Surgical window of opportunity clinical trial of abemaciclib and letrozole for endometrioid adenocarcinoma of the endometrium

Background: Abemaciclib inhibits cyclin dependent kinases (CDK) 4 and 6 and, in synergy with anti-estrogens, is an FDA approved treatment of ER+ breast cancer. We hypothesized that letrozole and abemaciclib will inhibit cellular proliferation in patients with endometrial cancer. Methods: This is a single-arm prospective multicenter surgical window of opportunity clinical trial for patients with endometrial cancer planned to undergo definitive management with hysterectomy. Patients received 14 days of abemaciclib 150 mg twice daily and letrozole 2.5 mg once daily. The primary endpoint was change in Ki-67 (%) from pretreatment biopsy to posttreatment hysterectomy specimen. Secondary endpoints included biological tumor characteristics (MMR, PTEN, PI3K, cyclin D1, pRB) associated with Ki-67 changes. Results: Twenty seven women were enrolled, 2 patients withdrew consent leaving 25 evaluable patients. The median age was 62 (IQR: 54–66) and 19 patients (76%) were menopausal. Most patients were White (68%), 24% identified as Black; 20% were of Hispanic ethnicity. All cancers were endometrioid with the majority FIGO grade 1 (76%) and 24% grade 2. Seven (28%) patients had mismatch repair deficient tumors. Mean baseline Ki-67 was 34% (SD 22%). After 2 weeks of treatment, mean Ki-67 reduction was 19% (SD 23%, p < 0.001) meeting the prespecified endpoint. We found no significant difference in the magnitude of Ki-67 reduction based upon pRb, PTEN, cyclin D1, p16, or MMR proteins. There were no serious adverse events recorded. Conclusions: Abemaciclib and letrozole induced a reduction in cellular proliferation in endometrioid endometrial cancer over a short two-week time period prior to surgery.