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Pembrolizumab Plus Chemoradiotherapy Approved for FIGO 2014 Stage III-IVA Cervical Cancer

Cervical cancer.

The FDA has granted approval for pembrolizumab (Keytruda®, Merck) with chemoradiotherapy (CRT) for patients with International Federation of Gynecology and Obstetrics (FIGO) 2014 Stage III-IVA cervical cancer.

For background: "Pembrolizumab has shown efficacy in patients with cervical cancer," said Domenica Lorusso, MD, PhD, an Associate Professor of Obstetrics and Gynecology at the Catholic University of Rome, and colleagues, in their updated results of the KEYNOTE-A18 trial (NCT04221945), on which approval was based. "The effect of chemoradiotherapy may be enhanced by immunotherapy."

What they studied: Efficacy of pembrolizumab plus CRT was studied in the phase 3, double-blind, placebo-controlled trial which enrolled 1,060 patients with cervical cancer—596 patients with FIGO 2014 Stage III-IVA disease and 462 patients with FIGO 2014 Stage IB2-IIB node-positive disease—who had not previously received definitive surgery, radiation, or systemic therapy. Patients were randomized 1:1 to receive either 200 mg of pembrolizumab plus CRT or placebo plus CRT every three weeks for five cycles, followed by 400 mg of pembrolizumab or placebo every six weeks for 15 cycles. CRT consisted of 40 mg/m2 of cisplatin intravenously (IV) weekly for five cycles, including an optional sixth cycle, and external beam radiation therapy (EBRT) followed by brachytherapy. Randomization was stratified by planned type of EBRT, disease stage, and planned total dose of radiotherapy.

The primary end points measured were progression-free survival, according to RECIST v1.1 or histopathologic confirmation, and overall survival.

What they found: In the overall population, progression-free survival saw a statistically significant improvement in those receiving pembrolizumab plus CRT compared with those receiving placebo. In the subgroup of 596 patients with FIGO 2014 Stage III-IVA disease, an exploratory analysis revealed a progression-free survival hazard ratio estimate of 0.59; in addition, 21% of patients receiving pembrolizumab experienced a progression event compared with 31% of patients receiving placebo. In the subgroup of 462 patients with FIGO 2014 Stage IB2-IIB disease, the exploratory analysis revealed a progression-free survival hazard ratio estimate of 0.91, suggesting that the progression-free survival improvement in the overall population was attributed primarily to patients with FIGO 2014 Stage III-IVA disease. Overall survival data was not mature at the time of the progression-free survival analysis.

Adverse events: The most common adverse reactions in ≥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.

Conclusion: "Pembrolizumab plus CRT showed a statistically significant and clinically meaningful improvement in progression-free survival and a favorable trend in overall survival compared with placebo plus CRT in patients with high-risk locally advanced cervical cancer and had a manageable safety profile," concluded Dr. Lorusso and colleagues, "These data suggest pembrolizumab plus CRT can be considered as a new standard of care for this population."

Instructions: The recommended dosage of pembrolizumab is 200 mg IV every three weeks or 400 mg IV every six weeks for up to 24 months, or until disease progression, unacceptable toxicity, or up to 24 months. Pembrolizumab should be administered before chemoradiotherapy when given on the same day.

For More Information

Lorusso D, Xiang Y, Hasegawa K, et al (2023). Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: A randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. Ann Oncol, 34(suppl_2):1279-1280. DOI:10.1016/j.annonc.2023.10.032

Clinicaltrials.gov (2023). Study of chemoradiotherapy with or without pembrolizumab (MK-3475) for the treatment of locally advanced cervical cancer (MK-3475-A18/KEYNOTE-A18/ENGOT-cx11/GOG-3047). NLM identifier: NCT04221945.

Ketruda® (pembrolizumab) prescribing information (2024). Merck. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf

US Food and Drug Administration (2024). FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 Stage III-IVA cervical cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemoradiotherapy-figo-2014-stage-iii-iva-cervical-cancer 

Image credit: Haymanj. Licensed under public domain.


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