Merck’s Keytruda Receives European Approval for Two New Indications in Gynaecologic Cancers

Overview

Merck, known as MSD outside of the United States and Canada, announced that the European Commission (EC) has approved two new indications for Keytruda (pembrolizumab), Merck’s anti-PD-1 therapy, in gynaecologic cancers. 

The Approvals

• The first approval is for Keytruda, in combination with carboplatin and paclitaxel, for the first-line treatment of primary advanced or recurrent endometrial carcinoma in adults who are candidates for systemic therapy. 
• The second approval is for Keytruda, in combination with chemoradiotherapy (CRT), for the treatment of FIGO (International Federation of Gynaecology and Obstetrics) 2014 Stage III-IVA locally advanced cervical cancer in adults who have not received prior definitive therapy. 
• With these decisions, Keytruda is now approved for 30 indications in the EU, including five in gynaecologic cancers – three in endometrial cancer and two in cervical cancer.

From the Merck Research Laboratories

• These Keytruda-based regimens have the potential to change the treatment paradigm for people with endometrial and cervical cancer, two of the most commonly diagnosed cancers among women in Europe,” said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. 
• These approvals underscore the continued expansion of the use of Keytruda in diverse patient populations and treatment settings with utility of Keytruda ranging from earlier lines of therapy to treating advanced disease.

Behind the Approval: Phase 3 NRG-GY018 trial

The EC approvals are based on results from the phase 3 NRG-GY018 trial, also known as KEYNOTE-868, and the Phase 3 KEYNOTE-A18 trial, also known as ENGOT-cx11/GOG-3047, respectively, and follow positive recommendations from the Committee for Medicinal Products for Human Use received in September 2024.

NRG-GY018/KEYNOTE-868

• In NRG-GY018/KEYNOTE-868, Keytruda in combination with carboplatin and paclitaxel, followed by Keytruda as a single agent, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to chemotherapy alone.

KEYNOTE-A18

In KEYNOTE-A18, Keytruda in combination with concurrent CRT demonstrated statistically significant and clinically meaningful improvements in overall survival (OS) and PFS compared to concurrent CRT alone for newly diagnosed patients with FIGO 2014 Stage III-IVA locally advanced cervical cancer.

Post Approvals

• These approvals allow marketing of these Keytruda regimens for these indications in all 27 EU member states, as well as Iceland, Liechtenstein, Norway and Northern Ireland. 
• Timing for commercial availability of Keytruda for these indications in individual EU countries will depend on multiple factors, including the completion of national reimbursement procedures.

Keytruda Study in 2024

• In June 2024, Keytruda in combination with carboplatin and paclitaxel, followed by Keytruda as a single agent, was approved in the US for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma based on PFS results from the NRG-GY018 trial. 
• The Keytruda regimen reduced the risk of disease progression or death by 70% (HR=0.30 [95% CI, 0.19-0.48]; p<0.0001) in patients whose cancer was mismatch repair deficient (dMMR) and by 40% (HR=0.60 [95% CI, 0.46-0.78]; p<0.0001) in patients whose cancer was mismatch repair proficient (pMMR) compared to placebo with carboplatin and paclitaxel followed by placebo alone.

Keytruda+CRT Approval 

• In January 2024, Keytruda in combination with CRT was approved in the US for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer based on PFS results from the KEYNOTE-A18 trial. 
• The Keytruda regimen reduced the risk of disease progression or death by 41% (HR=0.59 [95% CI, 0.43-0.82]) versus concurrent CRT alone for these patients.

NRG-GY018 Trial

• NRG-GY018, also known as KEYNOTE-868, is a randomized, double-blind, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT03914612 ) evaluating Keytruda in combination with standard of care chemotherapy (paclitaxel and carboplatin) versus placebo plus standard of care chemotherapy for the treatment of measurable stage III, IVA, IVB or recurrent endometrial cancer in pMMR and dMMR cohorts. 
• The primary endpoint is PFS, and secondary endpoints include overall survival, objective response rate (ORR), duration of response and safety. 
• The trial enrolled 810 patients who were randomized (1:1) to receive either:

Keytruda (200 mg intravenously [IV]) every three weeks (Q3W) plus paclitaxel (175 mg/m 2 IV) and carboplatin (Area Under Curve [AUC] 5 mg/mL/min IV) for six cycles, followed by Keytruda (400 mg IV) every six weeks (Q6W) for up to 14 cycles; Placebo IV Q3W plus paclitaxel (175 mg/m 2 IV) and carboplatin (AUC 5 mg/mL/min IV) for six cycles, followed by placebo IV Q6W for up to 14 cycles.

