Keytruda (pembrolizumab) + concurrent chemoradiotherapy significantly improved progression-free survival versus concurrent chemoradiotherapy alone in newly diagnosed, high-risk locally advanced cervical cancer- Merck Inc.

Results from the trial showed that Keytruda in combination with concurrent chemoradiotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to concurrent chemoradiotherapy alone for these patients. The findings are being presented for the first time today at 10:45 a.m. ET during a late-breaking abstract proffered paper session at the European Society for Medical Oncology (ESMO) Congress 2023 (abstract #LBA38).

After a median follow-up of 17.9 months (range, 0.9-31.0), the Keytruda regimen reduced the risk of disease progression or death by 30% (HR=0.70 [95% CI, 0.55-0.89]; p=0.0020) versus concurrent chemoradiotherapy alone in these patients. Median PFS was not reached in either group. The 24-month PFS rate was 67.8% for patients who received the Keytruda regimen compared to 57.3% for those who received concurrent chemoradiotherapy alone. In addition to an improvement in PFS, a favorable trend in overall survival (OS), the trial’s other primary endpoint, was observed for the Keytruda regimen versus concurrent chemoradiotherapy alone (HR=0.73 [95% CI, 0.49-1.07]); with only 103 events across both groups, these OS data are not mature and did not reach statistical significance at the time of this interim analysis. The trial is continuing, and follow-up of OS is ongoing. The safety profile of Keytruda in this trial was consistent with that observed in previously reported studies; no new safety signals were identified.

“Cervical cancer is the fourth most common cancer in women worldwide; however, over the past two decades, new treatment advances have been limited for patients diagnosed with locally advanced disease,” said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. “These positive results from the KEYNOTE-A18 trial demonstrate the potential of Keytruda in combination with concurrent chemoradiotherapy as a new treatment option for patients with high-risk cervical cancer, building on the established role of Keytruda for certain patients with advanced cervical cancer and our research efforts in earlier stages of disease.”

"This is the first phase III study in which an immunotherapy has demonstrated an improvement in progression-free survival in this patient population compared to standard of care,” said professor Domenica Lorusso, the study’s overall principal investigator, lead investigator for ENGOT and associate professor of Obstetrics and Gynecology at the Catholic University of Rome. “The results of this trial, finding the Keytruda regimen reduced the risk of disease progression or death by 30% compared to concurrent chemoradiotherapy alone, are compelling, especially considering newly diagnosed patients with high-risk locally advanced cervical cancer have not seen an advance in treatment options in 20 years.”

“Patients diagnosed with locally advanced cervical cancer face a poor prognosis and limited treatment options,” said Dr. Bradley Monk, oncologist and professor of obstetrics and gynecology at University of Arizona’s College of Medicine and Creighton University School of Medicine. “These results demonstrate that by moving an immunotherapy regimen to earlier stages of cervical cancer, we have the potential to improve outcomes for these patients compared to the current standard of care.”

Merck previously announced that based on these positive results, the FDA has granted priority review for a supplemental Biologics License Application (sBLA) for Keytruda in combination with concurrent chemoradiotherapy for the treatment of newly diagnosed patients with high-risk locally advanced cervical cancer. The FDA has set a Prescription Drug User Fee Act, or target action, date of January 20, 2024. The results are also being discussed with regulatory authorities worldwide.

In the U.S., Keytruda has two approved indications in cervical cancer: in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (Combined Positive Score [CPS] greater than 1) as determined by an FDA-approved test; and as a single agent, for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS greater than 1) as determined by an FDA-approved test. As announced, data spanning more than 15 types of cancer are being presented from Merck’s broad oncology portfolio and investigational pipeline at the ESMO Congress 2023.

Study design and additional data from KEYNOTE-A18/ENGOT-cx11/GOG-3047: KEYNOTE-A18, also known as ENGOT-cx11/GOG-3047, is a randomized, double-blind Phase III trial (ClinicalTrials.gov, NCT04221945) sponsored by Merck and conducted in collaboration with the European Network for Gynaecological Oncology Trial (ENGOT) groups and the GOG Foundation, Inc. (GOG) evaluating Keytruda in combination with EBRT plus concurrent chemotherapy (cisplatin), followed by brachytherapy (also known as concurrent chemoradiotherapy) compared to placebo plus concurrent chemoradiotherapy for the treatment of newly diagnosed high-risk (stage 1B2-2B with lymph node-positive disease, and stage 3-4A with and without lymph node-positive disease) locally advanced cervical cancer where patients are treated with definitive intent. The primary endpoints are PFS and OS, and secondary endpoints include complete response rate, objective response rate and safety.

The trial enrolled 1,060 patients who were randomized to receive :Keytruda (200 mg intravenously [IV]) on Day 1 of each three-week cycle (Q3W) for five cycles followed by Keytruda (400 mg by IV) on Day 1 of each six-week cycle (Q6W) for an additional 15 cycles plus concurrent chemoradiotherapy (cisplatin 40 mg/m2 by IV once per week [QW] for five or six weeks plus EBRT followed by brachytherapy with minimum total radiotherapy dose of 80 Gray Units [Gy] for volume-directed and 75 Gy for point-directed given with the total duration of radiation treatment not to exceed 50 days [with an extension to a maximum of 56 days for unforeseen delays]); or Placebo plus concurrent chemoradiotherapy (cisplatin 40 mg/m2 by IV QW for five or six weeks plus EBRT followed by brachytherapy with minimum total radiotherapy dose of 80 Gy for volume-directed and 75 Gy for point-directed given with the total duration of radiation treatment not to exceed 50 days [with an extension to a maximum of 56 days for unforeseen delays]).

The safety profile of Keytruda was consistent with that observed in previously reported studies. Treatment-related adverse events (TRAEs) occurred in 96% of patients receiving the Keytruda regimen and 96% of patients receiving the placebo regimen; Grade 3-5 TRAEs occurred in 67.0% versus 60.6%, respectively. Treatment-related adverse events led to discontinuation of all study treatment in 0% of patients treated with the Keytruda regimen and 0.2% treated with the placebo regimen. Additionally, TRAEs led to death in two (0.4%) patients receiving the Keytruda regimen and two (0.4%) patients receiving the placebo regimen. No new safety concerns were identified.

Immune-mediated adverse events (AEs) of any grade occurred in 32.6% of patients receiving the Keytruda regimen and 11.7% of patients receiving the placebo regimen. Grade 3-5 immune-mediated AEs occurred in 4.2% versus 1.1%, respectively. The most common of these all-grade immune-mediated AEs (occurring in more than two patients) was hypothyroidism (19.3%) in patients receiving the Keytruda regimen. Immune-mediated AEs did not lead to death in either arm.