FDA Grants Priority Review to Pembrolizumab Plus Chemoradiotherapy for High-Risk Locally Advanced Cervical Cancer

FDA

The FDA has granted priority review to a supplemental biologics license application (sBLA) seeking the approval of pembrolizumab (Keytruda) in combination with external beam radiotherapy (EBRT) plus concurrent chemotherapy, followed by brachytherapy, for the treatment of newly diagnosed patients with high-risk, locally advanced cervical cancer.¹

The sBLA is supported by data from the phase 3 KEYNOTE-A18 trial (NCT04221945), which demonstrated that treatment with pembrolizumab plus concurrent chemoradiotherapy led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with concurrent chemoradiotherapy alone.²

Additionally, findings showed that pembrolizumab plus concurrent chemoradiotherapy was associated with a favorable trend toward improved overall survival (OS); however, data were not mature. Regarding safety, data for pembrolizumab were consistent with its known toxicity profile, and no new safety signals were observed. Full data from KEYNOTE-A18 will be presented at an upcoming medical meeting.

“The standard of care for patients with locally advanced cervical cancer has not changed in more than two decades, and the majority of patients will experience recurrence or progression of their disease,” Gursel Aktan, MD, vice president of global clinical development at Merck Research Laboratories, stated in a news release.¹ “If approved, [pembrolizumab] will be the first immunotherapy available for patients with newly diagnosed high-risk locally advanced cervical cancer. We are committed to working closely with the FDA to bring [pembrolizumab] to these patients who are in need of additional treatment options.”

KEYNOTE-A18 was a randomized, double-blind, phase 3 trial that enrolled patients with high-risk locally advanced cervical cancer who have International Federation of Gynecology and Obstetrics (FIGO) 2014 stage IB2 to IIB and lymph node–positive disease or FIGO stage III to IVA disease.³ Patients need to have histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix.

Prior definitive surgery, radiation, systemic therapy, or immunotherapy were not permitted. Other key exclusion criteria included FIGO 2014 stage IVB disease, a history of or planned total hysterectomy, and previous systemic anticancer therapy within 4 weeks before randomization.

The study enrolled 1060 patients who were randomly assigned 1:1 to receive 200 mg of pembrolizumab on day 1 of each 3-week cycle for 5 cycles, followed by 400 mg of pembrolizumab on day 1 of each 6-week cycle for an additional 15 cycles, plus concurrent chemoradiotherapy, or placebo plus concurrent chemoradiotherapy.¹ Concurrent chemoradiotherapy was comprised of 40 mg/m2 of cisplatin once weekly for 5 or 6 weeks plus EBRT followed by brachytherapy with a minimum total radiotherapy dose of 80 Gy for volume-directed therapy and 75 Gy for point-directed therapy. The total duration of radiation treatment could not exceed 50 days, although it could be extended to a maximum of 56 days in the event of unexpected delays.

The primary end points were PFS and OS. Key secondary end points included complete response rate, objective response rate, and safety.¹

References

1. 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 September 20, 2023. https://www.merck.com/news/fda-grants-priority-review-to-mercks-application-for-keytruda-pembrolizumab-plus-concurrent-chemoradiotherapy-as-treatment-for-patients-with-newly-diagnosed-high-risk-locally-advanced/
2. 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 September 20, 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/
3. 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 July 20, 2023. Accessed September 20, 2023. https://clinicaltrials.gov/study/NCT04221945