On November 13, 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab (Keytruda) in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (combined positive score [CPS] ≥ 10) as determined by an FDA-approved test.
The FDA also approved the PD-L1 IHC 22C3 pharmDx as a companion diagnostic for selecting patients with triple-negative breast cancer for pembrolizumab.
KEYNOTE-355 Results
Approval was based on the phase III KEYNOTE-355 study, a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally recurrent unresectable or metastatic triple-negative breast cancer, who had not been previously treated with chemotherapy in the metastatic setting. Patients were randomly assigned (2:1) to receive pembrolizumab 200 mg on day 1 every 3 weeks or placebo in combination with different chemotherapy treatments (paclitaxel protein-bound, paclitaxel, or gemcitabine plus carboplatin) via intravenous infusion.
The main efficacy outcome measure was progression-free survival as assessed by blinded independent review according to RECIST 1.1, tested in the subgroup of patients with CPS ≥10. Median progression-free survival was 9.7 months (95% confidence interval [CI] = 7.6–11.3) in the pembrolizumab plus chemotherapy arm and 5.6 months (95% CI = 5.3–7.5) in the placebo arm (hazard ratio [HR] = 0.65; 95% CI = 0.49–0.86; one-sided P = .0012).
Adverse Events
The most common adverse reactions (incidence ≥ 20%) in patients receiving pembrolizumab plus chemotherapy in KEYNOTE-355 were fatigue, nausea, diarrhea, constipation, vomiting, alopecia, rash, cough, decreased appetite, and headache. The most common laboratory abnormalities (incidence ≥ 20%) in patients receiving pembrolizumab plus chemotherapy were anemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia, elevated ALT and AST, hyperglycemia, hypoalbuminemia, increased alkaline phosphatase, hypocalcemia, hyponatremia, hypophosphatemia, and hypokalemia.
The recommended pembrolizumab dose for adult patients with locally recurrent unresectable or metastatic triple-negative breast cancer is 200 mg every 3 weeks or 400 mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months. When given with pembrolizumab, either paclitaxel protein-bound 100 mg/m2 on days 1, 8, and 15 every 28 days; paclitaxel 90 mg/m2 on days 1, 8, and 15 every 28 days; or gemcitabine 1,000 mg/m2 plus carboplatin AUC 2 mg/mL/min on days 1 and 8 every 21 days is administered via intravenous infusion.
