ON SEPTEMBER 22, 2017, nivolumab (Opdivo) was granted accelerated approval for treatment of hepatocellular carcinoma in patients previously treated with sorafenib (Nexavar).^1,2 

Supporting Efficacy Data 

APPROVAL WAS based on findings in a 154-patient subgroup of the CheckMate 040 trial consisting of patients with hepatocellular carcinoma and Child-Pugh A cirrhosis whose disease progressed on or who were intolerant of sorafenib.^2,3 Patients could not have hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection or hepatitis D virus infection. Patients could have aspartate transaminase (AST) and alanine transaminase (ALT) levels up to five times the upper limit of normal (ULN) but a total bilirubin level < 3 mg/dL. Treatment consisted of nivolumab at 3 mg/kg via intravenous (IV) infusion every 2 weeks. 

The median age of study patients was 63 years (range = 19–81 years), 77% were male, 46% were white, Eastern Cooperative Oncology Group performance status was 0 or 1 in all patients, 31% had active hepatitis B virus infection, 21% had active hepatitis C virus infection, 49% had no evidence of active HBV or HCV, and an etiology of hepatocellular carcinoma was alcoholic liver disease in 18% and nonalcoholic liver disease in 6.5%. Child-Pugh class and score was A5 for 68%, A6 for 31%, and B7 for 1%; 71% had extrahepatic spread; 29% had macrovascular invasion; and 37% had alpha-fetoprotein levels ≥ 400 μg/L. Prior treatment included surgical resection (66%), radiotherapy (24%), and locoregional treatment (58%). A total of 23% were intolerant of sorafenib; 19% had received at least two prior systemic therapies. 

The confirmed overall response rate on a blinded independent central review using Response Evaluation Criteria in Solid Tumors 1.1 was 14.3% (95% confidence interval = 9.2%–20.8%), with 3 complete responses and 19 partial responses observed. The response duration ranged from 3.2 to 38.2+ months; 91% of responders had responses lasting at least 6 months, and 55% had responses lasting at least 12 months. 

How It Works 

NIVOLUMAB IS a human immunoglobulin G4 (IgG4) monoclonal antibody that binds the programmed cell death protein 1 (PD-1) receptor on T cells and prevents its interaction with the programmed cell death ligand 1 and 2 (PD-L1/PD-L2), thereby releasing PD-1 pathway–mediated inhibition of immune response, including antitumor immune response. Binding of PD-L1 and PD-L2 to the PD-1 receptor inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse tumor models, blocking PD-1 activity results in decreased tumor growth. 

Combined nivolumab- (anti–PD-1) and ipilimumab- (anti-cytotoxic T-lymphocyte–associated protein 4 [anti–CTLA-4]) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone and results in improved antitumor responses in metastatic melanoma. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased antitumor activity. 

How It Is Used 

THE RECOMMENDED nivolumab dose for treatment of hepatocellular carcinoma is 240 mg via 60-minute IV infusion every 2 weeks until disease progression or unacceptable toxicity. 

Infusion should be interrupted or slowed in patients with mild or moderate infusion reactions. Nivolumab should be discontinued for severe or life-threatening infusion reactions. There are no recommended dose modifications for hypothyroidism or hyperthyroidism. 

In patients receiving single-agent nivolumab, treatment should be withheld for grade 2 or 3 diarrhea or colitis; grade 2 pneumonitis; hepatitis—for ALT or AST levels > 3 up to 5 times ULN or total bilirubin > 1.5 up to 3 times ULN; grade 2 or 3 hypophysitis; serum creatinine > 1.5 to 6 times ULN; grade 2 adrenal insufficiency; grade 3 hyperglycemia; grade 3 rash or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis; new-onset moderate or severe neurologic signs or symptoms (potential immune-related encephalitis); and first occurrence of other grade 3 adverse reactions. 

Nivolumab should be permanently discontinued for grade 4 diarrhea or colitis; grade 3 or 4 pneumonitis; hepatitis—for AST or ALT levels > 5 times ULN or total bilirubin level > 3 times ULN; grade 4 hypophysitis; grade 3 or 4 adrenal insufficiency; grade 4 hyperglycemia; serum creatinine > 6 times ULN; grade 4 rash or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis; immune-mediated encephalitis; recurrence of grade 3 adverse reactions; life-threatening or grade 4 adverse reactions; grade 3 myocarditis; requirement of ≥ 10 mg/d of prednisone or equivalent for > 12 weeks; and persistent grade 2 or 3 adverse reactions lasting ≥ 12 weeks. 

Safety Profile 

THE NIVOLUMAB toxicity profile observed in patients with advanced hepatocellular carcinoma was generally similar to that observed in patients with other cancers, except for a higher incidence of elevations in transaminases and bilirubin levels. In CheckMate 040, grade 3 or 4 AST elevation occurred in 27 patients (18%), grade 3 or 4 ALT elevation occurred in 16 patients (11%), and grade 3 or 4 bilirubin elevation occurred in 11 patients (7%). Immune-mediated hepatitis requiring systemic corticosteroids occurred in 8 patients (5%). 

Common adverse reactions occurring in more than 20% of patients in nivolumab clinical trials include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia. 

Nivolumab carries warnings/precautions for immune-mediated adverse reactions including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. It also carries warnings/precautions for infusion reactions, complications of allogeneic hematopoietic stem cell transplantation after nivolumab treatment, and embryofetal toxicity. Patients should be monitored for changes in liver, thyroid, kidney, and neurologic function and for hyperglycemia. Breastfeeding women should discontinue breastfeeding with receiving nivolumab. ■

REFERENCES 

1. U.S. Food and Drug Administration: FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577166.htm. Accessed November 8, 2017. 

2. Opdivo (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, September 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/ label/2017/125554s041lbl.pdf. Accessed November 8, 2017. 

3. El-Khoueiry AB, Sangro B, Yau T, et al: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389:2492-2502, 2017.