Pembrolizumab Plus Chemoradiotherapy Meets PFS End Point in High-Risk Locally Advanced Cervical Cancer

The addition of pembrolizumab (Keytruda) to external beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy, improved progression-free survival (PFS) vs concurrent chemoradiotherapy alone in newly diagnosed patients with high-risk locally advanced cervical cancer, meeting one of the primary end points of the phase 3 KEYNOTE-A18 trial (ENGOT-cx11/GOG-3046; NCT04221945).¹

At the time of the prespecified interim analysis, which was conducted by an independent data monitoring committee, a favorable trend toward improved overall survival (OS) was observed with pembrolizumab plus concurrent chemoradiotherapy vs concurrent chemoradiotherapy alone; however, the data were not mature. The trial will continue, and follow-up of this end point is ongoing.

Moreover, the toxicity profile of pembrolizumab proved to be consistent with what has previously been reported with the immunotherapy. No new safety signals were observed.

“Patients with high-risk locally advanced cervical cancer often have a poor prognosis, with more than half of patients experiencing disease recurrence within 2 years. However, there have been limited new treatment advances for these patients beyond the current standard of care [SOC] in the past 20 years,” Professor Domenica Lorusso, MD, PhD, study principal investigator, lead investigator for ENGOT, and associate professor of Obstetrics and Gynecology at the Catholic University of Rome. “These results are very encouraging and support the use of pembrolizumab combined with the current SOC in locally advanced cervical cancer to help address the need for new treatment options beyond chemoradiotherapy alone.”

The randomized, double-blind, phase 3 KEYNOTE-A18 trial enrolled patients with high-risk locally advanced cervical cancer who have International Federation of Gynecology and Obstetrics (FIGO) 2014 stage IB2-IIB and lymph node–positive disease, and those with stage III-IVA with and without lymph node–positive disease.^1-3 Patients need to have histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. They could not have had prior definitive surgery, radiation, or systemic therapy, nor could they have previous immunotherapy.

Those with FIGO 2014 stage IVB disease, a history of or planned total hysterectomy, and previous systemic anticancer therapy within 4 weeks before randomization, were excluded.³

Study participants (n = 1060) were randomly assigned 1:1 to receive pembrolizumab at 200 mg on day 1 of each 3-week cycle for 5 cycles followed by pembrolizumab at 400 mg on day 1 of each 6-week cycle for an additional 15 cycles plus concurrent chemoradiotherapy, or placebo plus concurrent chemoradiotherapy.¹

Concurrent chemoradiotherapy treatment is comprised of cisplatin at 40 mg/m2 once weekly for 5 or 6 weeks plus EBRT followed by brachytherapy with minimum total radiotherapy dose of 90 Gy and 75 Gy for volume-directed and point-directed treatment, respectively. The total duration of radiation treatment could not exceed 50 days; however, if there were unforeseen delays, this could be extended to a maximum of 56 days.

PFS and OS served as the primary end points of this trial. Key secondary end points comprise complete response rate, objective response rate, and safety.¹ Investigators will also examine health-related quality of life.³

Merck shared that data from KEYNOTE-A18 will be presented at a future medical conference, and that the information will also be submitted to regulatory authorities.

References

1. Merck announces phase 3 KEYNOTE-A18 trial met primary endpoint of progression-free survival (PFS) in patients with newly diagnosed high-risk locally advanced cervical cancer. News release. Merck. July 19, 2023. Accessed July 19, 2023. https://www.merck.com/news/merck-announces-phase-3-keynote-a18-trial-met-primary-endpoint-of-progression-free-survival-pfs-in-patients-with-newly-diagnosed-high-risk-locally-advanced-cervical-cancer/
2. Study of chemoradiotherapy with or without pembrolizumab (MK-3475) for the treatment of locally advanced cervical cancer (MK-3475-A18/ENGOT-cx11/GOG-3047). ClinicalTrials.gov. Updated November 25, 2022. Accessed July 19, 2023. https://clinicaltrials.gov/study/NCT04221945
3. Lorusso D, Colombo N, Coleman RL, et al. ENGOT-cx11/KEYNOTE-A18: a phase III, randomized, double-blind study of pembrolizumab with chemoradiotherapy in patients with high-risk locally advanced cervical cancer. J Clin Oncol. 2020;38(suppl 15):TPS6096. doi:10.1200/JCO.2020.38.15_suppl.TPS6096