Pembrolizumab in Classical Hodgkin Lymphoma


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

On March 14, 2017, pembrolizumab (Keytruda) was granted accelerated approval for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma or those who have relapsed after three or more prior lines of therapy.1,2 

Supporting Efficacy Data 

APPROVAL WAS BASED on durable responses observed in 210 adults with classical Hodgkin lymphoma in a multicenter single-arm trial. The patients received pembrolizumab at 200 mg every 3 weeks until unacceptable toxicity or disease progression or for up to 24 months in patients without disease progression.2 Patients had refractory or relapsed disease after autologous hematopoietic stem cell transplantation (n = 129) and/or brentuximab vedotin (Adcetris; n = 175) and had received a median of four prior systemic therapies (range = 1–12). Response was assessed by blinded independent central review. 

Patients had a median age of 35 years (9% aged ≥ 65 years), 54% were male, 88% were white, all had an Eastern Cooperative Oncology Group performance status of 0 or 1, 58% were refractory to the last prior therapy, including 35% with primary refractory disease and 14% with disease chemorefractory to all prior regimens, 61% had undergone prior allogeneic hematopoietic stem cell transplantation, 83% had received prior brentuximab vedotin, and 36% had prior radiation therapy. 

Median follow-up was 9.4 months (range = 1–15 months). The overall response rate was 69% (95% confidence interval = 62%–75%), including partial response in 47% of patients and complete response in 22%. The estimated median response duration was 11.1 months (range = 0+ to 11.1). Efficacy in pediatric patients was extrapolated from results in adults. 

OF NOTE

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.

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 ligands, thereby inhibiting the PD-1 pathway–mediated 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 adults is 200 mg via intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity or for up to 24 months in patients without disease progression. The recommended dose in pediatric patients is 2 mg/kg (up to a maximum of 200 mg) via intravenous infusion over 30 minutes on the same schedule as in adults. 

PEMBROLIZUMAB IN CLASSICAL HODGKIN LYMPHOMA

  • Pembrolizumab (Keytruda) was granted accelerated approval for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma or those who have relapsed after three or more prior lines of therapy.
  • The recommended dose of pembrolizumab in adults is 200 mg via intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity or for up to 24 months in patients without disease progression.

Pembrolizumab treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, grade 3 or 4 endocrinopathies, grade 4 hematologic toxicity in classical Hodgkin lymphoma patients, grade 2 nephritis, aspartate transaminase (AST) or alanine transaminase (ALT) > 3 to 5 times or total bilirubin > 1.5 to 3 times the upper limit of normal (ULN), and any other severe or grade 3 treatment-related adverse reaction. Treatment can be resumed when adverse reactions recover to grade 0 or 1. 

Pembrolizumab should be permanently discontinued for grade 3 or 4 infusion-related reactions, any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy or hematologic toxicity in patients with classical Hodgkin lymphoma), grade 3 or 4 pneumonitis or recurrent grade 2 pneumonitis, grade 3 or 4 nephritis, AST or ALT > 5 times or total bilirubin > 3 times ULN, AST or ALT increases of ≥ 50% persisting for ≥ 1 week in patients with liver metastasis who began treatment with grade 2 increased AST or ALT, inability to reduce corticosteroid dose to ≥ 10 mg/d prednisone or equivalent within 12 weeks, persistent grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) that do not recover to grade 0 or 1 within 12 weeks of the last dose, and any recurrent severe or grade 3 treatment-related adverse reaction. 

Safety Profile 

IN THE STUDY in 210 adults, the most common adverse events of any grade were fatigue (26%), pyrexia (24%), and cough (24%). The most common grade 3 or 4 adverse events (all grade 3) were diarrhea (1.4%) and fatigue, pyrexia, dyspnea, and musculoskeletal pain (1% each). Serious adverse events occurred in 16% of patients, with those occurring in ≥ 1% consisting of pneumonia, pneumonitis, pyrexia, dyspnea, graft-vs-host disease, and herpes zoster. Hypothyroidism of any grade occurred in 14%; other potentially immune-related adverse events that occurred in less than 10% of patients included infusion reaction (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each). The most common grade 3 or 4 laboratory abnormalities were neutropenia (7%), anemia (6%), and thrombocytopenia (4%); hyperbilirubinemia of any grade occurred in 10%, with grade 3 or 4 events in 2.4%. Grade 3 or 4 transaminase elevations occurred in 2%. Adverse events requiring corticosteroid treatment occurred in 15%. Adverse events led to treatment interruption in 26% and treatment discontinuation in 5%. Two patients died of causes other than disease progression, consisting of one due to graft-vs-host disease after subsequent allogeneic hematopoietic stem cell transplantation and one due to septic shock. 

Safety was evaluated in 40 children with advanced melanoma, PD-L1–positive solid tumors, or lymphoma. The safety profile in the pediatric patients was similar to that observed in adults. Adverse reactions occurring at a higher rate (difference of 15% or greater) in children than adults included fatigue (45%), vomiting (38%), abdominal pain (28%), elevated transaminases (28%), and hyponatremia (18%). The U.S. Food and Drug Administration (FDA) has required the sponsor to evaluate the long-term safety of pembrolizumab in prepubertal patients and in those who have not completed pubertal development. 

OF NOTE

Pembrolizumab carries warnings/precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation after pembrolizumab, and embryofetal toxicity.

Pembrolizumab carries warnings/precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies (including hypophysitis, thyroid disorders, and type I diabetes), and nephritis, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation after pembrolizumab, and embryofetal toxicity. Hepatic, renal, and thyroid function should be routinely monitored. Breastfeeding women should discontinue treatment or breastfeeding. 

Labeling contains a new warning/precaution for complications of allogeneic hematopoietic stem cell transplantation after pembrolizumab. Transplant-related deaths have occurred, and health-care professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-vs-host disease, severe (grade 3 to 4) acute graft-vs-host disease, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse events. The FDA has required the sponsor to further study the safety of allogeneic hematopoietic stem cell transplantation after pembrolizumab therapy. ■

REFERENCES 

1. U.S. Food and Drug Administration: Pembrolizumab (Keytruda) for classical Hodgkin lymphoma. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm546893.htm. Accessed April 21, 2017. 

2. Keytruda (pembrolizumab) injection prescribing information, Merck Sharp & Dohme Corp., March 2017. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s015lbl.pdf. Accessed April 21, 2017. 



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