Ignacio Melero, MD, PhD
Patients with advanced hepatocellular carcinoma (HCC) had objective responses (OR) and prolonged survival when treated with single-agent nivolumab, data from a dose escalation/expansion trial showed.
Responses occurred in 18.1% of 182 patients with previously treated with sorafenib and in 21.7% of patients without exposure to sorafenib. Responses were observed in patients with tumors that expressed PD-L1 and in those whose tumors did not exhibit threshold expression of the protein.
Data from the 37-patient dose-escalation cohort showed that almost half of the patients remained alive at 18 months, Ignacio Melero, MD, PhD, professor of immunology at the University of Navarra in Pamplona, Spain, reported during his presentation at the 2017 Gastrointestinal Cancers Symposium in San Francisco. Toxicity was manageable and consistent across patient cohorts and similar to experience with the agent in other types of tumors.
“Nivolumab monotherapy provided early stable, and durable responses, irrespective of hepatitis C or B infection status, and responses were observed irrespective of PD-L1 expression,” Melero said in his conclusion. “Patient-reported quality-of-life measures were stable from baseline until week 25.”
A phase III trial has begun, evaluating nivolumab in patients with previously untreated advanced HCC, he added.
Patients with advanced HCC have a high unmet clinical need, Melero pointed out in the introduction of his presentation. Currently, no approved options for systemic therapy exist beyond the tyrosine kinase inhibitor sorafenib.
Nivolumab has demonstrated activity and a favorable safety profile across multiple tumor types, providing a rationale to evaluate the PD-1 inhibitor in advanced HCC. Melero reported findings from the Checkmate 040 study, a dose escalation-expansion study involving patients with or without hepatitis infection (HCV or HBV) and with or without prior exposure to sorafenib.
During the dose-escalation phase of the study, a total of 48 patients received nivolumab doses ranging from 0.1 to 10 mg/kg. The group comprised 23 patients without hepatitis infection, 10 with HCV, and 15 with HBV. Additionally, 37 of the patients had previously received sorafenib.
The expansion cohort included 214 patients who received the recommended phase II dose of 3 mg/kg. The group comprised 50 patients with HCV infection, 51 with HBV infection, and 113 uninfected patients. Melero said 145 of the patients had already been treated with sorafenib.
The primary endpoints were safety, tolerability, and OR in the expansion cohort. Secondary endpoints included OR in the dose-escalation group, as well as disease control rate, time to response, duration of response, and overall survival. Melero reported data from a median follow-up of 13.3 months in the dose-escalation group, and 10.5 months in the dose-expansion group.
The total study population of 262 patients (dose escalation and expansion phases combined) had a median age of 63, and men accounted for 79% of the population. Almost 70% of the patients had extrahepatic metastases. The Child-Pugh score was 5 in 73% of cases.
With respect to treatment history, 63% of the patients had undergone surgical resection, 19% had received radiotherapy, 54% had received additional local therapy, and 69% had received sorafenib (76% total had prior systemic therapy).
During the dose-escalation phase of the study, treatment-related adverse events (TRAEs) occurring in at least 10% of patients included rash (23%), pruritus (19%), diarrhea (10%), and decreased appetite (10%). No patient developed grade 3/4 TRAEs. The most common laboratory TRAEs were increased levels of AST (21%), lipase (21%), amylase (19%), and increase in ALT (15%).
In the 182 sorafenib-treated patients, 3 complete responses occurred in the dose-escalation phase, and 3 in the dose-expansion phase by investigator assessment. Additionally, 3 out of 37 patients in the dose-escalation phase had partial response, and 16 had stable disease. In the dose-escalation phase, 24 out of 145 patients had partial responses, and 66 others had stable disease.
By independent review, 8 out of 37 (21.6%) patients in the dose-escalation phase achieved OR, as did 27 of 145 (18.6%) in the dose-expansion phase.
The median time to response and duration of response were 1.9 and 17.1 months in the dose-escalation phase of the study, and 2.7 months and not yet reached in the dose-expansion phase.
With respect to survival, two-thirds of the patients in the dose-escalation phase remained alive at 6 and 9 months, 58% at 12 months, and 46% at 18 months. For the dose-expansion group, 82% of the patients were alive at 6 months, and 71% at 9 months. Data for 12- and 18-month survival were not yet available.
In the dose-expansion phase, a subgroup of 69 patients without exposure to sorafenib had an objective response rate of 21.7% (all partial response). An additional 43.5% of patients had stable disease. Survival at 6 and 9 months were 87% and 77%, respectively, Melero reported.
Melero I, Sangro B, Yau T, et al. Nivolumab dose escalation and expansion in patients with advanced hepatocellular carcinoma: the CheckMate 040 study. Abstract presented at: 2017 Gastrointestinal Cancers Symposium; January 19-21, 2017; San Francisco, CA.