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 June 13, 2018, pembrolizumab (Keytruda) was granted accelerated approval for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma or who have relapsed after at least two prior lines of therapy.1,2 Pembrolizumab is not recommended for the treatment of patients with primary mediastinal large B-cell lymphoma who require urgent cytoreductive therapy.
Supporting Efficacy Data
Approval was based on the finding of durable responses in 53 patients with relapsed or refractory primary mediastinal large B-cell lymphoma in the KEYNOTE-170 trial.2 Patients were not eligible if they had active noninfectious pneumonitis, allogeneic hematopoietic stem cell transplantation (HSCT) within the past 5 years (or > 5 years with symptoms of graft-vs-host disease), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. Patients received pembrolizumab at 200 mg every 3 weeks until unacceptable toxicity or disease progression or for up to 24 months in the absence of disease progression.
Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions.
The median age of patients was 33 years (range = 20–61 years), 57% were female, 92% were white, all had an Eastern Cooperative Oncology Group performance status of 0 or 1, the median number of prior lines of therapy for primary mediastinal large B-cell lymphoma was 3 (range = 2–8), 36% had primary refractory disease, 49% had relapsed disease refractory to the last prior therapy, 15% had untreated relapse, 26% had prior autologous HSCT, 32% had prior radiation therapy, and all had received rituximab (Rituxan) as part of a prior line of therapy.
With a median follow-up of 9.7 months, the objective response rate on blinded independent central review was 45%, including complete response in 11%. The median duration of response was not reached (range = 1.1+ to 19.2+ months). The median time to first objective response was 2.8 months (range = 2.1–8.5 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
In primary mediastinal large B-cell lymphoma, the recommended dose in adults is 200 mg via 30-minute intravenous (IV) infusion 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 30-minute IV infusion every 3 weeks until disease progression or unacceptable toxicity or for 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. 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 or primary mediastinal large B-cell lymphoma patients, grade 2 nephritis, grade 3 severe skin reactions or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis, aspartate transaminase (AST) level or alanine transaminase (ALT) level > 3 and up to 5 times or total bilirubin level > 1.5 and up 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 or primary mediastinal large B-cell lymphoma; grade 3 or 4 pneumonitis or recurrent grade 2 pneumonitis; grade 3 or 4 nephritis; grade 4 severe skin reactions or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis; AST or ALT level > 5 times or total bilirubin level > 3 times ULN; AST or ALT level increases of ≥ 50% persisting for ≥ 1 week in patients with liver metastasis who began treatment with grade 2 increased AST or ALT level; grade 3 or 4 myocarditis, encephalitis, or Guillain-Barré syndrome; inability to reduce the corticosteroid dose to ≤ 10 mg/d of 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.
The most common adverse reactions (≥ 20% of patients) in patients receiving pembrolizumab in clinical trials were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, skin reactions, endocrinopathies, and nephritis.
The most common adverse events of any grade among the 53 patients in KEYNOTE-170 were musculoskeletal pain (30%), upper respiratory tract infection (28%), pyrexia (28%), cough (26%), fatigue (23%), and dyspnea (21%). The most common grade 3 or 4 adverse events were dyspnea (11%) and arrhythmia (4%). Serious adverse events occurred in 26% of patients, including arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
(2%). Adverse events led to interruption and discontinuation of treatment in 15% and 8% of patients, respectively. Adverse events requiring systemic corticosteroid therapy occurred in 25%. Death occurred in 6 patients (11%) within 30 days of the start of treatment. Clinically important adverse events occurring in up to 10% of patients included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), thyroiditis, pericardial effusion, pneumonitis, arthritis, and acute kidney injury (2% each). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (18%), neutropenia (11%), hypophosphatemia (10%), and leukopenia (9%).
Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies (including 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, 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 as well as 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 or breastfeeding when receiving pembrolizumab. ■
1. U.S. Food and Drug Administration: FDA approves pembrolizumab for treatment of relapsed or refractory PMBCL. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm610670.htm. Accessed September 6, 2018.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck and Co, Inc, June 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/-label/2018/125514s030lbl.pdf. Accessed September 6, 2018.