FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer

On July 26, 2021, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck) for high-risk, early-stage, triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

FDA also granted regular approval to pembrolizumab in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10) as determined by an FDA approved test. FDA granted accelerated approval to pembrolizumab for this indication in November 2020.

The following trial 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 (NCT03036488), a randomized, multicenter, double-blind, placebo-controlled trial conducted in 1174 patients with newly diagnosed previously untreated high-risk early-stage TNBC (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 randomized (2:1) to pembrolizumab in combination with chemotherapy or placebo in combination with chemotherapy. Details of the chemotherapy regimen are in the drug label linked below.

The main efficacy outcome measures were pathological complete response (pCR) rate and event free survival (EFS). The pCR rate was 63% (95% 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 EFS event was 123 (16%) and 93 (24%), respectively (HR 0.63; 95% CI: 0.48, 0.82; p=0.00031).

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 TNBC 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.

View full prescribing information for Keytruda.

This review used the Real-Time Oncology Review (RTOR) 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 received breakthrough therapy designation for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

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