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 August 5, 2016, pembrolizumab (Keytruda) was granted accelerated approval for treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma and disease progression on or after platinum-containing chemotherapy.1,2
As a condition of the accelerated approval, Merck is required to conduct a multicenter randomized trial establishing the superiority of pembrolizumab over standard therapy to verify and describe the clinical benefit of pembrolizumab. Merck has an ongoing multicenter randomized trial (KEYNOTE-040) in patients with recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum-containing chemotherapy, with a primary endpoint of overall survival.
Supporting Efficacy Data
Approval was based on demonstration of durable objective responses among a cohort of 174 head and neck squamous cell carcinoma patients in an international, multicenter, open-label, multicohort study. Patients received pembrolizumab at 10 mg/kg every 2 weeks (n = 53) or 200 mg every 3 weeks (n = 121) until disease progression or unacceptable toxicity or for up to 24 months.
Patients had a median age of 60 years (32% ≥ 65 years), 82% were male, 75% were white, and 16% were Asian. In addition, 87% had M1 disease, 33% had human papillomavirus (HPV)-positive tumors, and 63% had received prior cetuximab (Erbitux). The median number of prior lines of therapy was two.
The objective response rate was 16% (95% confidence interval [CI] = 11%–22%), and the complete response rate was 5%. Median follow-up was 8.9 months. Among the 28 patients with response, median duration of response had not been reached (range = 2.4+ to 27.7+ months), with 23 showing a response for at least 6 months. The response rate and duration of response were similar irrespective of dosage regimen or HPV status.
How It Works
Binding of PD-L1 and PD-L2 (programmed cell death ligand 1 and 2) to the PD-1 (programmed cell death protein 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
The recommended dose of pembrolizumab in head and neck squamous cell carcinoma is 200 mg administered via intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in the absence of disease progression.
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 transaminase (AST) or alanine transaminase (ALT) > 3 to 5 times or total bilirubin > 1.5 to 3 times 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 or total bilirubin > 3 times upper limit of 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.
Safety was evaluated in 192 patients with head and neck squamous cell carcinoma receiving at least one dose of pembrolizumab. The most common adverse events (> 20%) were fatigue, decreased appetite, and dyspnea. The incidence of adverse events, including serious adverse reactions, was similar with the two dosage regimens. Adverse events were similar to those observed in patients with melanoma or non–small cell lung cancer, except for an increased incidence of facial edema (10% any grade, 2.1% grade 3/4) and new or worsening hypothyroidism (14.6% any grade).
Serious adverse events occurred in 45% of patients, with the most common (≥ 2%) being pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes, skin toxicity, myositis, and thyroid disorders. Pembrolizumab was discontinued due to adverse events in 17% of patients.
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 while receiving pembrolizumab. ■
1. U.S. Food and Drug Administration: Pembrolizumab (Keytruda). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm515627.htm. Accessed August 19, 2016.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck Sharp & Dohme Corp, August 2016. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s009lbl.pdf. Accessed August 19, 2016.
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 http://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).