Ivonescimab plus gemcitabine and cisplatin as first-line therapy for advanced biliary tract cancer: a multicenter, open-label phase 2 trial.

Patients with advanced biliary tract cancers (aBTC) are in urgent need of additional/new 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 (1000 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 (ORR) 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 by BTC tumor cell-T cell co-culture and BTC organoids-T cell. At data cutoff, 1 patient achieved complete response and 19 patients achieved partial response yielding an ORR of 66.7% (95% Confidence Interval [CI]: 47.2-82.7). The disease control rate was 100%.

The median progression-free survival (mPFS) was 8.5 months (95% CI: 7.6-10.5) and the median overall survival (mOS) was 16.8 months (95% CI: 11.1-22.5). Treatment-related adverse events occurred in 100.0% of patients with the most common being anemia (25, 83.3%), neutrophil count decreased (23, 76.7%), white blood cell count decreased (22, 73.3%), and platelet count decreased (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 showed potential anti-tumor activity and tolerable safety as first-line treatment of aBTC patients. Exploratory analyses suggest that MAP2K7 may serve as a candidate biomarker of resistance and a potential therapeutic target for optimizing ivonescimab-based therapy of aBTC patients.

Currently, the standard of care for first-line therapy in patients with aBTC is the addition of immune checkpoint inhibitors to chemotherapy based on the TOPAZ-1 and KEYNOTE-966 trials.

However, this new regimen only improved OS by less than 2 months. The ORR of 66.7%, DCR of 100% and the median overall survival of 16.8 months were observed with ivonescimab plus chemotherapy.

This study provides evidence supporting the potential role of ivonescimab plus chemotherapy as a first-line therapy for patients with treatment-naive unresectable locally advanced or metastatic BTC. NCT05214482 and NCT06048289. NCT05214482 and NCT06048289.