On May 5, 2021, pembrolizumab was granted accelerated approval for use in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma.1,2
Supporting Efficacy Data
Approval was based on a prespecified interim analysis of the first 264 randomly assigned patients in the ongoing multicenter, double-blind, phase III KEYNOTE-811 trial (ClinicalTrials.gov identifier NCT03615326).2 Patients with HER2‑positive advanced gastric or gastroesophageal junction adenocarcinoma who had not previously received systemic therapy for metastatic disease were randomly assigned to receive pembrolizumab at 200 mg (n = 133) or placebo (n = 131) every 3 weeks, both in combination with trastuzumab and either fluorouracil (5-FU) plus cisplatin (FP) or capecitabine plus oxaliplatin (CAPOX). Trastuzumab was given at 8 mg/kg in the first infusion and 6 mg/kg in subsequent cycles, followed by the investigator’s choice of FP with cisplatin at 80 mg/m2 for up to six cycles and 5-FU at 800 mg/m2/d for 5 days or CAPOX with oxaliplatin at 130 mg/m2 for up to six to eight cycles and capecitabine at 1,000 mg/m2 twice daily for 14 days. Pembrolizumab was administered prior to trastuzumab and chemotherapy on day 1 of each cycle. Treatment with pembrolizumab continued until disease progression, unacceptable toxicity, or a maximum of 24 months.
Among the 264 patients included in the analysis, median age was 62 years (range = 19–84 years; 41% ≥ 65 years), 82% were male, and 63% were White, 31% were Asian, and 0.8% were Black. All patients had an Eastern Cooperative Oncology Group performance status of 0 (47%) or 1; 97% had metastatic disease and 3% had locally advanced unresectable disease; 87% had tumors expressing PD-L1 with a combined positive score ≥ 1; 91% had tumors that were not microsatellite instability–high (MSI-H), 1% had MSI-H tumors, and 8% had unknown status; 87% received CAPOX as chemotherapy.
The main efficacy measure was overall response rate as assessed by a blinded independent review committee. An objective response was observed in 99 patients (74%, 95% confidence interval [CI] = 66%–82%; complete response in 11%) in the pembrolizumab group vs 68 patients (52%, 95% CI = 43%–61%; complete response in 3.1%) in the placebo group (P < .0001). The median duration of response was 10.6 months (range = 1.1+ to 16.5+ months) vs 9.5 months (range = 1.4+ to 15.4+ months), with responses lasting at least 6 months in 65% vs 53% of responders.
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. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. 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. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.
How It Is Used
The recommended dose of pembrolizumab for adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma in combination with trastuzumab and chemotherapy is 200 mg every 3 weeks or 400 mg every 6 weeks via 30-minute intravenous infusion, with pembrolizumab continued until disease progression, unacceptable toxicity, or up to 24 months. Pembrolizumab is administered prior to trastuzumab and chemotherapy when given on the same day.
Pembrolizumab has warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, and solid organ transplant rejection.
No dose reductions of pembrolizumab are recommended. In general, pembrolizumab should be withheld for grade 3 immune-mediated adverse reactions and permanently discontinued for grade 4 immune-mediated adverse reactions, recurrent grade 3 immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce the corticosteroid dose to ≤ 10 mg of prednisone or equivalent per day within 12 weeks of initiating steroids. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 reactions.
Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling. Product labeling provides recommended dosing modifications—including withholding, resuming, and discontinuing treatment—for the following immune-mediated adverse reactions: pneumonitis, colitis, hepatitis without and with tumor involvement of the liver, liver enzyme elevations when used in combination with axitinib, endocrinopathies, nephritis with renal dysfunction, exfoliative dermatologic conditions, myocarditis, neurologic toxicities, hematologic toxicity in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma, and infusion-related reactions.
The most common adverse events of any grade (≥ 20%) observed in patients receiving pembrolizumab in combination with chemotherapy in clinical trials have been fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, and weight loss.
The safety analysis of the KEYNOTE-811 study included 217 patients with HER2-positive gastric cancer who received pembrolizumab at 200 mg, trastuzumab, and CAPOX (n = 189) or FP (n = 28) every 3 weeks and 216 patients who received placebo, trastuzumab, and CAPOX (n = 187) or FP (n = 29) every 3 weeks. Median duration of exposure to pembrolizumab was 5.8 months (range = 1 day to 17.7 months). The adverse event profile observed in patients receiving pembrolizumab was consistent with the known pembrolizumab safety profile.
A difference of at least 5% in incidence was observed between the pembrolizumab and placebo groups for any-grade diarrhea (53% vs 44%) and nausea (49% vs 44%). No clinically meaningful differences between groups in the incidence of grade 3 to 4 adverse events were observed. A difference of at least 5% incidence between groups was observed for any-grade increased alanine aminotransferase (ALT; 34% vs 29%) and increased creatinine (20% vs 10%). No clinically meaningful differences between groups in the incidence of grade 3 to 4 laboratory abnormalities were observed.
Adverse events led to interruption of pembrolizumab in 58% of patients, the most common causes being neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased aspartate aminotransferase (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased ALT (2.3%), and vomiting (2.3%). Adverse events led to permanent discontinuation of pembrolizumab in 6% of patients, with the most common cause being pneumonitis (1.4%).
Pembrolizumab has warnings/precautions for immune-mediated adverse reactions. These reactions—which may be severe or fatal and can occur in any organ system or tissue—include immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection. Pembrolizumab also has warnings/precautions for infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation before or after treatment with a PD-1–/PD-L1–blocking antibody, including fatal or serious complications; 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 early identification and management of immune-mediated adverse reactions, including evaluation of liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Patients should be advised not to breastfeed while receiving pembrolizumab.
1. U.S. Food and Drug Administration: FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer. Accessed May 18, 2021.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck & Co, Inc, May 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s097lbl.pdf. Accessed May 18, 2021.