A supplemental biologics license application seeking the approval of pembrolizumab, external beam radiotherapy, and concurrent chemotherapy, followed by brachytherapy has been accepted for priority review by the FDA for advanced cervical cancer.
The FDA has accepted for priority review a new sBLA seeking the approval of pembrolizumab (Keytruda) in combination with external beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy as treatment for patients with newly diagnosed high-risk locally advanced cervical cancer.1
Data from the KEYNOTE-A18 trial (ENGOT-cx11/GOG-3047) showed that there was a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with pembrolizumab combined with concurrent chemoradiotherapy vs concurrent chemoradiotherapy alone.
The FDA has set a PDUFA, or target action, date of January 20, 2024.
“The standard of care for patients with locally advanced cervical cancer has not changed in more than 2 decades, and the majority of patients will experience recurrence or progression of their disease,” said Gursel Aktan, MD, vice president, global clinical development, Merck Research Laboratories, in a press release. “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.”
In the randomized, double-blind, phase 3 trial KEYNOTE-A18 trial, investigators are evaluating pembrolizumab in combination with EBRT plus concurrent chemotherapy consisting of cisplatin, followed by brachytherapy vs placebo plus concurrent chemoradiotherapy for the treatment of newly diagnosed high-risk locally advanced cervical cancer where patients are treated with definitive intent.
These patients are considered those with newly diagnosed high-risk cervical cancer if their disease is stage 1B2-2B with lymph node-positive disease, and stage 3-4A with and without lymph node-positive disease per FIGO 2014.
A total of 1,060 patients were enrolled and randomized. In the first arm, patients were treated with pembrolizumab 200 mg given via intravenous (IV) infusion on day 1 of each 3-week cycle for 5 cycles followed by pembrolizumab 400 mg IV on day 1 of each 6-week cycle for another 15 cycles combined with concurrent chemoradiotherapy made up of cisplatin 40 mg/m2 by IV once per week for 5-6 weeks with EBRT. This is followed by brachytherapy with minimum total radiotherapy dose of 80 Gy for volume-directed and 75 Gy if point-directed, given with the total duration of radiation treatment not to exceed 50 days. In the other arm, patients were treated with placebo instead of pembrolizumab plus concurrent chemoradiotherapy using the same regimen and dosing schedule.
Patients with newly diagnosed, high-risk, locally advanced cervical cancer who had histologically confirmed disease, an ECOG performance status of 0 or 1, tissue sample available for biopsy, radiographic evaluable disease per RECIST v1.1, and adequate organ function 7 days before starting study treatment were eligible for enrollment.2
In addition to the primary end point of PFS, investigators are also assessing overall survival. Secondary efficacy end points of the study include PFS by blinded independent central review (BICR), investigator-assessed PFS at 24 months, BICR-assessed PFS at 24 months, OS at month 36, complete response rate at week 12 by investigator assessment, CR rate at week 12 by BICR, investigator-assessed objective response rate (ORR), BICR-assessed ORR, investigator-assessed PFS in the PD-L1-positive population, BICR-assessed PFS in the PD-L1-positive population, investigator-assessed OS in the PD-L1-positive group, and OS by BICR in the PD-L1-positive.
For secondary safety end points, change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status Score, change from baseline in EORTC QLQ Symptom Specific Scale for Cervical Cancer, the number of patients with adverse events (AEs), and the number of patients who discontinue study treatment because of AEs are being evaluated.
Pembrolizumab, an anti-PD-1 therapy, currently has 2 approved indications in cervical cancer, including its use in combination with chemotherapy, with or without bevacizumab (Avastin) for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (combined positive score [CPS] ≥1), and used as a single agent for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1).1
If this combination of pembrolizumab with EBRT, and concurrent chemotherapy, followed by brachytherapy is approved, this would be the third approval for Merck for the treatment of patients with cervical cancer, as well as the first approved agent for patients with an earlier stage of the disease.