On January 12, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) with chemoradiotherapy for patients with International Federation of Gynecology and Obstetrics (FIGO) 2014 stage III–IVA cervical cancer.
KEYNOTE-A18
Efficacy was evaluated in KEYNOTE-A18 (ClinicalTrials.gov identifier NCT04221945), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1,060 patients with cervical cancer who had not previously received definitive surgery, radiation therapy, or systemic therapy. The trial included 596 patients with FIGO 2014 stage III–IVA disease and 462 patients with FIGO 2014 stage IB2–IIB, node-positive disease.
Patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg or placebo every 3 weeks for 5 cycles plus chemoradiotherapy, followed by pembrolizumab at 400 mg or placebo every 6 weeks for 15 cycles. The chemoradiotherapy regimen included intravenous cisplatin at 40 mg/m2 weekly for five cycles (with an optional sixth cycle) and external-beam radiation therapy (EBRT) followed by brachytherapy. Random assignment was stratified by planned type of EBRT, stage, and planned total radiotherapy dose.
The major efficacy outcome measures were progression-free survival assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or histopathologic confirmation and overall survival. The trial demonstrated a statistically significant improvement in progression-free survival in the overall population. In an exploratory subgroup analysis in the 596 patients with FIGO 2014 stage III–IVA disease, the progression-free survival hazard ratio (HR) estimate was 0.59 (95% confidence interval [CI] = 0.43–0.82). A total of 21% of patients in the pembrolizumab arm experienced a progression-free survival event compared with 31% of patients in the placebo arm. In contrast, in an exploratory subgroup analysis in the 462 patients with FIGO 2014 stage IB2–IIB disease, the progression-free survival hazard ratio estimate was 0.91 (95% CI = 0.63–1.31), indicating the progression-free survival improvement in the overall population was primarily attributed to patients with FIGO 2014 stage III–IVA disease. Overall survival data were not mature at the time of progression-free survival analysis.
The most common adverse reactions (≥ 10%) occurring in patients who received pembrolizumab with chemoradiotherapy were nausea, diarrhea, vomiting, urinary tract infection, fatigue, hypothyroidism, constipation, decreased appetite, weight loss, abdominal pain, pyrexia, hyperthyroidism, dysuria, rash, and pelvic pain.
The recommended dosing regimen for pembrolizumab is 200 mg intravenously every 3 weeks or 400 mg intravenously every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months. Pembrolizumab should be administered before chemoradiotherapy when given on the same day.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for the concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration and the Brazilian Health Regulatory Agency. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review designation.
