July 2015, Special ASCO Edition

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Immunotherapy Makes Headwinds into Liver Cancer


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, Assistant Professor of Clinical Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles.

The safety of nivolumab was also established, with manageable toxicity levels, regardless of HBV and HCV infection.

“Sorafenib remains the only standard-of-care systemic therapy for patients with advanced hepatocellular carcinoma, with median survival limited to <11 months,” said 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.”

The rationale for evaluating programmed death-1 (PD-1) therapy in hepatocellular carcinoma is extensive, he said. Hepatocellular carcinoma is typically an inflammation-associated cancer that can be immunogenic. Furthermore, HBV infection and HCV infection have been associated with the upregulation of PD-1. The upregulation of PD-1 and its ligand 1 have been associated with worse prognosis in hepatocellular carcinoma, especially after resection or ablation.

Study Details

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. Patients received nivolumab 0.1 to 10.0 mg/kg intravenously every 2 weeks for up to 2 years.

Overall, 47 patients were evaluable for safety (43 from the dose-escalation phase and 4 from the dose-expansion phase) at the time the interim analysis was presented. In all, 66% of patients had previous surgical resection, and 75% had previous systemic therapy (mostly with sorafenib). A maximum tolerated dose was not defined, and drug-related adverse events occurred in 68% of patients, with 19% being grade 3 or 4.

Increases in aspartate aminotransferase or alanine aminotransferase, an increase in lipase, and pruritus were the most common adverse events. Only 1 patient had grade 4 toxicity, which was an increase in lipase. Adverse events were consistent across all of the etiologic cohorts.

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.

Response was measured using the modified RECIST 1.1. Of 42 patients evaluable for response, 8 (19%) had an objective response (5% had a complete response and 14% had a partial response); 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 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%,” 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,” El-Khoueiry concluded.

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