In June 2018, pembrolizumab (Keytruda) was approved for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express programmed cell death ligand 1 (PD-L1; combined positive score [CPS] ≥ 1), as determined by a U.S. Food and Drug Administration (FDA)-approved test.1,2 The FDA concurrently approved PD-L1 IHC 22C3 pharmDx as a companion diagnostic.
Supporting Efficacy Data
The current approval was based on the finding of durable responses among 77 patients with recurrent or metastatic cervical cancer with PD-L1 CPS ≥ 1 in a cohort (total n = 98) of the multicohort phase II KEYNOTE-158 trial.2 Patients had to have received at least one line of therapy for recurrent or metastatic disease. Patients received pembrolizumab at 200 mg every 3 weeks until disease progression or unacceptable toxicity. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Among the 77 patients in the efficacy population, the median age was 45 years (range = 27–75 years); 81% were white and 14% were Asian; an Eastern Cooperative Oncology Group performance status was 0 or 1 in all; 92% had squamous cell carcinoma and 6% had adenocarcinoma; 95% had M1 disease and 5% had recurrent disease; and 35% had 1 and 65% had at least 2 prior lines of therapy in the recurrent or metastatic setting.
With a median follow-up of 11.7 months, the objective response rate on a blinded independent central review in the 77 patients was 14.3%, including a complete response in 2.6% of patients. The estimated median response duration among 11 responding patients was not reached (range = 4.1–18.6+ months), with 91% having a response duration of at least 6 months. No responses were observed in the 21 patients with no PD-L1 expression (CPS < 1).
How It Works
Binding of 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 an 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 cervical cancer is 200 mg via a 30-minute intravenous infusion given every 3 weeks until disease progression, 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 patients with classical Hodgkin lymphoma or primary mediastinal large B-cell
Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions.
lymphoma, grade 2 nephritis, grade 3 severe skin reactions or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis, aspartate transaminase (AST) 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 the following conditions: 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 and AST or ALT increases of ≥ 50% persisting for at least 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 its equivalent within 12 weeks; persistent grade 2 or 3 adverse reactions 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.
Among the total of 98 patients with cervical cancer receiving pembrolizumab in the KEYNOTE-158 cohort, the most common adverse events of any grade were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain (22%), abdominal pain (22%), and decreased appetite (21%). The most common grade 3 or 4 adverse events were urinary tract infection (6%), fatigue (5%), musculoskeletal pain (5%), hemorrhage (5%), and other infection (4%).
Pembrolizumab carries warnings/precautions for immune--mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, 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 hematopoietic stem cell transplantation, 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. 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 advanced cervical cancer with disease progression during or after chemotherapy. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm610572.htm. Accessed August 30, 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/2018/125514s034lbl.pdf. Accessed August 30, 2018.