About KEYNOTE-A18 Trial

• KEYNOTE-A18, also known as ENGOT-cx11/GOG-3047, is a randomized, double-blind phase 3 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) investigating Keytruda in combination with CRT (cisplatin and external beam radiotherapy [EBRT] followed by brachytherapy [BT]) compared to placebo plus concurrent CRT for the treatment of newly diagnosed high-risk (stage IB2-IIB with lymph node-positive disease, and stage III-IVA with and without lymph node-positive disease) locally advanced cervical cancer where patients are treated with definitive intent. 
• 1ry endpoints: - The primary endpoints are PFS and OS, and secondary endpoints include complete response rate, ORR and safety. 
• The trial enrolled 1,060 patients with cervical cancer who had not previously received any definitive surgery, radiation, or systemic therapy for cervical cancer. 
• Patients were randomized (1:1) to receive either: Keytruda (200 mg IV) Q3W for five cycles concurrent with cisplatin (40 mg/m 2 IV) weekly for five cycles (an optional sixth infusion could be administered per local practice) and radiotherapy (EBRT followed by BT), followed by Keytruda (400 mg IV) Q6W for 15 cycles; Placebo IV Q3W for five cycles concurrent with cisplatin (40 mg/m 2 IV) weekly for five cycles (an optional sixth infusion could be administered per local practice) and radiotherapy (EBRT followed by BT), followed by placebo IV Q6W for 15 cycles.

About Endometrial Carcinoma

• Endometrial carcinoma begins in the inner lining of the uterus, which is known as the endometrium, and is the most common type of cancer in the uterus. 
• Glbally, endometrial cancer is the sixth most common cancer in women and 15th most common cancer overall. 
• Worldwide, it is estimated there were approximately 420,368 patients diagnosed with endometrial cancer and 97,723 patient deaths from the disease in 2022. 
• In Europe, it is estimated there were approximately 124,874 patients diagnosed with endometrial cancer and 30,272 patient deaths from the disease in 2022.

About Cervical Cancer

• Cervical cancer forms in the cells lining the cervix, which is the lower part of the uterus. 
• All women are at risk for cervical cancer, and it is most frequently diagnosed between the ages of 35 and 44. 
• While screenings and prevention have resulted in declining cervical cancer rates, the disease continues to affect many people in the US and around the world. 
• Cervical cancer is the fourth most common cancer in women globally. 
• Worldwide, it is estimated there were approximately 662,301 patients diagnosed with cervical cancer and 348,874 patient deaths from the disease in 2022. 
• In Europe, it is estimated there were approximately 58,219 new cases of cervical cancer diagnosed and 26,950 patient deaths from the disease in 2022.

Merck’s Work on Gynaecologic Cancers

• Merck is advancing research aimed at expanding treatment options for certain breast and gynaecologic (ovarian, cervical and endometrial) cancers, with a goal of improving outcomes for more patients affected by these diseases. 
• Breast cancer and gynaecological cancers are the first and second most commonly occurring cancer types among women worldwide, respectively, and Merck aims to give patients facing these devastating diseases options. 
• With more than 20 clinical trials in more than 18,000 patients around the world, Merck is driving innovative research to purposefully advance standards of care in women’s cancers. 
• Merck’s research efforts include trials focused on evaluating its medicines in earlier stages, as well as identifying novel mechanisms and new combinations with these treatments. 
• Merck is working to develop a portfolio and pipeline to address the impact of women’s cancers on patients, their families and communities globally.

About Keytruda

• Keytruda is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumour cells. 
• Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumour cells and healthy cells.

Merck’s Immuno-Oncology Clinical Research Program

• Merck has the industry’s largest immuno-oncology clinical research program. 
• There are currently more than 1,600 trials studying Keytruda across a wide variety of cancers and treatment settings.
• The Keytruda clinical programme seeks to understand the role of Keytruda across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with Keytruda, including exploring several different biomarkers.

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