FDA Approves OPDIVO®/YERVOY® Combination for Advanced Hepatocellular Carcinoma 

SUMMARY: The FDA on March 10, 2020, granted accelerated approval to the combination of OPDIVI® (Nivolumab) and YERVOY® (Ipilimumab) for patients with HepatoCellular Carcinoma (HCC) who have been previously treated with NEXAVAR® (Sorafenib). The American Cancer Society estimates that for 2020, about 42,810 new cases of primary liver cancer will be diagnosed in the US and 30,160 patients will die of their disease. Liver cancer is seen more often in men than in women, and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C Virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and Type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma is the second most common cause of cancer-related deaths worldwide and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.
Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.
OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® was approved by the FDA in 2017, for the treatment of HCC, in patients who have been previously treated with NEXAVAR®. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4).
The present FDA approval was based on the CheckMate-040 study, which is an ongoing Phase I/II, open-label, multi-cohort study, investigating OPDIVO® or OPDIVO®-based combinations in patients with advanced HCC with and without Chronic Viral Hepatitis, who are naïve, intolerant to, or who have progressed during NEXAVAR® therapy. The OPDIVO® plus YERVOY® cohort of CheckMate-040 evaluated the Safety and Efficacy of the combination, in patients with previously treated advanced HCC. This cohort included a total of 49 patients with HCC who progressed on or were intolerant to NEXAVAR®. Patients received OPDIVO® 1 mg/kg IV in combination with YERVOY® 3 mg/kg IV, every 3 weeks for four doses, followed by single agent OPDIVO® 240 mg IV every 2 weeks, until disease progression or unacceptable toxicity. The main efficacy endpoints were Overall Response Rate (ORR) and Duration of Response (DoR), as determined by Blinded Independent Central Review.
At a median follow up of 28 months, the ORR with the OPDIVO® plus YERVOY® combination was 33%, with 8% Complete Responses (CR) and a 24% Partial Responses. The Duration of Responses ranged from 4.6 to over 30.5 months, with 31% of responses lasting at least 24 months. The most common adverse events with this combination therapy were fever, fatigue, diarrhea, rash, arthralgia, dyspnea, and hypothyroidism.
It was concluded that dual Immuno-Oncology therapy with a combination of OPDIVO® plus YERVOY® represents an important milestone, for patients with advanced Hepatocellular Carcinoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma