On August 20, 2018, pembrolizumab (Keytruda) in combination with pemetrexed (Alimta) and platinum was granted regular approval as first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.1,2
Pembrolizumab was previously granted accelerated approval in this indication in May 2017 based on improvements in overall response rate and progression-free survival with pembrolizumab plus pemetrexed and carboplatin vs pemetrexed and carboplatin alone in the KEYNOTE-021 study. The current approval represents fulfillment of a postmarketing commitment demonstrating the clinical benefit of pembrolizumab in this setting.
Pembrolizumab carries warnings/precautions for immune-mediated adverse events such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment; and embryofetal toxicity.
The regular approval is based on the findings from the phase III double-blind KEYNOTE-189 trial, showing improved overall and progression-free survival with the pembrolizumab plus chemotherapy combination.2,3 In the trial, 616 patients were randomly assigned 2:1 to receive pembrolizumab at 200 mg, pemetrexed at 500 mg/m2, and investigator choice of cisplatin at 75 mg/m2 or carboplatin AUC = 5 on day 1 of each 21-day cycle for 4 cycles followed by pembrolizumab at 200 mg and pemetrexed at 500 mg/m2 every 3 weeks (n = 410) or placebo plus chemotherapy at the same dose and schedule followed by placebo and pemetrexed at 500 mg/m2 every 3 weeks (n = 206). Treatmentcontinued until disease progression, unacceptable toxicity, or a maximum of 24 months. The primary efficacy outcome measures were overall and progression-free survival as assessed by a blinded independent review committee using (Response Evaluation Criteria in Solid Tumors v1.1).
The median age of patients was 64 years (range = 34–84 years, 49% ≥ 65 years), 59% were male, 94% were white, 18% had a history of brain metastases, 31% had tumor programmed cell death ligand 1 (PD-L1) expression tumor proportion score < 1% (negative), 12% were never smokers, and 72% received carboplatin. A total of 85 patients in the chemotherapy group received anti–programmed cell death protein 1 (anti–PD-1)/PD-L1 treatment at disease progression.
The median overall survival was not reached in the pembrolizumab group vs 11.3 months in the chemotherapy-alone group (hazard ratio [HR] = 0.49, P < .00001) in a prespecified interim analysis. The median progression-free survival was 8.8 months vs 4.9 months (HR = 0.52, P < .00001). The overall response rate was 48% vs 19% (P = .0001), and the median duration of response was 11.2 months vs 7.8 months.
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. 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 may 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 the current indication is 200 mg via intravenous (IV) 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 pemetrexed and carboplatin or cisplatin should be consulted for appropriate dosing and schedule.
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 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 (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 more than 5 times or total bilirubin more than 3 times ULN, AST or ALT increases of at least 50% 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 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 of any grade in the pembrolizumab group in KEYNOTE-189 were fatigue/asthenia (56% vs 58% in the chemotherapy-alone group), nausea (56% vs 52%), constipation (35% vs 32%), diarrhea (31% vs 21%), decreased appetite (28% vs 30%), rash (25% vs 17%), vomiting (24% vs 23%), cough (21% vs 28%), dyspnea (21% vs 26%), and pyrexia (20% vs 15%). The most common grade 3 or 4 adverse events in the pembrolizumab group included fatigue (12% vs 6%), vomiting (3.7% vs 3.0%), and dyspnea (3.7% vs 5%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (22% vs 25%), neutropenia (20% vs 19%), and anemia (17% vs 18%); among grade 3 or 4 nonhematologic abnormalities, hypophosphatemia occurred in 10% and hyperglycemia was observed in 9%.
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).
Adverse events led to discontinuation of pembrolizumab in 20% of patients, with the most common causes being pneumonitis (3%) and acute kidney injury (2%). Adverse events led to interruption of pembrolizumab in 53% of patients, with the most common causes being neutropenia (13%), fatigue/asthenia (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), and increased blood creatinine (3%).
Pembrolizumab carries warnings/precautions for immune-mediated adverse reactions such as pneumonitis, colitis, hepatitis, endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), nephritis, and skin adverse reactions including Stevens-Johnson syndrome or toxic epidermal necrolysis. In addition, pembrolizumab 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 (Thalomid) 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 grants regular approval for pembrolizumab in combination with chemotherapy for first-line treatment of metastatic nonsquamous NSCLC. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617471.htm. Accessed November 26, 2018.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck and Co, Inc, August 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s035lbl.pdf. Accessed November 26, 2018.
3. Gandhi L, Rodriguez‑Abreu D, Gadgeel S, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078-2092, 2018.