FDA Approves Opdivo in HCC

Opdivo (nivolumab) was granted FDA approval for the treatment of hepatocellular carcinoma (HCC) — regardless of PD-L1 status – for patients who have previously been treated with Nexavar (sorafenib).

The approval is based on 154 patients enrolled in the phase 1/2 CheckMate-040 trial, in which the overall response rate (ORR) by blinded independent central review (BICR) was 18.2 percent per mRECIST criteria for patients who had previously been treated with Nexavar. Additionally, 3.2 percent of patients experienced a complete response. The ORR by RECIST 1.1 was 14.3 percent with Opdivo and the response duration ranged from 3.2 to 38.2+ months.

“In recent years, there has been growing interest in leveraging immuno-oncology knowledge and discoveries to add to the treatment options available for patients with advanced-stage liver cancer,” Anthony B. El-Khoueiry, M.D., lead investigator and associate professor of clinical medicine and phase I program director at the Keck School of Medicine of University of Southern California (USC) and the USC Norris Comprehensive Cancer Center, said in a statement. “The approval of Opdivo provides us with an encouraging approach and a new treatment option for appropriate patients with HCC following prior systemic therapy.”

In the CheckMate-040 trial, 262 patients with advanced HCC with or without hepatitis C virus (HCV) or hepatitis B virus (HBV) infection were enrolled from Nov. 26, 2012, to Aug. 8, 2016. 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.

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 FDA approval was specifically for a dose of 240 mg every two weeks.

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.

According to findings presented at the 2017 ASCO Annual Meeting, in the Nexavar -experienced group in the expansion phase (145 patients), the mRECIST ORR by BICR was 19 percent. By RECIST v1.1 there were two complete responses (1 percent), 19 partial responses (13 percent) and 60 patients with stable disease (41 percent). The disease control rate (DCR; ORR plus stable disease) was 56 percent.

In the Nexavar -naïve group across both the dose expansion and escalation cohorts (80 patients), the ORR by BICR was 20 percent by RECIST v1.1 and 24 percent by mRECIST. The v1.1 analysis noted one complete response (1 percent), 15 partial responses (19 percent) and 27 patients with stable disease (34 percent). Median duration of response was 17 months.

In the treatment expansion cohort, the median overall survival (OS) was 15.6 months. The 12-month OS rate was 60 percent and the 18-month rate was 44 percent. In the Nexavar -naïve group, the median OS was 28.6 months with Opdivo. The 12- and 18-month OS rates were 73 percent and 57 percent, respectively.

Responses tended to occur early; 56 percent of Nexavar -naïve patients and 64 percent of Nexavar -experienced patients who responded did so within three months of initiation. Responses were ongoing in 50 percent of Nexavar -naïve patients and 39 percent of Nexavar -experienced patients.

Investigators assessed safety across the escalation and expansion phases. Twenty-three Nexavar -naïve patients (29 percent) experienced grade 3/4 treatment-related adverse events (TRAEs) and 78 percent experienced any-grade TRAEs. The most common (³10 percent) any-grade TRAEs were pruritus (24 percent), fatigue (20 percent), rash (16 percent) and diarrhea (13 percent). The most common (5 percent or more) grade 3/4 TRAEs were AST increased (9 percent), lipase increased (8 percent), amylase increased (6 percent) and ALT increased (5 percent).

In the Nexavar -experienced group, 77 percent of patients experienced any-grade TRAEs and 18 percent had grade 3/4 TRAEs. The most common (≥10 percent) any-grade TRAEs were fatigue (22 percent), pruritus (20 percent), rash (18 percent), and diarrhea (14 percent). The most common grade 3/4 TRAEs were fatigue (4 percent), AST increased (4 percent) and lipase increased (4 percent).

Investigators observed 1 dose-limiting toxicity, a grade 2 hepatic impairment in the dose-escalation phase. Maximum tolerated dose was not reached. One Nexavar -experienced patient died due to treatment-related pneumonitis.

“We are proud to bring the potential for clinically meaningful responses with Immuno-Oncology therapy to these advanced-stage HCC patients, who have had limited treatment options for years,” Chris Boerner, president, US Commercial, Bristol-Myers Squibb, said in a statement. “Today’s approval marks an important step toward our mission of delivering transformational medicines to treat conditions with a high unmet need.”

Approval for Opdivo is contingent upon findings from a larger trial. A phase 3 randomized trial of Opdivo versus Nexavar has been launched in the frontline setting, with an enrollment goal of 726 patients. The estimated primary completion date is October 2018 (NCT02576509).