A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor–Positive Recurrent Endometrial Cancer

Abstract

PURPOSE Estrogen receptor (ER)–positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/β-catenin (CTNNB1) pathway alterations in approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting. METHODS We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormonal therapy was allowed. Primary end points were objective response rate by RECIST 1.1 and progression-free survival (PFS) rate at 6 months. RESULTS At the data cutoff date (December 03, 2021), 30 patients (28 with endometrioid EC) initiated protocol therapy; 15 (50%) patients had prior hormonal therapy. There were nine total responses (eight confirmed), for an objective response rate of 30% (95% CI, 14.7 to 49.4), all in endometrioid adenocarcinomas. Median PFS was 9.1 months, PFS at 6 months was 55.6% (95% CI, 35.1 to 72), and median duration of response was 7.4 months. Most common ≥ grade 3 treatment-related adverse events were neutropenia (20%) and anemia (17%). Responses were observed regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status. Exploratory tumor profiling revealed several mechanistically relevant candidate predictors of response ( CTNNB1, KRAS, and CDKN2A mutations) or absence of response ( TP53 mutations), which require independent validation. CONCLUSION Letrozole/abemaciclib demonstrated encouraging and durable evidence of activity in recurrent ER positive endometrioid EC.

Do Not Forget about Hormonal Therapy for Recurrent Endometrial Cancer: A Review of Options, Updates, and New Combinations

“…The median duration of response was 7.4 months. The most common serious adverse events were due to bone marrow suppression [ 24 ]. A third randomized phase II trial by the NSGO has been presented but not yet published.…”

“…The investigators observed responses in the trial regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status (all patients had ER expression by trial design). When evaluating responses based on molecular subtypes, they found responses in all subtypes except in the copy-number high (p53 abnormal) group and recommended future studies to further evaluate possible predictors of response, such as mutations of CTNNB1, KRAS, and CDKN2A [ 24 ].…”

“…A second, further downstream target that has been studied extensively in breast cancer and is now being evaluated in endometrial cancer are the cyclin-dependent kinases 4 and 6 (CDK4/6). In addition to direct activation by ER, both the PI3K/Akt/mTOR pathway and a second pathway that is commonly altered in endometrial cancer [ 11 ], the receptor tyrosine kinase (RTK)/RAS/β-catenin (CTNNB1) pathway, can activate CDK4/6, leading to cell cycle progression via retinoblastoma (RB1), therefore causing cell proliferation and growth [ 24 , 25 ]. The inhibition of CDK4/6 has gained attention recently with the published results of two clinical trials in the treatment of endometrial cancer.…”

Biomarker-driven therapy in endometrial cancer

“…47 More recently, a phase II study of letrozole plus abemaciclib in estrogen receptor-positive recurrent/persistent endometrial cancer found a 30% ORR (95% CI 14.7% to 49.4%). 48 Hormonal therapy plus cyclin-dependent kinase 4/6 inhibitors need further evaluation in phase III trials.…”

Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential

“…Multiple clinical trials about palbociclib treated in various tumors such as breast cancer, ovarian cancer, Pancreatic Ductal Adenocarcinoma. Besides, other CDK4/6 inhibitors such as Abemaciclib [ 170 ], Ribociclib [ 171 ], Lerociclib [ 172 ], Trilaciclib [ 173 ], Dinaciclib [ 174 ], and SHR6390 [ 175 ] are also being adopted in clinical testing.…”