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FDA Approved Merck’s Keytruda Plus Chemotherapy for Advanced or Recurrent Endometrial Carcinoma

Updated: Jun 19

Merck’s immunotherapy Keytruda (pembrolizumab) has received FDA approval for use in combination with carboplatin and paclitaxel to treat adult patients with primary advanced or recurrent endometrial carcinoma. This marks the first approval of an anti-PD-1 therapy in combination with chemotherapy for this condition, regardless of the mismatch repair status of the cancer.

This is the third approval for Keytruda in treating endometrial carcinoma and the 40th overall indication for the drug in the United States. The approval is based on results from the Phase 3 NRG-GY018 trial (KEYNOTE-868), which demonstrated significant reductions in disease progression or death when KEYTRUDA was combined with carboplatin and paclitaxel, followed by KEYTRUDA alone. Specifically, the therapy reduced the risk of disease progression or death by 40% in patients with mismatch repair proficient (pMMR) cancer and by 70% in those with mismatch repair deficient (dMMR) cancer, compared to the placebo group receiving the same chemotherapy regimen.

In the study, for pMMR patients, the median progression-free survival (PFS) was 11.1 months for the Keytruda combination group versus 8.5 months for the placebo group. For dMMR patients, the median PFS was not reached in the Keytruda group compared to 6.5 months in the placebo group.

The NRG-GY018 trial was conducted by NRG Oncology with sponsorship from the U.S. National Cancer Institute (NCI). Merck supported the trial through a Cooperative Research and Development Agreement with the NCI.

Clinical Trial and Data Overview

The Phase 3 trial enrolled 810 patients with advanced or recurrent endometrial carcinoma, stratified by mismatch repair status into two cohorts: 222 patients with dMMR and 588 with pMMR. Eligible patients included those with measurable Stage III, measurable Stage IVA, Stage IVB, or recurrent endometrial cancer. Participants had not received prior systemic therapy, or if they had, it was adjuvant chemotherapy with a minimum 12-month interval since the last treatment.

Patients were randomized to receive either KEYTRUDA (200 mg every three weeks) plus paclitaxel and carboplatin for six cycles, followed by KEYTRUDA (400 mg every six weeks) for up to 14 cycles, or a placebo plus the same chemotherapy regimen, followed by a placebo for up to 14 cycles. Treatment continued until disease progression, unacceptable toxicity, or up to approximately 24 months. Tumor status was assessed every nine weeks for the first nine months, then every 12 weeks.

The primary efficacy measure was PFS, with overall survival (OS) as an additional outcome measure. The study showed significant PFS improvements in both dMMR and pMMR populations for those treated with the KEYTRUDA combination compared to the placebo combination. OS data were not mature at the time of the analysis, with 12% deaths in the dMMR group and 17% in the pMMR group.

A total of 759 patients received KEYTRUDA and chemotherapy for six cycles, followed by either KEYTRUDA or placebo for up to 14 cycles. The median duration of KEYTRUDA exposure was 5.6 months. Serious adverse reactions occurred in 35% of patients receiving the KEYTRUDA combination, compared to 19% in the placebo combination. Fatal adverse reactions included COVID-19 and cardiac arrest.

Expert Commentary and Safety Information

Dr. Ramez N. Eskander, the principal investigator and associate professor at UC San Diego School of Medicine, highlighted the significance of the trial, stating that it is the first to evaluate anti-PD-1 immunotherapy plus chemotherapy in separate cohorts of pMMR and dMMR tumors. He emphasized that the combination represents a new frontline option for these patients, showing a meaningful progression-free survival benefit compared to chemotherapy alone.

Immune-mediated adverse reactions can occur in any organ system and may be severe or fatal. Reactions can happen during or after treatment with KEYTRUDA, including conditions like pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, and others. Early identification and management are crucial. KEYTRUDA should be withheld or discontinued based on the severity of the reaction, and corticosteroids should be administered if appropriate. KEYTRUDA can also cause severe infusion-related reactions and fetal harm if administered to pregnant women. For comprehensive safety information, see the "Selected Important Safety Information" section below.


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