FDA Approves Pembrolizumab in Combination for High-Risk, Early-Stage Triple-Negative Breast Cancer

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On July 26, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) for high-risk, early-stage triple-negative breast cancer in combination with chemotherapy as a neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

The FDA also granted regular approval to pembrolizumab in combination with chemotherapy for 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 granted accelerated approval to pembrolizumab for this indication in November 2020.

The KEYNOTE-522 trial ( identifier: NCT03036488) was the basis of the neoadjuvant and adjuvant approval, as well as the confirmatory trial for the accelerated approval.


The efficacy of pembrolizumab in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with pembrolizumab as a single agent was investigated in KEYNOTE-522, a randomized, multicenter, double-blind, placebo-controlled trial conducted in 1,174 patients with newly diagnosed, previously untreated, high-risk, early-stage triple-negative breast cancer (tumor size > 1 cm but ≤ 2 cm in diameter with nodal involvement, or tumor size > 2 cm in diameter regardless of nodal involvement). Patients were enrolled regardless of tumor PD-L1 expression.

Patients were randomly assigned 2:1 to receive pembrolizumab in combination with chemotherapy or placebo in combination with chemotherapy.

The main efficacy outcome measures were the pathologic complete response rate and event-free survival. The pathologic complete response rate was 63% (95% confidence interval [CI] = 59.5%–66.4%) for patients who received pembrolizumab in combination with chemotherapy compared with 56% (95% CI = 50.6%–60.6%) for patients who received chemotherapy alone. The number of patients who experienced an event-free survival was 123 (16%) and 93 (24%), respectively (hazard ratio = 0.63, 95% CI = 0.48–0.82, P = .00031).

The most common adverse reactions reported in ≥ 20% of patients in trials of pembrolizumab in combination with chemotherapy were 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.

The recommended dosage of pembrolizumab for triple-negative breast cancer is 200 mg every 3 weeks or 400 mg every 6 weeks as an intravenous infusion over 30 minutes. Pembrolizumab is administered in combination with chemotherapy for neoadjuvant treatment for 24 weeks, and then as a single agent for adjuvant treatment for up to 27 weeks.

This review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 5 months ahead of the FDA goal date.

This application was granted Priority Review; pembrolizumab also received Breakthrough Therapy designation for this indication.