ON NOVEMBER 9, 2018, pembrolizumab (Keytruda) was granted accelerated approval for treatment of patients with hepatocellular carcinoma previously treated with sorafenib (Nexavar).^1,2

Supporting Efficacy Data

APPROVAL WAS BASED on durable responses in the phase II KEYNOTE-224 trial (ClinicalTrials.gov identifier NCT02702414).^2,3 In the trial, 104 patients who had disease progression on or after treatment with sorafenib or were intolerant to sorafenib received pembrolizumab at 200 mg every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Patients had to have measurable disease. Patients with active autoimmune disease, more than one etiology of hepatitis, medical conditions requiring immunosuppression, or clinical evidence of ascites on physical exam were ineligible. The major efficacy outcome measure was confirmed overall response rate, as assessed by independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The median age of patients was 68 years, 83% were male, 81% were white and 14% Asian, and all had an Eastern Cooperative Oncology Group performance status of 0 or 1. Overall, 21% were hepatitis B virus (HBV)-seropositive and 25% were hepatitis C virus (HCV)-seropositive; 9 patients (9%) were seropositive for both, with all of the HBV cases and 3 of the HCV cases being inactive. Extrahepatic disease was present in 64%, and 17% had vascular invasion. All patients received prior sorafenib; 20% were intolerant of it. No patient received any prior systemic therapy other than sorafenib.

The confirmed independent central review–assessed overall response rate was 17%, with 1 complete response and 17 partial responses. The response duration ranged from 3.1 to 16.7 months, with 89% of responses being at least 6 months and 56% being at least 12 months.

How It Works

BINDING OF programmed cell death ligand 1 (PD-L1) and PD-L2 to the programmed cell death protein 1 (PD-1) receptor found on T cells inhibits T-cell proliferation and cytokine production. Pembrolizumab is an anti–PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. Upregulation of PD-1 ligands is observed in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.

How It Is Used

THE RECOMMENDED DOSE of pembrolizumab in hepatocellular carcinoma is 200 mg via intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of the product labeling.

No dose reductions of pembrolizumab are recommended. Prescribing information provides recommendations for withholding or discontinuing pembrolizumab for immune-mediated pneumonitis; immune-mediated hepatitis; immune-mediated endocrinopathies, nephritis, and adverse skin reactions; recurrent immune-mediated adverse reactions, an inability to taper corticosteroid treatment; persistent grade 2 or adverse reactions (excluding endocrinopathy); and infusion-related reactions.

For immune-mediated hepatitis in patients with hepatocellular carcinoma, treatment should be withheld for aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at least 5 times the upper limit of normal (ULN) if baseline less than 2 times ULN; AST or ALT more than 3 times baseline if baseline at least 2 times ULN; total bilirubin more than 2.0 mg/ dL if baseline less than 1.5 mg/dL; or total bilirubin more than 3.0 mg/dL, regardless of baseline levels. Treatment can be resumed when AST or ALT and total bilirubin recover to grade 0 or 1 or to baseline.

For immune-mediated hepatitis in patients with hepatocellular carcinoma, treatment should be permanently discontinued for ALT or AST levels more than 10 times ULN; Child-Pugh score at least 9 points; gastrointestinal bleeding suggestive of portal hypertension; new onset of clinically detectable ascites; or encephalopathy.

Safety Profile

THE MOST COMMON adverse events of any grade (≥ 20% of patients) in clinical trials of pembrolizumab as a single agent have been fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

Among the 104 patients with hepatocellular carcinoma who received pembrolizumab in KEYNOTE-224, the median duration of exposure to pembrolizumab was 4.2 months. Adverse events in patients with hepatocellular carcinoma were generally similar to those in patients with melanoma or non–small cell lung cancer treated with pembrolizumab, with the exception of an increased incidences of ascites and immune-mediated hepatitis. Grade 3 or 4 laboratory abnormalities that occurred at a higher incidence were elevated AST, ALT, and hyperbilirubinemia.

Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis; colitis; hepatitis; endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes); nephritis; skin adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis; infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment; and embryofetal toxicity. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. In organ transplant recipients, the benefit of pembrolizumab should be considered against the risk of possible organ rejection. Breastfeeding women should discontinue treatment with pembrolizumab or breastfeeding. ■

REFERENCES

1. U.S Food and Drug Administration: FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. Available at www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm625705.htm. Accessed December 11, 2018.

2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck and Co., Inc., November 2018. Available at https://www. accessdata.fda.gov/drugsatfda_docs/label/2018/125514s042lbl.pdf. Accessed December 11, 2018.

3. Zhu AX, Finn RS, Edeline J, et al: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial. Lancet Oncol 19:940-952, 2018.