The U.S. Food & Drug Administration has approved use of a new treatment option for patients with advanced or recurring uterine cancer. The approval follows the completion of the first Phase 3 trial which was designed to to statistically evaluate the anti-PD1 immunotherapy, pembrolizumab (Keytruda®, Merck & Co/MSD) with carboplatin and paclitaxel, followed by single-agent pembrolizumab, for adult patients with primary advanced or recurrent endometrial (uterine) carcinoma.
“Endometrial cancer is now the most common gynecologic cancer in the U.S., and deaths from the disease are projected to surpass deaths from ovarian cancer in 2024, underscoring the need for treatment advances for more patients,” said Gursel Aktan, MD, Ph.D, vice president, global clinical development, Merck Research Laboratories.
“This approval represents the first and only anti-PD-1-based option for adult patients with primary advanced or recurrent endometrial carcinoma regardless of mismatch repair status, building on the established role of pembrolizumab in certain types of advanced endometrial carcinoma,” Aktan added.
Advanced or recurring uterine cancer
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.
According to data from the American Cancer Society, [2] uterine cancers, when caught early, are very treatable. Endometrial cancer is the most common form of uterine cancer, and statistics from the National Cancer Institute (NCI), [3] show that approximately 3 in 100 women will be diagnosed with uterine cancer at some point in their lives.
In the United States, in real numbers this translates to an approximately 67,880 new cases of cancer of the uterus and approximately 13,250 deaths from the disease in 2024.
However, the available data also shows that nearly 85% of patients diagnosed with uterine cancer are, due to newer, highly effective treatments, expected to live at least 5 years after their initial diagnosis.
Cause
Although the exact cause of endometrial (uterine) cancer is, in most cases, unknown, experts believe that changes in the level of estrogen and progesterone in the body plays an important part. When the levels of those hormones fluctuate, it affects your endometrium and when the balance between those two hormones shifts towards an increased level of estrogen, it causes endometrial cells to divide and multiply. When uncontrolled, this may result in cancer.
Clinical study
Efficacy of the new treatment option for women diagnosed with primary advanced or recurrent endometrial carcinoma was evaluated in KEYNOTE-868/NRG-GY018 (NCT03914612), a multicenter, randomized, double-blind, placebo-controlled trial enrolling 810 patients with advanced or recurrent endometrial (uterine) carcinoma. The trial included two separate cohorts based on mismatch repair (MMR) status: 222 patients in the mismatch repair deficient (dMMR) cohort, and 588 patients in the mismatch repair (pMMR) proficient cohort. Patients were randomized (1:1) to one of the following treatment arms:
- Pembrolizumab 200 mg every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by pembrolizumab 400 mg every 6 weeks for up to 14 cycles.
- Placebo every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by placebo every 6 weeks for up to 14 cycles.
In this study, randomization was stratified according to MMR status, ECOG performance status (0 or 1 vs. 2), and prior adjuvant chemotherapy.
Study outcome
The major efficacy outcome measure was progression-free survival (PFS), assessed by the investigator according to RECIST 1.1. In the dMMR cohort, median PFS was not reached (NR) (95% CI: 30.7, NR) in the pembrolizumab and chemotherapy arm and 6.5 months (95% CI: 6.4, 8.7) in the placebo and chemotherapy arm (Hazard ratio [HR] 0.30 [95% CI: 0.19, 0.48]; p-value <0.0001). In the pMMR cohort, median PFS was 11.1 months (95% CI: 8.7, 13.5) in the pembrolizumab and chemotherapy arm and 8.5 months (95% CI: 7.2, 8.8) for those receiving placebo and chemotherapy arm (HR 0.60 [95% CI: 0.46, 0.78; p-value <0.0001).
Adverse reactions associated with pembrolizumab and chemotherapy were generally similar to those previously reported for pembrolizumab or chemotherapy with the exception of a higher incidence of rash. See the prescribing information for complete adverse reactions.
Eskander, Ramez, MDRecommended dose
Based on the outcomes of the study, the recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.
According to Ramez N. Eskander, MD, principal investigator, associate professor in the Department of Obstetrics, Gynecology, and Reproductive Services at University of California San Diego School of Medicine and gynecologic oncologist at Moores Cancer Center at University of California San Diego Health, “the addition of pembrolizumab to chemotherapy represents a new frontline therapeutic option for patients with primary advanced or recurrent endometrial carcinoma.”
“This is the first Phase 3 trial to statistically evaluate an anti-PD-1 immunotherapy plus chemotherapy combination in patients with pMMR and dMMR tumors as two independent cohorts,” Eskander noted.
These outcomes demonstrate a statistically significant and clinically meaningful progression-free survival benefit compared to chemotherapy alone, regardless of mismatch repair status,” he concluded.
Clinical trial
Testing the Addition of the Immunotherapy Drug Pembrolizumab to the Usual Chemotherapy Treatment (Paclitaxel and Carboplatin) in Stage III-IV or Recurrent Endometrial Cancer – ClinicalTrials.gov ID NCT03914612
Highlights of prescribing information
Pembrolizumab (Keytruda®, Merck & Co/MSD) [Prescribing Information]
Reference
[1] Endometrial Cancer, American Cancer Society (ACS), Online. Last accessed on July 3, 2024
[2] Cancer Stat Facts: Uterine Cancer. National Cancer institute (NCI). Online. Last accesses on July 3, 2024.
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