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Pembrolizumab in Adult and Pediatric Classical Hodgkin Lymphoma


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On October 14, 2020, the approval of pembrolizumab was extended for the following indications1,2:

  • adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL)
  • pediatric patients with refractory cHL or cHL that has relapsed after two or more lines of therapy.

Supporting Efficacy Data

Approval was based on findings in the open-label phase III KEYNOTE-204 trial (ClinicalTrials.gov identifier NCT02684292).2 In the trial, 304 adults with relapsed or refractory cHL after at least one multiagent regimen were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks (n = 151) or brentuximab vedotin at 1.8 mg/kg every 3 weeks (n = 153) until disease progression, unacceptable toxicity, or for up to 2 years.

Eligibility requirements included an absolute neutrophil count ≥ 1,000/μL, platelet count ≥ 75,000/μL, and hepatic transaminases ≤ 2.5 times and bilirubin ≤ 1.5 times the upper limit of normal. The trial excluded patients with active noninfectious pneumonitis, prior pneumonitis requiring steroids, active autoimmune disease, a medical condition requiring immunosuppression, or allogeneic hematopoietic stem cell transplantation (HSCT) within the past 5 years.

OF NOTE

Pembrolizumab has warnings/precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic HSCT before and after pembrolizumab treatment, and embryofetal toxicity.

Median patient age was 35 years (range = 18–84 years); 57% were male; 77% were White. Overall, 42% were refractory to their last prior therapy, 29% had primary refractory disease, 37% had prior autologous HSCT, 5% had received prior brentuximab vedotin, and 39% had prior radiation therapy. The median number of prior therapies was two (range = 1–10) in the pembrolizumab group and three (range = 1–11) in the brentuximab vedotin group, with 18% in both groups having had one prior line of therapy.

Efficacy was based on progression-free survival on blinded independent central review assessment using the 2007 revised International Working Group criteria. Median progression-free survival was 13.2 months (95% confidence interval [CI] = 10.9–19.4 months) in the pembrolizumab group vs 8.3 months (95% CI = 5.7–8.8 months) in the brentuximab vedotin group (hazard ratio = 0.65, 95% CI = 0.48–0.88, P = .0027).

Objective response rates were 66% (including complete response in 25%) vs 54% (including a complete response in 24%). Median response durations were 20.7 months (range = 0.0+ to 33.2+ months) vs 13.8 months (range = 0.0+ to 33.9+ months).

The use of pembrolizumab in pediatric patients with cHL is supported by evidence from adequate and well-controlled studies of adults, with additional pharmacokinetic and safety data from pediatric patients.

How It Works

Binding of PD-L1 and PD-L2 to the PD-1 receptor found on T cells 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 of tumors. 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 ligands, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.

How It Is Used

In the current indications, the recommended dose of pembrolizumab in adults is 200 mg every 3 weeks or 400 mg every 6 weeks via 30-minute intravenous (IV) infusion, with treatment continued until disease progression, unacceptable toxicity, or up to 24 months. For pediatric patients, the recommended dose is 2 mg/kg every 3 weeks up to a maximum of 200 mg via 30-minute IV infusion, with treatment continued until disease progression, unacceptable toxicity, or up to 24 months.

No dose reductions of pembrolizumab are recommended. Treatment should be withheld or discontinued to manage adverse reactions. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 reactions.

KEY POINTS

  • Approval of pembrolizumab was extended for adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) and pediatric patients with refractory cHL or cHL that has relapsed after two or more lines of therapy.
  • The recommended dose of pembrolizumab in adults is 200 mg every 3 weeks or 400 mg every 6 weeks via 30-minute intravenous infusion, with treatment continued until disease progression, unacceptable toxicity, or up to 24 months.

Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling. Product labeling provides recommended dosing modifications—including withholding, resuming, and discontinuing treatment—for the following adverse reactions: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis in patients with and without hepatocellular carcinoma, liver enzyme elevations in patients with renal cell carcinoma receiving combination therapy, immune-mediated endocrinopathies, immune-mediated nephritis, immune-mediated skin adverse reactions, hematologic toxicity in patients with cHL or primary mediastinal large B-cell lymphoma, other immune-mediated adverse reactions, recurrent immune-mediated adverse reactions, inability to taper corticosteroid treatment, persistent grade 2 or 3 adverse reactions (excluding endocrinopathy), and infusion-related reactions.

Safety Profile

The most common adverse events of any grade (≥ 20% of patients) reported with pembrolizumab alone in clinical trials have been fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

In the KEYNOTE-204 trial, the median duration of exposure to pembrolizumab was 10 months (range = 1 day to 2.2 years), with 68% of patients receiving at least 6 months and 48% receiving at least 1 year of treatment.

Adverse events of any grade occurring in at least 20% of pembrolizumab recipients were upper respiratory tract infection (41% vs 24% in the brentuximab vedotin group), musculoskeletal pain (32% vs 29%), diarrhea (22% vs 17%), cough (20% vs 14%), pyrexia (20% vs 13%), fatigue (20% vs 22%), and rash (20% vs 19%). The most common grade 3 or 4 adverse events included pneumonitis (5%), diarrhea (2.7%), upper respiratory tract infection (1.4%), and vomiting (1.4%). The most common grade 3 or 4 laboratory abnormalities were thrombocytopenia (10%), lymphopenia (9%), and neutropenia (8%).

Serious adverse events occurred in 30% of the pembrolizumab group, with those occurring in at least 1% of patients including pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Adverse events requiring systemic corticosteroids occurred in 38% of patients given pembrolizumab, including pneumonitis in 11%. Adverse events requiring dosage interruption in at least 3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase, and pneumonia. Discontinuation of treatment due to adverse events occurred in 14% of patients, including pneumonitis in 7%. Three patients died of causes other than disease progression, two of them of complications after allogeneic HSCT and one of an unknown cause.

Pembrolizumab has warnings/precautions for immune-mediated pneumonitis; immune-mediated colitis; immune-mediated hepatitis (and hepatotoxicity in combination with axitinib); immune-mediated endocrinopathies (including adrenal insufficiency, hypophysitis, thyroid disorders, and type 1 diabetes); immune-mediated nephritis; immune-mediated skin adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis; other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic HSCT before and after pembrolizumab treatment; and embryofetal toxicity. Treatment of patients with multiple myeloma with a PD-1– or PD-L1–blocking antibody in combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials.

Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. Patients undergoing allogeneic HSCT after pembrolizumab treatment should be monitored for hepatic veno-occlusive disease and grade 3 or 4 acute graft-vs-host disease, including hyperacute graft-vs-host disease, steroid-requiring febrile syndrome, and other immune-mediated adverse reactions. For patients with a history of allogeneic HSCT, the benefit of pembrolizumab must be weighed against the risk of graft-vs-host disease. Patients should be advised not to breastfeed while receiving pembrolizumab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA extends approval of pembrolizumab for classical Hodgkin lymphoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-extends-approval-pembrolizumab-classical-hodgkin-lymphoma. Accessed October 23, 2020.

2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck & Co, October 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s085lbl.pdf. Accessed October 23, 2020.


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