Efficacy was evaluated in KEYNOTE-A18 (NCT04221945), a multicenter, randomized, double-blind, placebo-controlled trial in 1,060 patients with cervical cancer who had not previously received definitive surgery, radiation, or systemic therapy. The trial included 596 patients with FIGO 2014 stage III–IVA disease and 462 patients with node-positive FIGO 2014 stage IB2–IIB disease.
Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo every three weeks for 5 cycles plus CRT followed by pembrolizumab 400 mg or placebo every six weeks for 15 cycles. The CRT regimen included IV cisplatin 40 mg/m2 weekly for five cycles (with an optional sixth cycle) and external beam radiation therapy (EBRT) followed by brachytherapy. Randomization was stratified by planned type of EBRT, stage, and planned total radiotherapy dose.
The major efficacy outcome measures were investigator-assessed progression-free survival (PFS) according to RECIST v1.1 or histopathologic confirmation and overall survival (OS). The overall trial population demonstrated a statistically significant improvement in PFS. In an exploratory subgroup analysis in the 596 patients with FIGO 2014 stage III–IVA disease, the PFS hazard ratio (HR) estimate was 0.59 (95% CI = 0.43, 0.82); 21% of patients in the pembrolizumab arm experienced a PFS event compared to 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 PFS HR estimate was 0.91 (95% CI: 0.63, 1.31), indicating that the PFS improvement in the overall population was primarily attributed to patients with FIGO 2014 Stage III-IVA disease. OS data were not mature at the time of PFS analysis.
The most common adverse reactions occurring in at least 10% of 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 IV every three weeks or 400 mg IV every six weeks for up to 24 months or until patients experience disease progression or unacceptable toxicity. Pembrolizumab should be administered before chemoradiotherapy when given on the same day.
The review was conducted under Project Orbis, an FDA Oncology Center of Excellence (OCE) initiative. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. FDA collaborated with the Australian Therapeutic Goods Administration and the Brazilian Health Regulatory Agency for the review. The application reviews are ongoing at the other regulatory agencies.
The applicant used the Assessment Aid to facilitate FDA’s review, and the application was granted priority review. FDA-expedited programs are described 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 800-FDA-1088.
For assistance with single-patient applications for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.