Local therapy overcomes primary resistance to target-immunotherapy combination in unresectable hepatocellular...

To evaluate the characteristics and management of primary (PR) and acquired resistance (AR) to immune checkpoint inhibitor (ICI) combination treatment in patients with unresectable hepatocellular carcinoma (uHCC).

Patients with uHCC who received ICI combination therapy were retrospectively included. Baseline characteristics, pattern of progression, post-resistance management, and prognosis were recorded and analyzed according to resistance type. The primary endpoint was overall survival (OS).

A hundred and eighty-eight out of 262 patients (71.8%) developed resistance, including 35.1% with PR and 36.6% with AR. All AR developed within 2 years. Patients with AR had better general conditions, smaller tumors, fewer vessel invasion and better prognosis (median OS [mOS]: 25.8 vs. 8.63 months) than those with PR. Patients with AR were less likely to have multiple lesions and sites exhibiting progression. Occurrence of new lesions led to a decrease in OS in patients with PR but an increase in those with AR. Patients with either PR or AR receiving post-resistance anti-tumor treatment showed improved OS, but patients with AR had significantly longer OS than those with PR. The combination of subsequent local therapy (mOS 25.6 vs. 10.0 months) and changes in the ICI regimen (mOS 27.5 vs. 13.4 months) led to improved OS among patients with PR.

AR normally develops within 2 years after the beginning of treatment. Patients with AR have better characteristics in general, less invasive pattens of progression, and better prognosis compared to those with PR. Subsequent local therapy and changes in ICI treatment showed potential to overcome primary resistance.