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 30, 2018, pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel was approved as first-line treatment of metastatic squamous non–small cell lung cancer (NSCLC).1,2
Supporting Efficacy Data
APPROVAL WAS based on the findings of the phase III double-blind KEYNOTE-407 trial.2,3 In the trial, 559 patients, regardless of programmed cell death ligand 1 (PD-L1) tumor expression status, were randomly assigned to receive pembrolizumab at 200 mg (n = 278) or placebo (n = 281) in combination with carboplatin (AUC = 6) and investigator’s choice of paclitaxel (200 mg/m2) every 3 weeks or nab-paclitaxel (100 mg/m2) weekly in a 3-week cycle for 4 cycles followed by pembrolizumab or placebo.2,3 Patients continued to receive pembrolizumab or placebo until disease progression, unacceptable toxicity, or a maximum of 24 months. Patients in the placebo group were offered pembrolizumab monotherapy at the time of disease progression. Patients with autoimmune disease who required systemic therapy within 2 years of treatment, who had a medical condition that required immunosuppression, or who had received at least 30 Gy of thoracic radiation within the prior 26 weeks were not eligible for the study.
The median age of patients was 65 years (55% ≥ 65 years); 81% were male; 77% were white; 71% had an Eastern Cooperative Oncology Group performance status of 1; 8% had a history of brain metastases; 35% had a tumor PD-L1 expression tumor proportion score less than 1% (PD-L1–negative); 19% were from the East Asian region; and 60% received paclitaxel.
Efficacy measures were assessed by blinded independent central review. The median overall survival was 15.9 months in the pembrolizumab plus chemotherapy group vs 11.3 months in the placebo plus chemotherapy group (hazard ratio [HR] = 0.64, P = .0017). The median progression-free survival was 6.4 vs 4.8 months (HR = 0.56, P < .0001). The analysis of objective response was limited to the initial 204 patients randomly assigned to treatment (101 in pembrolizumab group, 103 in the placebo group); the overall response rate was 58% vs 35% (P = .0008). The estimated median response duration was 7.2 vs 4.9 months.
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 ligands, 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 NSCLC 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. Pembrolizumab should be given prior to chemotherapy when given on the same day. Prescribing information for chemotherapy should be consulted for appropriate dosing and schedule.
Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of 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 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) more than 3 and up to 5 times or total bilirubin more than 1.5 and up to 3 times the upper limit of normal; and any other grade 2 or 3 treatment-related adverse reaction, based on severity and type. 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 more than 5 times or total bilirubin more than 3 times the upper limit of normal; AST or ALT increases of at least 50% from baseline persisting for at least 1 week in patients with liver metastasis who began treatment with grade 2 increased AST or ALT; grade 3 or 4 myocarditis, encephalitis, or Guillain-Barré syndrome; inability to reduce the corticosteroid dose to up 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 events (at least 20% of patients) reported in clinical trials of pembrolizumab plus chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, and peripheral neuropathy.
Safety data were available for the first 203 patients who received pembrolizumab and chemotherapy (n = 101) or placebo and chemotherapy (n = 102) in the KEYNOTE-407 trial. Prescribing information does not provide detailed specific information on adverse reactions or laboratory abnormalities in the trial. Prescribing information states that the adverse events observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189, which evaluated first-line pembrolizumab plus chemotherapy in patients with metastatic nonsquamous NSCLC, with the exception that increased rates of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the pembrolizumab plus chemotherapy group vs the placebo plus chemotherapy group in KEYNOTE-407.
The most common adverse events occurring in at least 20% of patients who received pembrolizumab were fatigue/asthenia, nausea, constipation, diarrhea, vomiting, pyrexia, decreased appetite, rash, cough, dyspnea, alopecia, and peripheral neuropathy. Pembrolizumab was discontinued due to adverse events in 15% of patients, with no single type of adverse event accounting for a majority. Adverse events leading to interruption of pembrolizumab occurred in 43% of patients, with the most common being thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent serious adverse events were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%).
Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), nephritis, as well as skin adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis. The drug also carries warnings/precautions for infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation 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. 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. ■
1. U.S. Food and Drug Administration: FDA approves pembrolizumab in combination with chemotherapy for first-line treatment of metastatic squamous NSCLC. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm624659.htm. Accessed January 7, 2019.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck and Co., Inc., October 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s041lbl.pdf. Accessed January 7, 2019.
3. Paz-Ares L, Luft A, Vicente D, et al: Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379:2040-2051, 2018.