New Pembrolizumab Indications Approved for Triple-Negative Breast Cancer

Triple-negative breast cancer cell.

The FDA has granted approval to pembrolizumab (Keytruda®, Merck) for patients with high-risk early-stage triple-negative breast cancer (TNBC) as neoadjuvant treatment in combination with chemotherapy and as single-agent adjuvant treatment following surgery. In addition, the FDA has confirmed the November 2020 accelerated approval of pembrolizumab in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC with a programmed death ligand 1 (PD-L1) combined positive score (CPS) of ≥10.

“High-risk early TNBC is frequently associated with early recurrence and high mortality,” wrote Peter Schmid, MD, PhD, FRCP, Professor of Cancer Medicine at Queen Mary University of London’s Barts Cancer Institute, and colleagues, in their February 2020 publication of results of KEYNOTE-522 (NCT03036488), which served as the basis for the new indications and the confirmation of the accelerated approval. “Pembrolizumab, an anti–programmed death 1 (PD-1) monoclonal antibody, has been shown to have antitumor activity and a range of mainly low-grade toxic effects in patients with metastatic TNBC, especially when used as first-line treatment. Immune checkpoint inhibition may enhance endogenous anticancer immunity after increased release of tumor-specific antigens with chemotherapy.”

KEYNOTE-522, a randomized, multicenter, double-blind phase 3 trial, enrolled 1,174 patients with newly diagnosed, untreated, high-risk early-stage TNBC, which was defined as tumor size between >1 cm and ≤2 cm in diameter with nodal involvement, or as tumor size >2 cm with or without nodal involvement. Patients were randomized in a 2:1 ratio to receive neoadjuvant therapy consisting of intravenous pembrolizumab in combination with chemotherapy or placebo plus chemotherapy, which consisted of paclitaxel/carboplatin for the first four cycles and either doxorubicin or epirubicin plus cyclophosphamide for four subsequent cycles.

After completing or discontinuing their first neoadjuvant treatment, patients could begin a second regimen or undergo surgery, either breast conservation or mastectomy with sentinel lymph node evaluation or axillary dissection. In the adjuvant phase, patients received either pembrolizumab or placebo once every three weeks for a maximum of nine cycles, in combination with radiation therapy as indicated. The primary end points were pathological complete response and event-free survival in the intention-to-treat population, with secondary end points of overall survival, safety, and analyses in patients with PD-L1–positive tumors.

Pembrolizumab in combination with chemotherapy produced a pathological complete response rate of 63% compared with 56% for those receiving placebo/chemotherapy. Event-free survival events occurred in 123 patients (16%) in the pembrolizumab/chemotherapy group and in 93 patients (24%) of those in the placebo/chemotherapy group (hazard ratio 0.63).

Adverse events occurring in at least 20% of patients in trials of pembrolizumab plus chemotherapy include fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.

“In summary, the addition of pembrolizumab to platinum-containing neoadjuvant chemotherapy resulted in a significant increase in the percentage of patients who had a pathological complete response,” concluded Dr. Schmid and colleagues in their publication in the New England Journal of Medicine. “The benefit with respect to pathological complete response was observed across most prognostic risk categories, including the category of patients with low PD-L1 expression. Safety was consistent with known profiles of each regimen.”

The recommended dose of pembrolizumab as neoadjuvant treatment is 200 mg every three weeks or 400 mg every six weeks as an intravenous infusion administered over 30 minutes, in combination with chemotherapy, for 24 weeks, followed by single-agent adjuvant treatment for up to 27 weeks.

For More Information

Schmid P, Cortes J, Pusztai L, et al (2020). Pembrolizumab for early triple-negative breast cancer. N Engl J Med, 382(9):810-821. DOI:10.1056/NEJMoa1910549 (2020). Study of pembrolizumab (MK-3475) plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy and pembrolizumab vs placebo as adjuvant therapy in participants with triple-negative breast cancer (TNBC) (MK-3475-522/KEYNOTE-522). NLM identifier: NCT03036488.

Keytruda® (pembrolizumab) prescribing information (2021). Merck. Available at:

US Food & Drug Administration (2021). FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. Available at:

Image credit: Wei Qian. Courtesy of the National Cancer Institute and the University of Pittsburgh Cancer Institute

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