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 October 2, 2015, the U.S. Food and Drug Administration granted pembrolizumab (Keytruda) accelerated approval for the treatment of patients with metastatic non–small cell lung cancer (NSCLC) with progression on or after platinum-containing therapy and with tumors expressing programmed cell death ligand 1 (PD-L1).1
Initially indicated for the treatment of metastatic melanoma, pembrolizumab is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test (Dako), which is designed to detect PD-L1 expression in NSCLC. Patients with EGFR or ALK tumor aberrations should have disease progression on approved therapy for these aberrations prior to receiving pembrolizumab treatment.
Supporting Efficacy Data
Approval was based on objective response rate in a subgroup of 61 patients, from a larger multicenter open-label multicohort study (N = 550), who had advanced NSCLC progressing after platinum-based chemotherapy and, if appropriate, targeted therapy for ALK or EGFR aberrations and who had PD-L1–positive tumors (≥ 50% tumor cells) based on the results of the 22C3 pharmDx diagnostic test.2 This group received pembrolizumab at 10 mg/kg every 2 (n = 27) or 3 (n = 34) weeks until unacceptable toxicity or disease progression.
Patients had a median age of 60 years (34% ≥ 65 years), 61% were male, 79% were white, 34% and 64% had Eastern Cooperative Oncology Group performance status of 0 and 1, 21% had squamous and 75% nonsquamous histology, 98% had M1 disease, 11% had brain metastases, 10% had EGFR aberrations and 0% had ALK aberrations, and the number of prior therapies was one in 26%, two in 30%, and at least three in 44%.
Response rates and duration of response were similar with every-2-week and every-3-week dosing. On independent review, the overall objective response rate was 41% (95% confidence interval = 29%–54%, all partial responses). Median response duration had not been reached at last analysis. Among the 25 patients with response, 21 patients (84%) had an ongoing response at the last analysis, with 11 (44%) having an ongoing response of at least 6 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–programmed cell death (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 is 2 mg/kg via intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.
Pembrolizumab infusion should be stopped and treatment permanently discontinued for grade 3 or 4 infusion-related reactions. Treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, grade 3 or 4 endocrinopathies, grade 2 nephritis, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 to 5 times the upper limit of normal or total bilirubin > 1.5 to 3 times the upper limit of normal, 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 any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy), grade 3 or 4 pneumonitis or recurrent grade 2 pneumonitis, grade 3 or 4 nephritis, AST or ALT > 5 times normal or total bilirubin > 3 times normal, AST or ALT increases of ≥ 50% in patients with liver metastasis who began treatment with grade 2 increased AST or ALT, grade 3 or 4 infusion-related reactions, inability to reduce corticosteroid dose to ≥ 10 mg/d of prednisone or the 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.
No dose adjustment is needed for patients with renal impairment. No dose adjustment is needed for patients with mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment
Among the 550 patients with metastatic NSCLC in the large open-label trial receiving nivolumab (Opdivo) at 2 mg/kg every 3 weeks (n = 61) or 10 mg/kg every 2 or 3 weeks (n = 489), the most common adverse events of any grade were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%). The most common grade 3 adverse events were fatigue (4%) and dyspnea (4%).
The most common laboratory abnormalities of any grade were hyperglycemia (48%), hyponatremia (38%), anemia (36%), and hypoalbuminemia (32%); the most common grade 3 or 4 events were hyponatremia (6%) and hyperglycemia (3%). The incidence of adverse events and serious adverse events were similar with the every-2-week and every-3-week 10 mg/kg schedules.
Serious adverse events occurred in 38% of patients, with the most common occurring in ≥ 2% of patients being pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Treatment was discontinued due to adverse events in 14% of patients.
Among immune-related adverse events, pneumonitis occurred in 3.5% of patients, colitis in 0.7%, hypophysitis in 0.2%, hyperthyroidism in 1.8%, and hypothyroidism in 6.9%. Rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis were each observed in < 1%.
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, and embryofetal toxicity. Hepatic, renal, and thyroid function should be routinely monitored. Breastfeeding women should discontinue breastfeeding.
Other causes should be excluded for suspected immune-mediated adverse reactions. Based on the severity of the adverse reaction, pembrolizumab should be withheld and corticosteroid treatment started. Upon improvement of adverse reactions to no worse grade 1 or less, corticosteroid taper should be started and continued over at least 1 month. Pembrolizumab can be resumed when the adverse reaction remains no greater than grade 1 after steroid taper. ■
1. U.S. Food and Drug Administration: Pembrolizumab injection. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm465650.htm. Accessed October 7, 2015.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck Sharp & Dohme Corp, October 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s005lbl.pdf. Accessed October 7, 2015.