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Palbociclib plus letrozole improves PFS in advanced endometrial cancer



Adding palbociclib to letrozole significantly prolonged progression-free survival (PFS) in a phase 2 trial of patients with advanced or recurrent estrogen receptor (ER)–positive endometrial cancer.

This was the first randomized trial to evaluate the efficacy of a CDK4/6 inhibitor in combination with an aromatase inhibitor in patients with advanced or recurrent ER-positive endometrial cancer, noted study investigator Mansoor Raza Mirza, MD, PhD, of Rigshospitalet Copenhagen University Hospital.

Dr. Mirza presented results from this study, ENGOT-EN3-NSGO/PALEO, at the European Society for Medical Oncology Virtual Congress 2020.

Palbociclib is a selective inhibitor of CDK4/, both of which are involved in cell-cycle transitions, Dr. Mirza explained. He observed that endometrial endometrioid adenocarcinomas are hormone dependent, and endocrine treatment with an aromatase inhibitor is well established. Palbociclib has been shown to be superior, when combined with letrozole, to letrozole alone in ER-positive breast cancer.

For the ENGOT-EN3-NSGO/PALEO study, investigators enrolled 77 patients with ER-positive advanced/recurrent endometrial cancer. Patients had received at least one prior systemic therapy, no prior endocrine therapy (except medroxyprogesterone acetate and megestrol acetate), and no prior CDK inhibitor.

Patients were randomized 1:1 to receive oral letrozole (2.5 mg on days 1-28) and either palbociclib (125 mg on days 1-21) or placebo (125 mg on days 1-21) in a 28-day cycle until progression. Baseline characteristics were similar between the treatment arms.


Of the 77 patients enrolled, 73 were evaluable. The primary endpoint was PFS.

The median PFS in the intention-to-treat population was 3.0 months in the placebo arm and 8.3 months in the palbociclib arm (hazard ratio, 0.56; 95% confidence interval, 0.32-0.98; P = .0376).

Looking at stratification factors, PFS was higher in the palbociclib arm among the large majority (about 85%) of patients who had received no prior medroxyprogesterone acetate or megestrol acetate (HR, 0.55; 95% CI, 0.29-01.04; P = .0615) and among patients with relapsed disease (HR, 0.61; 95% CI, 0.34-1.09; P = .0916).

The disease control rate at 24 weeks, a secondary endpoint, was 63.6% in the palbociclib arm and 37.8% in the placebo arm.


Adverse events were more frequent in the palbociclib arm, with neutropenia being the most common.

Rates of adverse event–related dose reduction (to 100 mg or 75 mg) were 36% in the palbociclib arm and 3% in the placebo arm.

Adverse event–related discontinuation rates were 25% and 19% for palbociclib and letrozole, respectively, in the palbociclib arm and 14% and 11% for placebo and letrozole, respectively, in the placebo arm.

“The toxicity of palbociclib plus letrozole combination therapy was manageable, with most patients remaining on treatment until disease progression,” Dr. Mirza said.

He noted that an analysis of patient-reported outcomes revealed no detrimental effect on quality of life with the combination therapy.

Next steps

“Compared with placebo plus letrozole, the combination of palbociclib plus letrozole demonstrated clinically meaningful improvement in PFS,” Dr. Mirza said. “These results merit a phase 3 validation trial.”

“There is a huge rationale for using this drug in endometrial cancer,” commented study discussant Domenica Lorusso, MD, PhD, of Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Catholic University of Sacred Hearth in Rome.

Dr. Lorusso said hormone receptor expression, which has been identified as a strong predictor of CDK4/6 inhibitor activity, is present in up to 90% of patients with type 1 and in about 65% of patients with type 2 endometrial cancer.

Response rates, in experience with aromatase inhibitors, have been “quite disappointing, in the 10%-20% range,” Dr. Lorusso said, with “dismal prognosis” and guidelines stating that “no standard second-line treatment has been identified.”

This research was sponsored by investigators, but Pfizer provided a study grant. Dr. Mirza disclosed relationships with Pfizer, AstraZeneca, Biocad, Clovis Oncology, Genmab, Karyopharm Therapeutics, Merck, Oncology Adventure, Roche, Seattle Genetics, Sera Prognostics, Sotio, GlaxoSmithKline, Zai Lab, and Boehringer Ingelheim. Dr. Lorusso disclosed relationships with AstraZeneca, Biocad, Clovis Oncology, Genmab, Merck, Roche, Tesaro, Amgen, Immunogen, and Pharma Mar.

SOURCE: Mirza MR et al. ESMO 2020, Abstract LBA28.

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