Immunotherapy with nivolumab resulted in durable responses and promising overall survival (OS) in a dose-escalation and expansion trial of patients with advanced liver cancer. The 12-month OS rate exceeded 60% in patients in whom sorafenib had failed, and responses occurred in patients with the hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, reported Anthony B. El-Khoueiry, MD, Norris Comprehensive Cancer Center, Los Angeles, at ASCO 2015.
“Sorafenib remains the only standard-of-care systemic therapy for patients with advanced hepatocellular carcinoma, with median survival limited to <11 months,” said Dr El-Khoueiry. “Patients who progress on sorafenib have no standard-of-care second-line therapy options. Based on recently completed phase 3 trials in the setting of sorafenib failure, the median survival with best supportive care is approximately 7 to 8 months.”
Hepatocellular carcinoma is typically an inflammation-associated cancer that can be immunogenic. Furthermore, HCV infection and HBV infection have been associated with the upregulation of PD-1. The upregulation of PD-1 and its ligand 1 (PD-L1) have been associated with worse prognosis in hepatocellular carcinoma, especially after resection or ablation.
In the phase 1/2 study, nivolumab was evaluated in patients enrolled in dose escalation in 2 parallel cohorts—patients with HBV or HCV and uninfected patients. Dose escalation was followed by ongoing dose expansion. Patients were permitted ≥1 lines of previous systemic therapy, including sorafenib.
Overall, 47 patients were evaluable for safety (43 from the dose-escalation phase and 4 from the dose-expansion phase) at the time of the interim analysis presented at ASCO 2015. A maximum tolerated dose was not defined, and drug-related adverse events occurred in 68% of patients, with 19% being grade 3 or 4.
Currently, 17 patients remain in the study; a total of 30 patients discontinued treatment, with 26 discontinuations resulting from disease progression, 2 from drug-related adverse events, and 2 from achieving a complete response.
Of 42 patients who were evaluable for response, 8 (19%) had an objective response (5% had a complete response and 14% had a partial response). In all, 48% of the patients had stable disease.
Responses occurred across all the etiologic cohorts. “In addition to the confirmed responses,…40% of patients had some reduction in the size of their tumors,” said Dr El-Khoueiry. Among the 8 responders, 7 had responses lasting >9 months, and responses are ongoing in 6 patients. Of the 8 patients who responded, 7 did so within 3 months of beginning treatment.
The OS rate at 12 months is 62%. “To put this in context, the 12-month OS rate after sorafenib failure, based on recently completed phase 3 trials, is about 30%,” Dr El-Khoueiry said.
“The durable responses and prolonged stable diseases, along with the encouraging 12-month OS, lend strong support to the ongoing dose-expansion phase of the study to validate the promising signal and for continued exploration of nivolumab in hepatocellular carcinoma,” Dr El-Khoueiry concluded.