On November 13, 2020, pembrolizumab (Keytruda) was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for use in combination with chemotherapy for patients with locally recurrent unresectable or metastatic triple-negative breast cancer with tumors expressing PD-L1 (Combined Positive Score [CPS] ≥10), as determined by an FDA approved test.1,2 The FDA concurrently approved the PD-L1 IHC 22C3 pharmDx test as a companion diagnostic for selecting patients with triple-negative breast cancer for pembrolizumab treatment.
Supporting Efficacy Data
Approval was based on findings in the subgroup of patients in the multicenter, double-blind, phase III KEYNOTE-355 trial (ClinicalTrials.gov identifier NCT02819518) who had a PD-L1 CPS ≥ 10.2 The trial enrolled 847 patients irrespective of tumor PD-L1 expression who had not previously received chemotherapy in the metastatic setting. Patients were randomly assigned 2:1 to receive pembrolizumab at 200 mg on day 1 every 3 weeks
Pembrolizumab has warnings/precautions for immune-mediated adverse reactions (pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, and dermatologic adverse reactions) as well as solid organ transplant rejection.
vs placebo, both in combination with a chemotherapy regimen. Chemotherapy regimens consisted of paclitaxel protein-bound at 100 mg/m2 on days 1, 8, and 15 every 28 days, paclitaxel at 90 mg/m2on days 1, 8, and 15 every 28 days, or gemcitabine at 1,000 mg/m2 and carboplatin AUC = 2 mg/mL/min on days 1 and 8 every 21 days. Overall, 38% of patients had a tumor PD-L1 CPS ≥ 10.
Among the 220 patients in the pembrolizumab group vs 103 in the placebo group with a PD-L1 CPS ≥ 10, median progression-free survival on blinded independent review using Response Evaluation Criteria in Solid Tumors v1.1 was 9.7 months (95% confidence interval [CI] = 7.6–11.3 months) vs 5.6 months (95% CI = 5.3–7.5 months), with a hazard ratio of 0.65 (95% CI = 0.49–0.86, P = .0012). A confirmed objective response was observed in 53% vs 40% of patients, including a complete response in 17% vs 13%, and median duration of response was 19.3 months (95% CI = 9.9–29.8 months) vs 7.3 months (95% CI = 5.3–15.8 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. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor 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, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response.
How It Is Used
The recommended pembrolizumab dose for adults with locally recurrent unresectable or metastatic triple-negative breast cancer is 200 mg every 3 weeks or 400 mg every 6 weeks via 30-minute intravenous (IV) infusion administered prior to chemotherapy when given on the same day until disease progression, unacceptable toxicity, or up to 24 months. When given with pembrolizumab, paclitaxel protein-bound at 100 mg/m2 on days 1, 8, and 15 every 28 days, paclitaxel at 90 mg/m2 on days 1, 8, and 15 every 28 days, or gemcitabine at 1,000 mg/m2 plus carboplatin AUC = 2 mg/mL/min on days 1 and 8 every 21 days are administered via IV infusion.
No dose reductions of pembrolizumab are recommended. Treatment should be withheld or discontinued to manage adverse reactions. 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.
Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling. Product labeling provides recommended dosing modifications for immune-mediated adverse reactions.
Safety data are from the total of 596 patients receiving pembrolizumab plus chemotherapy and 281 receiving placebo plus chemotherapy in KEYNOTE-355. The median duration of exposure to pembrolizumab in the trial was 5.7 months (range = 1 day to 33 months).
The most common adverse events of any grade (incidence ≥ 20%) in patients receiving pembrolizumab plus chemotherapy in -KEYNOTE-355 were fatigue/asthenia, nausea, alopecia, diarrhea, constipation, vomiting, rash, cough, decreased appetite, and headache. The most common grade 3 or 4 adverse events included fatigue/asthenia and vomiting. The most common grade 3 or 4 laboratory abnormalities were neutropenia, leukopenia, lymphopenia, anemia, thrombocytopenia, and increased alanine aminotransferase.
Serious adverse events occurred in 30% of patients in the pembrolizumab-plus-chemotherapy group, with the most common being pneumonia, anemia, and thrombocytopenia. Adverse events led to interruption of pembrolizumab in 50% of patients. Pembrolizumab was permanently discontinued due to adverse events in 11% of patients. Fatal adverse events occurred in 2.5% of patients receiving pembrolizumab plus chemotherapy, including cardiorespiratory arrest and septic shock.
Pembrolizumab has warnings/precautions for immune-mediated adverse reactions, which may be severe or fatal and can occur in any organ system or tissue. Pembrolizumab also has warnings/precautions for infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment, and embryofetal toxicity.
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 locally recurrent unresectable or metastatic triple negative breast cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-pembrolizumab-locally-recurrent-unresectable-or-metastatic-triple. Accessed December 10, 2020.
2. Keytruda (pembrolizumab) injection for intravenous use. Merck & Co, November 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s088lbl.pdf. Accessed December 10, 2020.