Opdivo Granted Priority Review to Treat Liver Cancer

Opdivo (nivolumab) was granted a priority review designation by the Food and Drug Administration (FDA) to treat patients with hepatocellular carcinoma (HCC) who have previously had treatment with Nexavar (sorafenib), according to Bristol-Myers Squibb, the manufacturer of the PD-1 inhibitor.

The supplemental Biologics License Application (sBLA) for Opdivo is based on safety and efficacy findings from the phase 1/2 CheckMate-040 trial, which were published in The Lancet and will be presented at the 2017 ASCO Annual Meeting. The FDA is scheduled to make it its final decision on or before Sept. 24, 2017.

“We believe the FDA acceptance of our application for Opdivo with priority review status is an important recognition of the significant unmet need for patients with HCC, which is often diagnosed in the advanced stage when treatment options are limited,” Ian M. Waxman, M.D., development lead, Gastrointestinal Cancers, Bristol-Myers Squibb, said in a statement. “We are committed to exploring new treatment options for these patients and look forward to working with the FDA to potentially extend the use of Opdivo as a treatment option in this setting.”

Between Nov. 26, 2012, and Aug. 8, 2016, the phase 1/2 CheckMate-040 trial accrued 262 patients with advanced hepatocellular carcinoma with or without hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. There were 48 patients in the dose-escalation phase and 214 patients in the dose-expansion phase. Seventy-seven percent of patients in the dose-escalation phase and 68 percent of patients in the expansion phase had prior Nexavar.

The median age of patients in the escalation phase was 62 years (range, 55-69), 75 percent of patients were male, 58 percent were white and 40 percent had an ECOG performance status (PS) of 1. Seventy-five percent had surgical resection and 21 percent had received radiotherapy.

In the expansion phase the median age was of patients was 64 years (range, 56-70), 80 percent of patients were male, 49 percent were white, 47 percent were Asian and 36 percent had an ECOG PS of 1. Sixty percent of patients had surgical resection and 19 percent had received radiotherapy.

In the escalation phase, patients received 0.1 to 10 mg/kg of IV Opdivo every two weeks. Patients in the expansion phase received Opdivo at 3 mg/kg every two weeks.

The overall objective response rate (ORR) in the escalation phase was 15 percent, including three complete responses (CRs) and four partial responses (PRs). Five of the seven responses occurred with three months of initiating Opdivo. The median duration of response was 17 months and the median time to progression was 3.4 months. The disease control rate was 58 percent.

The six-month and nine-month overall survival rates were each 66 percent. In the dose escalation phase, the median overall survival was 15.0 months.

The ORR in the expansion group was 20 percent, including three CRs and 39 PRs. Combining these responses with 96 (45 percent) patients who had stable disease, the disease control rate was 64 percent (138/214). The three CRs occurred in two patients without viral hepatitis and one patient with HBV infections. All three patients had prior Nexavar.

Twenty-nine (69 percent) of the 42 responses occurred before three months. The median duration of response was 9.9 months and the median time to progression was 4.1 months.

The six- and nine-month OS rates in the expansion cohort were 83 percent and 74 percent, respectively. The six- and nine-months progression-free survival rates were 37 percent and 28 percent, respectively.

The researchers retrospectively assessed PD-L1 expression levels and response among 174 (81 percent) patients with available data in the expansion group. Thirty-four patients had PD-L1 expression on at least 1 percent of their tumor cells, and 140 patients had PD-L1 expression on less than 1 percent. The ORRs were 26 percent and 19 percent, in the higher and lower PD-L1 groups, respectively.

The researchers reported that Opdivo was tolerable with a manageable safety profile during the dose-escalation phase. A maximum-tolerated dose was not reached. Twenty-five percent (12/48) of patients had grade 3/4 treatment-related adverse events (AEs). There were three treatment-related serious AEs: pemphigoid, adrenal insufficiency, and liver disorder.

Safety in the expansion cohort was similar to the escalation cohort. Grade 3/4 and serious treatment-related AEs occurred in 19 percent and 4 percent of patients, respectively. The incidence of symptomatic treatment-related AEs was comparable in patients, regardless of whether or not they had an HCV or HBV infection. Twenty-four patients discontinued treatment due to AEs, and there were no deaths related to treatment.