FDA Approves Pembrolizumab Plus Chemoradiotherapy in High-Risk Cervical Cancer

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Positive findings from the KEYNOTE-A18 trial support the approval of pembrolizumab, radiotherapy, and concurrent chemotherapy in patients with high-risk locally advanced cervical cancer.

Female reproductive system: ©nerthuz - stock.adobe.com

Female reproductive system: ©nerthuz - stock.adobe.com

  • Pembrolizumab (Keytruda) is now the first immunotherapy approved for the intent-to-treat (ITT) population of patients with newly diagnosed, high-risk, locally advanced cervical cancer.
  • Pembrolizumab has already been approved in 17 cancer types with 38 indications.
  • The recommended dosing regimen for pembrolizumab is 200 mg via intravenous (IV) infusion every 3 weeks or 400 mg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months.

The FDA has approved pembrolizumab plus external beam radiotherapy (EBRT) and concurrent chemotherapy as a treatment for patients with newly diagnosed, high-risk, locally advanced cervical cancer. The approval is supported by findings from the KEYNOTE-A18 trial.1

“At the first interim analysis after 237 events, we reduced the risk of recurrence or death by 30% with a hazard ratio of .70. [These are] early results because again, this is a first interim analysis, but at 2 years and with most of the patients still on treatment, we were able to reduce the risk of recurrence or death by more than 10%,” Bradley J. Monk, MD, FACS, FACOG, gynecologic oncologist with Florida Cancer Specialists & Research Institute, told Targeted OncologyTM.

Findings from the KEYNOTE-A18 trial were published in the Annals of Oncology and presented at the 2023 European Society for Medical Oncology (ESMO) Annual Congress. A total of 1060 patients were randomized to pembrolizumab and concurrent chemotherapy (n = 529) or placebo and concurrent chemoradiotherapy (n = 531). As of the data cutoff of January 9, 2023, with a median follow-up of 17.9 months (range, 0.9-31.0), the pembrolizumab arm had a 67.8% 24-month progression-free survival (PFS) vs 57.3% in the placebo arm, and median PFS was not reached in either arm (HR, 0.70; 95% CI, 0.55-0.89; P =.0020). Overall survival (OS) data was not yet mature, but there was a favorable OS trend (HR, 0.73; 95% CI, 0.49-1.07).2,3 

For safety, treatment-related adverse event (TRAE) incidence grade ≥3 was 67.0% in the pembrolizumab arm and 60.0% in the placebo arm.4

“We had preliminary evidence that it was safe, and it was. Now we have evidence that it's effective,” added Monk.

About the KEYNOTE-A18 Study

The randomized, phase 3, double-blind KEYNOTE-A18 study evaluated the efficacy and safety of pembrolizumab plus concurrent chemoradiotherapy compared with placebo plus concurrent chemoradiotherapy in patients with locally advanced cervical cancer. The primary end points were PFS and OS. The secondary end points included complete response rate, objective response rate, EORTC quality-of-life, incidence of TRAEs, and incidence of study discontinuation due to TRAEs.5

Patients in the experimental arm of the study receivepembrolizumab 200 mg intravenously (IV) on day 1 of a 3-week cycle (Q3W) for 5 cycles followed by 400 mg of pembrolizumab IV on day 1 of a 6-week cycle for another 15 cycles. During the Q3W dosing, patients receive concurrent chemoradiotherapy with cisplatin 40 mg/m2 IV once weekly for 5 or 6 weeks plus EBRT followed by brachytherapy with a minimum total radiotherapy dose of 75 or 80 Gy within 50 days.

Patients were eligible to participate if they had high-risk locally advanced cervical cancer with FIGO 2014 stage IB2-IIB with node-positive disease or FIGO 2014 stage III-IVA disease. Patients must be treatment-naïve, not be pregnant or breast feeding, have an ECOG performance status of 0 or 1, and adequate organ function within 7 days of treatment start. Patients were not eligible to participate if they have a diagnosis of immunodeficiency or are receiving chronic systemic steroid therapy, have an additional malignancy, or have an active autoimmune disease.

REFERENCES:
1. FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 Stage III-IVA cervical cancer. News release. FDA. January 12, 2024. Accessed January 12, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemoradiotherapy-figo-2014-stage-iii-iva-cervical-cancer
2. FDA grants priority review to Merck’s application for KEYTRUDA (pembrolizumab) plus concurrent chemoradiotherapy as treatment for patients with newly diagnosed high-risk locally advanced cervical cancer. News release. Merck. September 20, 2023. Accessed November 29, 2023. https://tinyurl.com/yc5m5wfn 
3. Selected indications for KEYTRUDA (pembrolizumab). Keytruda. Accessed November 29, 2023. https://tinyurl.com/76hr36ku 
4. Lorusso D, Xiang Y, Hasegawa K, et al. 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. 2023;34(S2):S1279-S1280. doi:10.1016/j.annonc.2023.10.032
5. Study of chemoradiotherapy with or without pembrolizumab (MK-3475) for the treatment of locally advanced cervical cancer (MK-3475/KEYNOTE-A18/ENGOT-cx11/GOG-3047). ClinicalTrials.gov. Updated July 20, 2023. Accessed November 29, 2023. https://clinicaltrials.gov/study/NCT04221945 
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