William A. Zammarrelli

A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor–Positive Advanced or Recurrent Endometrial Cancer

Abstract Purpose: Inhibition of the cyclin D–cyclin-dependent kinase (CDK)4/6–INK4–retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer are suboptimal, perhaps due to genomic alterations that promote estrogen receptor–independent cyclin D1–CDK4/6 activation. We hypothesized that the addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant would be an effective therapeutic strategy in patients with advanced or recurrent endometrial cancer. Patients and Methods: In this phase II study, patients with advanced or recurrent endometrial cancer received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included estrogen receptor or progesterone receptor expression ≥1% by IHC, measurable disease, ≤2 prior lines of chemotherapy, and ≤1 prior lines of hormonal therapy. The primary endpoint was the objective response rate by RECIST v1.1. Results: Twenty-seven patients initiated therapy, and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number–low/no specific molecular profile tumors, 1 response (9%) was in a microsatellite instability–high tumor, and no responses were observed in copy number–high/TP53abnormal tumors. The objective response rate was 44% (90% confidence interval, 27.0%–62.1%). The median duration of response was 15.6 months. The median progression-free survival was 9.0 months (90% confidence interval, 1.8–20.4). The most common grade ≥3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified. Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent endometrial cancer; a randomized trial is planned. See related commentary by Garg and Oza, p. 2073

Risk Stratification of Stage I Grade 3 Endometrioid Endometrial Carcinoma in the Era of Molecular Classification

PURPOSE The role of adjuvant therapy in stage I grade 3 endometrioid endometrial carcinoma (EEC) is debatable. We sought to define the agreement between Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) high-intermediate risk (HIR) and Gynecologic Oncology Group (GOG)-99 HIR criteria, assess their concordance with The Cancer Genome Atlas molecular subtypes, and evaluate oncologic outcomes in this population. METHODS We identified patients with stage I grade 3 EECs who underwent surgical staging at our institution from January 2014 to January 2020. Patients were stratified into PORTEC-1 HIR, GOG-99 HIR, and The Cancer Genome Atlas molecular subtypes. Adjuvant treatment, and progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS Seventy-five patients were included. The agreement between PORTEC-1 and GOG-99 HIR classification was 68% (95% CI, 56.2 to 78.3), with a kappa of 0.36 ( P = .001). There was no agreement between PORTEC-1 or GOG-99 HIR classification and a dichotomized molecular classification (copy number-high [CN-H] v other subtypes), with a kappa of 0.03 ( P = .39) and −0.03 ( P = .601), respectively. There was no difference in PFS between PORTEC-1 HIR and non-HIR (HR, 10.9; 95% CI, 0.28 to 4.21) or between GOG-99 HIR and non-HIR (HR, 1.22; 95% CI, 0.32 to 4.6) stage I grade 3 EECs. Patients with CN-H compared with non-CN-H EEC had worse PFS (HR, 5.67; 95% CI, 1.73 to 18.63) and OS (HR, 5.05; 95% CI, 1.13 to 22.5). CONCLUSION In surgically staged patients with stage I grade 3 EEC, PORTEC-1 and GOG-99 HIR criteria were not prognostic and did not identify CN-H patients. Patients with CN-H EEC had worse PFS and OS compared with those with other molecular subtypes. The integration of the molecular classification with recognized clinicopathologic factors may identify patients with higher-risk stage I grade 3 EEC who benefit from additional therapy.