FDA Grants Priority Review to Merck’s Sbla for Keytruda

US FDA grants priority review to Merck’s sBLA for Keytruda plus chemotherapy to treat primary advanced or recurrent endometrial carcinoma

Overview

Merck, known as MSD outside of the United States and Canada, announced the US Food and Drug Administration (FDA) has accepted for priority review a new supplemental Biologics License Application (sBLA) seeking approval for Keytruda, Merck’s anti-PD-1 therapy, in combination with standard of care chemotherapy (carboplatin and paclitaxel), followed by Keytruda as a single agent for the treatment of patients with primary advanced or recurrent endometrial carcinoma. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 21, 2024.

Trials Behind sBLA

• The sBLA is based on data from the phase 3 NRG-GY018 trial. 

• Results from the study, presented at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer and simultaneously published in the New England Journal of Medicine.

• It showed Keytruda plus chemotherapy reduced the risk of disease progression or death by 46% (HR=0.54 [95% CI, 0.41-0.71]; p<0.00001) in patients whose cancer was mismatch repair proficient (pMMR) and by 70% (HR=0.30 [95% CI, 0.19-0.48]; p<0.00001) in patients whose cancer was mismatch repair deficient (dMMR), compared to chemotherapy alone.

Words from Principal Investigetor

Endometrial cancer is the most common type of gynaecological cancer, and frontline treatment options are limited for patients with advanced stage or recurrent disease,” said Dr. Ramez Eskander, principal investigator and gynecologic oncologist, University of California San Diego, Moores Cancer Center. The use of Keytruda in this setting has the potential to address a significant unmet need for these patients.

Words from Merck

If approved, Keytruda would be the first immunotherapy indicated for the frontline treatment of advanced endometrial cancer regardless of mismatch repair status,” said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. “We are committed to working closely with the FDA to bring Keytruda to these patients who are in need of additional treatment options, and we thank our collaborators for their partnership on this study.

Research Sponspors

• This trial was sponsored by the US National Cancer Institute (NCI), part of the National Institutes of Health. 

• NRG Oncology designed and led the trial with funding from the NCI and participation from all the National Clinical Trials Network (NCTN) Groups. 

• Merck provided funding and support through a Cooperative Research and Development Agreement (CRADA) between Merck and NCI.

Project Orbis & Current Review

This review is also being conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among its international partners. Health authorities in Israel, Canada, Australia, Singapore and Brazil will review this application as part of Project Orbis.

Approved indications of Keytruda

In the US, Keytruda has two approved indications in endometrial cancer. 

• One indication, based on KEYNOTE-775/Study 309, is in combination with Lenvima (lenvatinib), in collaboration with Eisai, for the treatment of patients with advanced endometrial carcinoma that is pMMR, as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. 

• The second indication, based on KEYNOTE-158, is as a single agent, for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Merck’s Studies on Keytruda

• Merck has a comprehensive clinical development program in breast and gynaecologic (ovarian, cervical, and endometrial) cancers, comprised of more than 20 Merck-sponsored Phase 3 studies evaluating Keytruda as monotherapy and in combination with other medicines. 

• In endometrial cancer, Merck is evaluating Keytruda in the first-line setting for advanced or recurrent disease that is dMMR (KEYNOTE-C93/ENGOT-en15/GOG-3064) and in the adjuvant setting (KEYNOTE-B21/ENGOT-en11/GOG-3053).

About NRG-GY018

• NRG-GY018, also known as Merck’s KEYNOTE-868, is a randomized, blinded, placebo-controlled phase 3 trial (ClinicalTrials.gov, NCT03914612) evaluating KEYTRUDA in combination with standard of care chemotherapy (carboplatin and paclitaxel) 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 progression-free survival (PFS), and secondary endpoints include overall survival, objective response rate, duration of response and safety. 

The trial enrolled 816 patients who were randomized to receive:

1. Keytruda plus chemotherapy (carboplatin and paclitaxel) every three weeks for approximately six cycles followed by Keytruda as a single agent every six weeks for up to 14 cycles, or Placebo plus chemotherapy (carboplatin and paclitaxel) every three weeks for approximately six cycles.

2. Enrolled patients were required to have MMR IHC testing prior to randomization; 591 patients were determined to have pMMR tumours, and 225 were determined to have dMMR tumours.

Endometrial carcinoma: Epidemology

• 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. 

• In the US, it is estimated there will be approximately 67,880 new cases of uterine body cancer and approximately 13,250 deaths from the disease in 2024. 

• Globally, endometrial cancer is the sixth most common cancer in women and 15th most common cancer overall.

Merck & Cancer Research

• Merck is advancing research aimed at improving outcomes for patients affected by breast and gynaecologic (ovarian, cervical and endometrial) cancers. Merck has a comprehensive clinical development program across these cancers, comprised of more than 20 Merck-sponsored phase 3 studies evaluating Keytruda as monotherapy and in combination with other medicines. 

• In the US, Keytruda currently has two approved indications for triple-negative breast cancer and five approved indications across gynaecologic cancers (see indications below). 

• Among Merck’s research efforts are trials focused on evaluating Keytruda in earlier stages of these cancers, as well as identifying new combinations and coformulations with Keytruda. 

• Merck is also evaluating multiple investigational candidates in breast and gynaecologic cancers.

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 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.

Keytruda in Endometrial Carcinoma

• Keytruda, in combination with lenvatinib, is indicated for the treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA-approved test or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

• Keytruda, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or mismatch repair deficient (dMMR), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
About Lenvima
• Lenvima, discovered and developed by Eisai, is an orally available multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). 

• Lenvima inhibits other kinases that have been implicated in pathogenic angiogenesis, tumour growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRa), KIT, and RET. 

• In syngeneic mouse tumour models, Lenvima decreased tumour-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either.

Merck’s Goal in Oncology

• Merck’s goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. 

• At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. 

• As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumour types. 

• We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers.