed using BTC tumor cell-T-cell co-culture and BTC organoid-T-cell co-culture models.

At data cut-off, one patient achieved complete response and 19 patients achieved partial response, yielding an objective response rate of 66.7% (95% CI 47.2-82.7). The disease control rate was 100%. The median progression-free survival was 8.5 months (95% CI 7.6-10.5) and the median overall survival was 16.8 months (95% CI 11.1-22.5). Treatment-related adverse events occurred in all patients, with the most common being anemia (25, 83.3%), decreased neutrophil count (23, 76.7%), decreased white blood cell count (22, 73.3%), and decreased platelet count (22, 73.3%). No treatment-related deaths occurred. Additionally, exploratory proteomic and functional analyses identified MAP2K7 as a resistance-associated biomarker. MAP2K7 was upregulated in non-responders, and MAP2K7 suppression enhanced ivonescimab-mediated antitumor activity in immune co-culture models.

Ivonescimab plus chemotherapy demonstrated potential antitumor activity and a tolerable safety profile as a first-line treatment for patients with aBTC. Exploratory analyses suggest that MAP2K7 may serve as a candidate biomarker of resistance and a potential therapeutic target for optimizing ivonescimab-based therapy in patients with aBTC.

Currently, the standard of care for first-line treatment of patients with advanced biliary tract cancer is the addition of immune checkpoint inhibitors to chemotherapy, based on the TOPAZ-1 and KEYNOTE-966 trials. However, the clinical benefit of these regimens remains limited, with a median overall survival improvement of less than 2 months compared with chemotherapy alone. In this study, ivonescimab plus chemotherapy demonstrated an objective response rate of 66.7%, a disease control rate of 100%, and a median overall survival of 16.8 months. These findings suggest that ivonescimab plus chemotherapy warrants further investigation as a potential first-line treatment option for patients with treatment-naive, unresectable locally advanced or metastatic BTC.

NCT05214482 and NCT06048289.