The following is a message from the Director of the FDA Oncology Center of Excellence, Dr. Richard Pazdur:
On January 12, 2024, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck) with chemoradiotherapy (CRT) for patients with FIGO 2014 Stage III-IVA cervical cancer.
Full prescribing information for Keytruda will be posted here.
Efficacy was evaluated in KEYNOTE-A18 (NCT04221945), a multicenter, randomized, double-blind, placebo-controlled trial enrolling 1060 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 FIGO 2014 Stage IB2-IIB, node-positive disease.
Patients were randomized (1:1) to receive pembrolizumab 200 mg or placebo every 3 weeks for 5 cycles + CRT, followed by pembrolizumab 400 mg or placebo every 6 weeks for 15 cycles. The CRT regimen included cisplatin 40 mg/m2 IV weekly for 5 cycles (with an optional 6th 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 progression- free survival (PFS) assessed by the investigator according to RECIST v1.1, or histopathologic confirmation, and overall survival (OS). The trial demonstrated a statistically significant improvement in PFS in the overall population. 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), and 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 (≥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 IV every 3 weeks or 400 mg IV 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 concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA) and the Brazilian Health Regulatory Agency (ANVISA). 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. 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 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.
Follow the Oncology Center of Excellence on X (formerly Twitter) @FDAOncology.
