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

5596 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. Endometrioid endometrial cancer frequently express the estrogen receptor and harbors PTEN, PI3K, KRAS and CTNNB1 mutations which induce estrogen-mediated upregulation of cyclin D1 and cancer cell proliferation. We hypothesized that the combination of letrozole and abemaciclib will inhibit cellular proliferation, as measured by Ki-67, 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 surgical management with hysterectomy. Eligibility criteria included endometrioid histology, no prior treatment for endometrial cancer, and a window of greater than 15 days prior to scheduled hysterectomy. Patients received 14 days of abemaciclib 150mg twice daily and letrozole 2.5mg 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. The planned sample size was n=21 evaluable patients which would achieve 80% power with two-sided α = 0.05 to detect a 12.9% decrease in Ki67 expression based on a paired t-test. Results: A total of 27 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. Median BMI was 37 (IQR: 30-40). All cancers were endometrioid with the majority being FIGO grade 1 (76%) and 24% grade 2. Nine (33%) patients had mismatch repair deficient tumors. Twenty-two (88%) patients were stage I, two (8%) stage II, and 1 (4%) stage IV. Mean baseline Ki-67 was 34% (SD 22%). After 2 weeks of treatment with abemaciclib and letrozole mean Ki67 was 14% (SD 16%). The 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 present or absent staining for pRb, PTEN, cyclin D1, p16, or MMR proteins. Post-menopausal patients had a decrease in Ki-67 of 26% compared to 15% for those who were premenopausal, but this did not reach statistical significance (p=0.5). There were no serious adverse events recorded. The most common study related adverse events were grade 1-2 diarrhea (68%) and grade 1-2 nausea (36%). Two patients had grade 3 hematological events (anemia and neutropenia), which resolved. Conclusions: Abemaciclib and letrozole induced a reduction in cellular proliferation in endometrioid endometrial cancer over a relatively short two week time period prior to surgery, suggesting clinical efficacy. Clinical trial information: NCT04049227 .