On March 10, 2020, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was granted accelerated approval for treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.^1-3

Supporting Efficacy Data

The approval was based on findings in a cohort (cohort 4) of multicenter, multiple cohort, open-label CheckMate 040 trial (ClinicalTrials.gov identifier NCT01658878), a trial conducted in patients with hepatocellular carcinoma who experienced disease progression on or were intolerant to sorafenib.^2-4 A total of 49 patients received nivolumab at 1 mg/kg in combination with ipilimumab at 3 mg/kg every 3 weeks for 4 doses, followed by single-agent nivolumab at 240 mg every 2 weeks until disease progression or unacceptable toxicity.

The median age of patients was 60 years (range = 18–80 years); 88% were male; 74% were Asian and 25% were white; an Eastern Cooperative Oncology Group performance status was 0 (61%) or 1 (39%) in all patients; 57% had active hepatitis B infection and 8% had active hepatitis C infection; Child-Pugh class and score were A5 for 82% and A6 for 18%; 80% had extrahepatic disease spread; 35% had vascular invasion; and 51% had alpha-fetoprotein levels ≥ 400 μg/L. Prior treatment included surgery in 74%, radiotherapy in 29%, and local treatment in 59%. All patients had received prior sorafenib, with 10% being intolerant, and 29% had received two or more prior systemic therapies.

An objective response on blinded independent central review using Response Evaluation Criteria in Solid Tumors v1.1 was observed in 16 patients (33%), with a complete response observed in 4 (8%). The response duration ranged from 4.6 to 30.5+ months, with responses lasting at least 6 months, at least 12 months, and at least 24 months in 88%, 56%, and 31% of responders, respectively.

How It Is Used

In the current indication, the recommended doses are nivolumab at 1 mg/kg followed by ipilimumab at 3 mg/kg on the same day every 3 weeks for four doses, then nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks until disease progression or unacceptable toxicity.

For management of adverse reactions, if either agent is withheld, the other agent should also be withheld. For both agents, infusion should be interrupted or slowed in patients with mild or moderate infusion-related reactions and discontinued in patients with severe or life-threatening infusion-related reactions.

Nivolumab prescribing information provides instructions on dose modification for the following conditions: diarrhea or colitis; pneumonitis; hepatitis/non–hepatocellular carcinoma; hepatitis/hepatocellular carcinoma; hypophysitis; adrenal insufficiency, type 1 diabetes; nephritis and renal dysfunction; rash or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis; encephalitis; persistent grade 2 or 3 adverse reactions; grade 3 or 4 adverse reactions; grade 3 myocarditis; and requirement for 10 mg/d or higher of prednisone or its equivalent for more than 12 weeks.

Ipilimumab prescribing information provides instructions on dose modification for the following conditions: endocrine adverse reactions; ophthalmologic adverse reactions; grade 2 and persistent grade 2 adverse reactions; inability to reduce the corticosteroid dose to 7.5 mg prednisone or its equivalent per day; and grade 3 or 4 adverse reactions.

Safety Profile

The most common adverse reactions of any grade (≥ 20%) observed in patients receiving nivolumab plus ipilimumab in clinical trials are fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, decreased weight, and dizziness.

Among the 49 patients in the CheckMate 040 trial cohort, the most common adverse events of any grade were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), hypothyroidism (20%), dizziness (20%), and decreased weight (20%). The most common grade 3 or 4 adverse events were rash (8%), abdominal pain (6%), and ascites (6%). The most common grade 3 or 4 laboratory abnormalities were increased aspartate transaminase (AST; 40%), hyponatremia (32%), increased lipase (26%), and increased alanine transaminase (21%).

Serious adverse events occurred in 59% of patients, with the most common being pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased bilirubin, and pneumonitis. Treatment was discontinued in 29% of patients and delayed in 65% due to adverse events.

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-related reactions, complications of allogeneic hematopoietic stem cell transplantation, embryofetal toxicity. Patients should be advised not to breastfeed when receiving nivolumab.

Ipilimumab has a boxed warning for immune-mediated adverse reactions. Ipilimumab also carries warnings/precautions for immune-mediated adverse reactions (including hepatitis, endocrinopathies, pneumonitis, nephritis, and renal dysfunction), encephalitis, infusion-related reactions, and embryofetal toxicity. Patients should be advised not to breastfeed when receiving ipilimumab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma. Accessed April 3, 2020.

2. Yervoy (ipilimumab) injection for intravenous use prescribing information, Bristol-Myers Squibb Company, March 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125377s108lbl.pdf. Accessed April 3, 2020.

3. Opdivo (nivolumab) injection for intravenous use prescribing information, Bristol-Myers Squibb Company, March 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125554s078lbl.pdf. Accessed April 3, 2020.

4. Kudo M, Matilla A, Santoro A, et al: Checkmate-040: Nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B status. 2019 Gastrointestinal Cancers Symposium. Abstract 327. Presented January 18, 2019.