1. Almost half of patients (47%) had either an objective response or had progression free survival for at least 6 months after starting therapy.

2. Most common adverse events included diarrhea, fatigue, elevated creatinine, neutropenia, and anemia.

Evidence Rating Level: 2 (Good)

Study Rundown: Estrogen is a primary oncogenic driver of most endometrial cancers (EC). Hormone therapy alone, however, shows modest benefit for most patients. Recent studies have found phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/b-catenin (CTNNB1) pathways, which are present in most EC, are involved in endocrine therapy resistance through another pathway; upregulation of cyclin D1, cyclin-dependent kinases 4 and 6 (CDK4/6), retinoblastoma, transcription factor E2F, ultimately upregulating transcription of genes and tumor progression. This study looked at a combination therapy of aromatase inhibitor letrozole with CDK4/6 inhibitor abemaciclib in estrogen receptor (ER)-positive recurrent EC. Primary endpoints included objective response (OR) or progression-free survival (PFS) for at least 6 months after starting therapy. Secondary endpoints included duration of PFS, overall survival (OS), duration of response (DOR), and adverse events. Almost a third of patients were found to have a partial OR, more than a third had stable disease, and less than a third had disease progression. Altogether, almost half of patients were found to meet either of the primary end points. Most common adverse events included diarrhea, fatigue, elevated creatinine, neutropenia, and anemia. Biomarkers were also analyzed from most patients and the following was found; no significant association between progesterone receptor status and response to treatment, TP53 mutations had reduced clinical benefit, mismatch repair deficiency was found to have clinical benefit. Limitations to this study included a small sample size, lack of a control group, and lack of diversity in patients. Strengths of this study included investigation of biomarkers. Overall, letrozole and abemaciclib shows some effect in ER–positive recurrent endometrial cancer and should be further investigated.

Click to read the study in JCO

Relevant Reading: Integrated genomic characterization of endometrial carcinoma

In-Depth [prospective cohort]: This is a single-arm, two-stage, phase II study that investigated the efficacy of abemaciclib (150 mg by mouth twice daily) and letrozole (2.5 mg by mouth once daily) in patients with pathologically confirmed ER-positive EC which was recurrent or metastatic and found to be resistant to standard therapy. A total of 30 patients were enrolled with a median follow-up time of 12.5 months. Almost half of patients were found to meet either of the primary end points (46.7%, 95%CI, 28.3 to 65.7). They found a partial OR in 30% (95%CI, 14.7 to 49.4) of patients, another 43% of patients experienced stability in their disease and 23% had progressive disease. OR were found in patients with endometrioid EC and those patients had a median DOR of 7.4 months. Generally median PFS was 9.1 months (95%CI, 3.5 to 16.5) and median OS was 21.6 months. Most common adverse events included diarrhea (70%), fatigue (67%), and elevated creatinine (33%), with adverse events grade 3 or higher being neutropenia (20%) and anemia (17%). With regards to biomarkers, which were analyzed from 90% of patients, they found no significant association between progesterone receptor status and response to treatment. Three patients had mismatch repair deficiency and all three were found to have clinical benefit, meanwhile it was found that only 18% of TP53-mutated vs 82% of TP53 wild type patients found clinical benefit. Overall, the combination of letrozole and abemaciclib have some positive effect in ER–positive recurrent endometrial cancer and there is a need for further investigation.

Image: PD

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