On September 22, 2017, pembrolizumab (Keytruda) was granted accelerated approval for treatment of recurrent locally advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with tumors expressing programmed cell death ligand 1 (PD-L1), as determined by a U.S. Food and Drug Administration (FDA)-approved test.1,2 Patients must have had disease progression on or after at least two prior systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2-targeted therapy.
The FDA concurrently approved the PD-L1 IHC 22C3 pharmDx for selecting patients with gastric cancer for treatment with pembrolizumab. If PD-L1 expression is not detected in an archival gastric cancer specimen, the FDA recommends assessing the feasibility of a fresh tumor biopsy.
Supporting Efficacy Data
Approval is based on findings in the KEYNOTE 059 trial in 259 patients with gastric or gastroesophageal junction adenocarcinoma.2 Among the 259 patients, 143 (55%) had tumors expressing PD-L1 and either microsatellite stable (MSS) or undetermined microsatellite instability (MSI) or deficient mismatch repair (dMMR) status. PD-L1 expression was assessed by the PD-L1 IHC 22C3 pharmDx Kit, with PD-L1 positivity being based on a combined positive score ≥ 1. The combined positive score is calculated as the number of PD-L1–staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of tumor cells evaluated, multiplied by 100.
Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity.
Among the 143 patients with tumors expressing PD-L1 who were either MSS or had unknown MSI or dMMR status, the median age was 64 years (47% ≥ 65 years), 77% were male, 82% were white and 11% were Asian, all had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 85% had M1 and 7% had M0 disease. Objective response occurred in 19 patients (13.3%, 95% confidence interval = 8.2%–20.0%), with 1.4% having a complete response. Among the responding patients, the response duration ranged from 2.8+ to 19.4+ months, with 11 responders (58%) having a response duration of at least 6 months and 5 (26%) having a response duration of at least 12 months.
Among the total of 259 patients in the trial, 7 (3%) had tumors that were determined to be MSI-high. Responses were observed in 4 (57%) of these patients, with 1 having a complete response. The response duration ranged from 5.3+ to 14.1+ 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, 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 gastric cancer is 200 mg via 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 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 classical Hodgkin lymphoma patients, grade 2 nephritis, grade 3 severe skin reactions or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis, aspartate transaminase (AST) or alanine transaminase (ALT) > 3 and up to 5 times or total bilirubin > 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), 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 levels > 5 times or total bilirubin > 3 times ULN, AST or ALT level increases of ≥ 50% persisting for ≥ 1 week in patients with liver metastasis who began treatment with grade 2 increased AST or ALT level, inability to reduce corticosteroid dose to ≤ 10 mg/d 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.
No specific safety data for KEYNOTE 059 are provided in product labeling. Adverse reactions occurring in patients with gastric cancer in KEYNOTE 059 were similar to those described in labeling for patients with melanoma or non–small cell lung cancer. The most common adverse reactions (≥ 20% of patients) are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, and constipation. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, skin reactions, endocrinopathies, and nephritis.
Pembrolizumab carries warnings/precautions for immune--mediated pneumonitis, immune-mediated colitis, immune--mediated hepatitis, immune-mediated endocrinopathies (including hypophysitis, thyroid disorders, and type I diabetes), 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. 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 accelerated approval to pembrolizumab for advanced gastric cancer. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577093.htm. Accessed November 8, 2017.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck and Co., Inc., September 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s024lbl.pdf. November 8, 2017.