Palbociclib Plus Letrozole May Increase PFS for ER+ Endometrial Cancer

Patients who received palbociclib plus letrozole experienced a median PFS of 8.3 months (95% CI, 4.6-11.2), compared to 3.1 months (95% CI, 2.7-6.8) for patients given placebo plus letrozole.

Palbociclib (Ibrance) in combination with letrozole (Femara) yielded greater progression-free survival (PFS) vs placebo plus letrozole in advanced or recurrent, estrogen receptor (ER)-positive endometrial cancer, as shown in data from the phase 2 ENGOT-EN3/PALEO trial (NCT02730429).

Findings published in Gynecologic Oncology showed that at a median follow-up of 21.9 months (95% CI, 16.7-22.3), the median PFS was 8.3 months (95% CI, 4.6-11.2) in patients treated with palbociclib plus letrozole (n = 36) vs 3.1 months (95% CI, 2.7-6.8) for those given placebo plus letrozole (n = 37; HR, 0.57; 95% CI, 0.32-0.99; P =.44).

“Compared with placebo/letrozole, the palbociclib/letrozole combination demonstrated a statistically significant…and clinically meaningful PFS improvement, meeting the primary objective and demonstrating preliminary evidence of activity,” lead study author Mansoor R. Mirza, MD, chief oncologist in the Department of Oncology at Rigshopitalet, the Copenhagen University Hospital, in Denmark, and coauthors wrote in the publication. “Notably, the treatment effect in patients at second-or-later relapse appeared similar to that in patients at first relapse.”

ENGOT-EN3/PALEO Background and Design

The randomized, multicenter, double-blind, placebo-controlled study evaluated palbociclib/letrozole vs placebo/letrozole in patients who had endometrioid endometrial cancer that was ER-positive (≥10% expression by immunohistochemistry). Patients needed to have primary stage IV disease or disease progression following at least 1 prior systemic therapy, and measurable or evaluable disease per RECIST 1.1 criteria was also required. Prior endocrine therapies were prohibited except for. medroxyprogesterone (MPA) or megestrol acetate. An ECOG performance status of 0 or 1 was needed for enrollment.

Patients were randomly assigned 1:1 to the palbociclib/letrozole and placebo/letrozole arms. All patients were treated with oral letrozole at 2.5 mg on days 1 to 28 with either palbociclib at 125 mg per day or placebo on days 1 to 21 in 28-day cycles until disease progression, unacceptable toxicity, deterioration to ECOG performance status of 3 or greater, or consent withdrawal.

Patients were stratified based on the number of prior lines of chemotherapy (0 vs 1 vs ≥2), disease measurability status (measurable vs evaluable non-measurable), and previous treatment with MPA and/or megestrol acetate (yes vs no).

The primary end point was investigator-assessed PFS. Secondary end points included objective response rate (ORR) per RECIST 1.1 criteria, disease control rate (DCR), overall survival (OS), and safety. The data cutoff for this analysis was November 1, 2020.

Patient Baseline Characteristics

In the palbociclib/letrozole and placebo/letrozole arms, respectively, median ages at baseline were 68.5 years (interquartile range [IQR], 63-73) and 67.0 years (IQR, 61-72); all patients from both arms were White; the majority in both arms had an ECOG performance status of 0 (palbociclib arm, 50%; placebo arm, 62%) or 1 (42%; 27%); performance status data were missing for the remainder of patients (8%; 11%). Relevant comorbidities at baseline included hypertension (53%; 49%), previous cancer (3%; 8%), diabetes (17%; 8%), and ischemic heart disease (6%; 0%).

Based on RECIST 1.1 criteria, measurable disease was observed in 89% and 84% of patients in the palbociclib/letrozole and placebo/letrozole arms, respectively; unmeasurable disease was observed in 11% and 16% of patients, respectively. FIGO stages included stage I (palbociclib arm, 28%; placebo arm, 38%), stage II (19%; 19%), stage III (25%; 19%), stage IVA (0%; 5%), and stage IVB (14%; 14%). Most patients received prior chemotherapy (83%; 78%). The majority received adjuvant/first-line platinum-based chemotherapy (56%; 62%). Prior platinum-based chemotherapy as second-line therapy was received by 14% and 3% of patients in the experimental and control arms, respectively. the majority of patients had received at least 1 prior line of therapy (53%; 46%); others received no prior lines of therapy (14%; 11%) or at least 2 prior lines of therapy (33%; 43%).

Additional Efficacy and Safety Data

The ORR was 9% (95% CI, 2%-24%) in the palbociclib/letrozole arm vs 16% (95% CI, 6%-32%) in the placebo/letrozole arm. Notably, at 26 weeks, 64% of patients (95% CI, 45%-80%) in the palbociclib/letrozole arm achieved disease control vs 38% (95% CI, 22%-55%) in the placebo/letrozole arm.

At the primary analysis for PFS, OS data were immature; however, by the final analysis, 34 deaths were reported (HR, 1.15; 95% CI, 0.58-2.26). The 1-year OS rates were 71% vs 78% with palbociclib/letrozole and placebo/letrozole, respectively; 2-year OS rates were 49% vs 48%, respectively

By the final cutoff date, all patients except for 3 in each arm had discontinued treatment, mainly because of disease progression (palbociclib arm, n = 27; placebo arm, n = 31).

In the palbociclib/letrozole arm, grade 3/4 adverse effects (AEs) were more common (67%) than in the placebo/letrozole arm (30%); no grade 5 AEs were reported in either arm. Higher incidences of all-grade hematologic AEs were associated with palbociclib/letrozole vs placebo/letrozole, respectively, including neutropenia (67%; 44%), leucopenia (25%; 6%), and anemia (36%; 8%). Overall, the most common AEs of any grade included neutropenia (67%; 44%), pain (39%; 8%), anemia (36%; 8%), leucopenia (25%; 6%), and nausea (22%; 3%).

“The safety profile of palbociclib/letrozole was as predicted from experience in breast cancer, with no new signals,” study authors wrote. “In breast cancer, hematologic toxicities with palbociclib tend to appear in early cycles and rarely lead to treatment discontinuation. In our trial, 13 patients required dose reductions; adjusting the dosing regimen may reduce the incidence of dose-limiting hematologic toxicity in future trials.”

Study authors concluded that phase 3 validation will be required to account for recent advances in the management of endometrial cancer.

Reference

Mirza MR, Bjørge L, Marmé F, et al. Palbociclib plus letrozole in estrogen receptor-positive advanced/recurrent endometrial cancer: double-blind placebo-controlled randomized phase II ENGOT-EN3/PALEO trial. Gynecol Oncol. 2025;192:128-136. doi:10.1016/j.ygyno.2024.12.003