The CDK4 / 6 inhibition will increase the PFS in endometrial most cancers

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Women with advanced hormone receptor (HR) -positive endometrial cancer lived more than twice as long without the disease getting worse when they received the CDK inhibitor palbociclib in addition to hormone therapy, according to a small randomized study.

The 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.

The addition of letrozole also increased toxicity, as a quarter of the patients in the combination group discontinued treatment because of adverse events (AEs). Most patients, however, found the regimen tolerable, reported Dr. Mansoor R. Mirza from Copenhagen University Hospital in 2020 in the European Society Virtual Congress of Medical Oncology (ESMO).

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

“The toxicity of combination therapy with palbociclib and letrozole was manageable, and most patients remained on treatment until disease progression. No adverse effects on quality of life were observed with combination therapy. These results merit a phase III validation study,” noted Mirza .

New approaches to cancer therapy are increasingly targeting cell cycle checkpoints. Palbociclib inhibits cyclin A, a cyclin-dependent kinase involved in the transition from G1 to S phase and from G2 to M phase in the cell cycle, Mirza explained. In HR-positive breast cancer, the combination of palbociclib and letrozole was shown to be better than letrozole alone.

Endometrioid endometrial cancer is hormone dependent, and endocrine therapy with an AI is well established, Mirza said. The collective knowledge of disease biology and the results of previous clinical studies provided a rationale for studying the combination of palbociclib and an AI in HR-positive endometrial cancer.

ENGOT-EN3 / NSGO-PALEO, conducted in Scandinavia, Germany, Spain and Italy, included patients with advanced (stage IV) or recurrent endometrial endometrioid cancer associated with HR expression of ≥ 10%. Eligible patients had received no endocrine therapy other than 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 study had a target hazard ratio (HR) of 0.625 for palbociclib versus placebo.

The data analysis included 73 patients with a mean age of approximately 68 years. Approximately 15% of patients had previously received MPA / MA therapy, and nearly 90% of the study population had one or more previous lines of therapy.

Analysis of the primary endpoint gave a HR of 0.56 for disease progression or death and met 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 whether they had received MPA / MA or whether they had relapse 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 a dose reduction of palbociclib, a quarter of patients stopped palbociclib, and about 20% of patients in the combination arm stopped letrozole (compared with four in the placebo arm).

Assessment of the patient-reported results revealed no significant difference between the treatment arms during the study.

The ESMO invited panelist Dr. med. Domenica Lorusso from the National Cancer Institute in Milan found that letrozole has limited activity in advanced or recurrent endometrial cancer. The rationale for using palbociclib was evidence that resistance to endocrine therapy is associated with persistent dependence on cyclin D1 and CDK4 / 6. In addition, palbociclib has shown preclinical activity in endometrial cancer associated with the expression of retinoblastoma proteins, suppressing tumor growth and reducing proliferative activity, which is reflected in Ki67.

Phase I studies with palbociclib and other CDK4 / 6 inhibitors in advanced / relapsed endometrial cancer showed DCRs in the range of 27% to 92%.

Lorusso acknowledged that the results represent a positive outcome and a significant increase in disease control. She proposed two proposals for a Phase III study 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 uterine serous cancer, which is associated with altered expression of cell cycle-related genes in approximately 85% of cases.

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

Last updated on September 21, 2020

  • Charles Bankhead is Senior Editor on Oncology and also specializes in Urology, Dermatology and Ophthalmology. He joined MedPage Today in 2007. follow

Disclosure

The study was supported by the Nordic Society for Gynecological Oncology in collaboration with the European Network of Gynecological Oncological Trial Groups, the Intergroup of Gynecological Cancer, the East German Society for Gynecological Oncology, Italian multicenter studies in ovarian cancer and gynecological malignancies, and the Grupo Espanol de Investigacion Ovario.

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

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