Pembrolizumab and Chemotherapy – Biomarker-Independent FDA Approval in Uterine Cancer

On June 17, 2024, the United States Food and Drug Administration (FDA) approved treatment for adults with advanced or recurrent endometrial cancer using pembrolizumab (Keytruda, Merck) plus chemotherapy followed by pembrolizumab as a single agent.

This approval had previously applied only to a molecular subtype accounting for approximately 30% of endometrial cancers: dMMR disease .

Biomarker-independent FDA approval means that treatment can be used for all patients regardless of the presence of a specific biomarker, such as dMMR. In this case, pembrolizumab plus chemotherapy has been approved for all patients with advanced or recurrent endometrial cancer, and treatment is no longer limited to those with the dMMR molecular subtype.

The Trial Leading to FDA Approval: KEYNOTE-868/NRG-GY018

Pembrolizumab's effectiveness was evaluated in KEYNOTE-868/NRG-GY018, a multicenter, randomized, double-blind, placebo-controlled clinical trial. It included 810 patients with advanced or recurrent endometrial carcinoma in two separate patient groups:

• The dMMR (mismatch repair-deficient) cohort and
• The pMMR (mismatch repair-proficient) cohort.

Patients were randomized in a 1:1 ratio to one of the treatment arms:

1. Pembrolizumab Arm: Every 3 weeks, 200 mg pembrolizumab, 175 mg/m² paclitaxel, and carboplatin at AUC 5 mg/mL/min for 6 chemotherapy cycles, followed by 400 mg pembrolizumab every 6 weeks for up to 14 cycles.
2. Placebo Arm: Every 3 weeks, placebo, 175 mg/m² paclitaxel, and carboplatin at AUC 5 mg/mL/min for 6 chemotherapy cycles, followed by placebo every 6 weeks for up to 14 cycles.

Randomization was stratified by MMR status, ECOG performance status (0 or 1 versus 2), and prior adjuvant chemotherapy.

Efficacy Results

The main efficacy measure, assessed by investigators according to RECIST 1.1 criteria, was progression-free survival (PFS) .

• dMMR Cohort: In the pembrolizumab plus chemotherapy arm, median PFS was not reached (NR) (95% CI: 30.7, NR), compared with 6.5 months in the placebo plus chemotherapy arm (95% CI: 6.4, 8.7) (HR 0.30 [95% CI: 0.19, 0.48]; p-value <0.0001).
• pMMR Cohort: Median PFS in the pembrolizumab plus chemotherapy arm was 11.1 months (95% CI: 8.7, 13.5), compared with 8.5 months in the placebo plus chemotherapy arm (95% CI: 7.2, 8.8) (HR 0.60 [95% CI: 0.46, 0.78; p-value <0.0001]).

Side Effects

Adverse reactions associated with pembrolizumab plus chemotherapy were generally similar to those previously reported for pembrolizumab or chemotherapy. However, an increased incidence of rash was observed.

Recommended Pembrolizumab Dosage

• For Patients Weighing ≥ 30 kg: 200 mg pembrolizumab every 3 weeks or 400 mg every 6 weeks.
• Treatment Duration: Until disease progression, unacceptable toxicity, or up to 24 months of treatment.

This new treatment option represents an important advance for patients with advanced or recurrent endometrial cancer, with the potential to improve both survival and quality of life.