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The indication is for adult patients with primary advanced or recurrent endometrial carcinoma and is the third indication that pembrolizumab has received for this disease state.
The FDA has approved pembrolizumab (Keytruda; Merck) in combination with carboplatin and paclitaxel, followed by pembrolizumab as a single agent, to treat adult patients with primary advanced or recurrent endometrial carcinoma. The approval is based on data from the phase 3 NRG-GY018 trial (NCT03914612) that demonstrated the pembrolizumab combination regimen reduced the risk of disease progression or death compared with pembrolizumab alone.1
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“Endometrial cancer is now the most common gynecologic cancer in the US, 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, PhD, vice president, global clinical development, Merck Research Laboratories, in a news release.1
Pembrolizumab is an anti-programmed death receptor-1 (PD-1) therapy that increases the immune system’s ability to detect and fight tumor cells. The therapy is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands—PD-L1 and PD-L2—and activating T lymphocytes that can affect both health cells and tumor cells.1
The multicenter, randomized, double-blind, placebo-controlled phase 3 NRG-GY018 trial (NCT03914612)—also called KEYNOTE-868—evaluated pembrolizumab in combination with carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel in 810 adult patients with advanced or recurrent endometrial carcinoma. Patients were assigned into cohorts based on their mismatch repair (MMR) status, with 222 patients (27%) in the MMR deficient (dMMR) group, and the remaining 588 (73%) in the MMR proficient (pMMR) group. Treatment during the trial was divided into a combination phase and maintenance phase.1,2
Trial Name: 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
Sponsor: National Cancer Institute (NCI)
Completion Date (Estimated): May 10, 2024
Patients were randomly assigned to receive the pembrolizumab combination regimen or the placebo combination regimen. Those in the pembrolizumab group received 200 mg of pembrolizumab intravenously (IV) every 3 weeks plus 175 mg/m2 of paclitaxel and 5 mg/mL/minute of carboplatin for 6 cycles, and those in the placebo group received placebo every 3 weeks paclitaxel and carboplatin at the same doses and timelines. All medications were administered as an IV infusion on day 1 of each treatment cycle, and continued until disease progression, unacceptable toxicity, or if a maximum of 20 cycles (up to 24 months) was reached. Additionally, for the maintenance phase, patients received either 400 mg of pembrolizumab or placebo every 6 weeks for up to 14 cycles.1,2
The trial’s primary end point was progression-free survival (PFS), which was defined as the duration of time from study entry to time of progression or death and was assessed up to 5 years. Secondary end points included overall survival (OS), incidence of adverse events (AEs), duration of objective response, and quality of life, among others, all of which were assessed up to 5 years.1,2
For patients whose cancer was pMMR, the median PFS in the pembrolizumab regimen group was 11.1 months (95% CI, 8.7-13.5) compared with the placebo regimen group which was 8.5 months (95% CI, 7.2-8.8). For those whose cancer was dMMR, median PFS was not reached in the pembrolizumab regimen group (95% CI, 30.7-NR); however, it was 6.5 months in the placebo regimen group (95% CI, 6.4-8.7). Further, at the time of PFS analysis, the OS data were not mature (dMMR: 12% deaths, pMMR: 17% deaths).1
“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 as monotherapy and in combination with [Lenvatinib (Lenvima; Eisai],” said Aktan in the news release.1
According to the investigators, serious AEs occurred in approximately 35% of patients who received pembrolizumab, compared with 19% of patients receiving placebo. Additionally, fatal AEs occurred in 1.6% of patients in the pembrolizumab group, with the most common occurrences being COVID-19 (0.5%) and cardiac arrest (0.3%). Pembrolizumab was discontinued for AEs in approximately 14% of patients. Chemotherapy dose reduction was required in 29% and 23% of patients in the pembrolizumab regimen and placebo regimen groups, respectively. With the exception of rash (all grades: 33%; grades 3 and 4: 2.9%), AEs in patients treated with pembrolizumab plus chemotherapy were generally similar to those receiving pembrolizumab alone or chemotherapy alone, according to the investigators.1
“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 2 independent cohorts,” said principal investigator Ramez N. Eskander, MD, associate professor, department of Obstetrics, Gynecology, and Reproductive Services at University of California San Diego School of Medicine, and gynecologic oncologist, Moores Cancer Center at University of California San Diego Health, in the news release. “The addition of pembrolizumab to chemotherapy represents a new frontline therapeutic option for patients with primary advanced or recurrent endometrial carcinoma, demonstrating a statistically significant and clinically meaningful PFS benefit compared to chemotherapy alone, regardless of mismatch repair status.”1
