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