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CDK4/6 Inhibition Boosts PFS in Endometrial Cancer

— Median PFS more than doubled by adding palbociclib to endocrine therapy

Last Updated September 21, 2020
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Women with advanced, hormone receptor (HR)-positive endometrial cancer lived more than twice as long without disease progression if they received the CDK inhibitor palbociclib in addition to hormonal therapy, a small randomized trial showed.

Median progression-free survival (PFS) increased from 3.0 months with letrozole alone to 8.3 months with letrozole plus palbociclib (Ibrance). The combination achieved a disease control rate (DCR, response plus stable disease) of 63.6% versus 37.8% with letrozole alone.

Adding letrozole also added toxicity, as a fourth of patients in the combination group discontinued treatment because of adverse events (AEs), but most patients found the regimen tolerable, reported Mansoor R. Mirza, MD, of Copenhagen University Hospital, during 2020 European Society for Medical Oncology (ESMO) virtual congress.

"[This] is the first randomized trial to evaluate the efficacy of a CDK4/6 inhibitor in combination with an aromatase inhibitor (AI) in patients with advanced or recurrent estrogen receptor-positive endometrial cancer," Mirza concluded. "Compared with placebo and letrozole, the combination of palbociclib and letrozole demonstrated clinically meaningful improvement in progression-free survival," he stated.

"The toxicity of palbociclib and letrozole combination therapy was manageable, and most patients remained on treatment until disease progression. No detrimental effect on quality of life was observed with combination therapy. These results merit a phase III validation trial," Mirza noted.

Increasingly, new approaches to cancer therapy target cell-cycle checkpoints. Palbociclib inhibits cyclin A, a cyclin-dependent kinase involved in the transition from G1 to S-phase and G2 to M-phase in the cell cycle, Mirza explained. In the setting of HR-positive breast cancer, the combination of palbociclib and letrozole to letrozole alone.

Endometrioid endometrial cancers are hormone dependent, and endocrine therapy with an AI is well established, Mirza said. The collective knowledge about the biology of disease and results of prior clinical trials provided a rationale to study the combination of palbociclib and an AI in HR-positive endometrial cancer.

The , conducted in Scandinavia, Germany, Spain, and Italy, included patients with advanced (stage IV) or recurrent endometrial endometrioid cancer associated with HR expression ≥10%. Eligible patients had received no endocrine therapy except medroxyprogesterone acetate (MPA) or megestrol acetate (MA).

All patients received standard letrozole therapy and were randomized to palbociclib or placebo. The primary endpoint was PFS, and the trial had a target hazard ratio (HR) of 0.625 for palbociclib versus placebo.

Data analysis included 73 patients, who had a median age of about 68. About 15% of the patients had prior MPA/MA therapy, and almost 90% of the study population had one or more prior lines of therapy.

Analysis of the primary endpoint yielded an HR of 0.56 for disease progression or death, meeting the statistical criteria for a positive study (95% CI 0.32-0.98, P=0.0376). Patients appeared to benefit from the addition of palbociclib regardless of whether they had received MPA/MA or whether they had relapsed or primary advanced endometrial cancer.

The addition of palbociclib was associated with increased rates of AEs, particularly neutropenia, pain, hypertension, anemia, and leukopenia. About a third of patients required palbociclib dose reductions, a fourth of patients discontinued palbociclib, and about 20% of patients in the combination arm discontinued letrozole (as compared with four in the placebo arm).

Assessment of patient-reported outcomes showed no significant difference between the treatment arms during the trial.

ESMO invited discussant Domenica Lorusso, MD, PhD, of the National Cancer Institute in Milan, noted that letrozole has limited activity in advanced or recurrent endometrial cancer. The rationale for using palbociclib included evidence that resistance to endocrine therapy is associated with continued dependence on cyclin D1 and CDK4/6. Additionally, palbociclib exhibited preclinical activity in endometrial cancer associated with retinoblastoma protein expression, suppressing tumor growth and reducing proliferative activity, as reflected by Ki67.

Phase I trials of palbociclib and other CDK4/6 inhibitors in advanced/relapsed endometrial cancer produced DCRs ranging from 27% to 92%.

Lorusso acknowledged the results as representing a positive outcome and a substantial increase in disease control. She offered two suggestions for a phase III trial of the combination: careful monitoring of patients for toxicity (especially neutropenia), as patients with primary advanced or relapsed endometrial cancer tend to be older; consider including patients with serous carcinoma of the uterus, which are associated with altered expression of cell cycle-related genes in about 85% of cases.

Looking ahead, she said rational combinations to evaluate include a CDK4/6 inhibitor with immunotherapy or a PI3K-AKT inhibitor.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ֱ in 2007.

Disclosures

The study was supported by the Nordic Society for Gynecologic Oncology in collaboration with the European Network of Gynecological Oncological Trial Groups, Gynecologic Cancer Intergroup, Nor Eastern German Society of Gynecological Oncology, Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies, and Grupo Espanol de Investigacion en Cancer de Ovario.

Mirza disclosed relevant relationships with AstraZeneca, Biocad, Clovis Oncology, Geneos, Genmab, Karyopharm Therapeutics, Merck, Mersana, Merck Sharp & Dohme, Oncology Venture, Pfizer, Roche, Seattle Genetics, Sera Prognostics, Sotio, Tesaro/GlaxoSmithKline, ZaiLab, and Boehringer Ingelheim.

Primary Source

European Society for Medical Oncology

Mirza MR, et al "A randomized double-blind placebo-controlled phase II trial of palbociclib combined with letrozole in patients with estrogen receptor-positive advanced/recurrent endometrial cancer. ENGOT-EN3/NSGO-PALEO" ESMO 2020; Abstract LBA28.