Article

Letrozole Plus Abemaciclib Elicits Promising Responses in ER+ Endometrial Cancer

Author(s):

Dual inhibition with letrozole and abemaciclib displayed response and survival benefits in patients with recurrent estrogen receptor–positive endometrioid endometrial cancer.

Panagiotis A. Konstantinopoulos, MD, PhD

Panagiotis A. Konstantinopoulos, MD, PhD

Dual inhibition with letrozole (Femara) and abemaciclib (Verzenio) displayed response and survival benefits in patients with recurrent estrogen receptor (ER)–positive endometrioid endometrial cancer, according to findings from a phase 2 trial (NCT03675893) published in the Journal of Clinical Oncology.

At a median follow-up of 12.5 months, the predetermined criteria for both overall responses and progression-free survival (PFS) had been met. Among 30 enrolled patients, there were 9 total responses, for an objective response rate (ORR) of 30% (99% CI, 14.7%-49.4%). The median duration of response (DOR) was 7.4 months (95% CI, 3–nonevaluable [NE]). Thirteen patients (43.3%) had stable disease (SD), with 5 having SD of 6 months or longer.

The median PFS was 9.1 months (95% CI, 3.5-16.5) with a 6-month PFS rate of 55.6% (95% CI, 35.1%-72.0%). The median overall survival (OS) was 21.6 months (95% CI, 10.6-NE).

Among responders there were 8 confirmed partial responses and 1 unconfirmed; for the patients with the unconfirmed response measurable lesions had tumor shrinkage of –31% prior to withdraw of consent.

All patients who achieved responses had endometrioid tumors. In addition, 4 patients who responded had received prior hormonal therapy and 5 patients who achieved responses had not received prior hormonal therapy.

“A clinically important finding of our study was that activity of letrozole/abemaciclib was demonstrated in patients who had previously received hormonal therapy including prior AI [aromatase inhibitor], tamoxifen, and progestin monotherapy as well as patients who had previously received letrozole/everolimus and megestrol/tamoxifen combinations,” wrote Panagiotis A. Konstantinopoulos, MD, PhD, director of Translational research in Gynecologic Oncology at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School.

“These responses suggest that letrozole/abemaciclib may not be cross-resistant with other hormonal approaches and may represent a viable salvage endocrine therapy regimen for patients with ER-positive endometrioid endometrial cancer.”

Endometrioid is the most common endometrial cancer histology. This tumor type accounts for nearly 80% of endometrial cancer cases. Moreover, the disease is understood to be driven by hormones, specifically though estrogen signaling.

Following progression with chemotherapy and immunotherapy, standard of care dictates that many patients with ER-positive endometrioid endometrial cancer will receive hormonal/endocrine therapy. In some cases, patients will receive hormonal therapy upfront as it may be less toxic and therefore preferable for those with minimally symptomatic disease.

Unfortunately, investigators have noted that endocrine therapy is usually associated with modest responses, which are brief in duration. Only a small portion of patients achieve extended benefit with this treatment. Therefore, novel treatments designed for this patient population represent an unmet need in the space, according to study authors.

Investigators hypothesized that a combination regimen of the AI letrozole and the CDK4/6 inhibitor abemaciclib would induce promising responses in this population because the extensive crosstalk between estrogen receptor, PI3K and RTK/RAS/ CTNNB1 pathway is associated with the upregulation of cyclin D1. These clinical pathways are present in ER-positive endometrial cancers, and an upregulation of cyclin D1 is involved with CDK4/6 and represents a key mediator of hormonal therapy resistance.

To that end, a single-arm, 2-stage, phase 2 study was designed to see whether the CDK4/6 inhibitor, abemaciclib, could be effective in combination with letrozole. The primary objective was to determine clinical activity via ORR and the rate of patients who achieved a PFS of 6 months or greater. Secondary end points included PFS, OS, DOR, and safety.

Eligible participants needed pathologically confirmed endometrial cancer that was recurrent, metastatic, or resistance to standard therapies. All patients with endometrial cancer were permitted in the first stage of the study; however, to be eligible for the second stage, patients also needed histologically confirmed endometrioid endometrial cancer or endometrial carcinoma with an endometroid epithelial component. All enrolled patients had ER-disease (≥ 1% of tumor cell nuclei being immunoreactive by immunohistochemistry). There was no limit or prior therapies; previous hormonal therapy, including prior letrozole therapy, was permitted. The exclusion criteria included prior CDK4/6 treatment, active brain metastases, and concomitant therapy with moderate or strong CYP3A4 inducers, or strong inhibitors of CYP3A4.

A total of 30 patients were enrolled between September 18, 2019, and August 30, 2021; 28 of whom had endometrioid histology and 29 had received at least 1 prior line of chemotherapy. Participants received the recommended phase 2 dose of abemaciclib, 150 mg twice daily, and letrozole, 2.5 mg once daily—both agents were taken by mouth.

In regard to safety, the most common grade 3 or 4 treatment-related adverse events (TRAEs) were neutropenia, which occurred in 20% of patients (n = 6), and anemia, which occurred in 17% of patients (n = 5). No grade 5 toxicities TRAEs were reported.

Other notable TREAs included diarrhea, which is associated with abemaciclib and was experienced by 70% of patients (n = 21), as well as increases in creatinine, which was observed in 33% of patients (n = 10) and all instances were grade 1 or 2.

Moreover, 53% of patients (n = 16) required at least 1 abemaciclib dose reduction mostly related to diarrhea (n = 7) and fatigue (n = 6). Two patients required treatment discontinuation because of toxicities.

“Letrozole/abemaciclib met the prespecified criteria to be considered worthy of further investigation in patients with recurrent ER-positive endometrioid endometrial cancer and unlimited prior lines of therapy,” study authors concluded. “Letrozole/abemaciclib demonstrated an acceptable safety profile with only 2 patients discontinuing protocol therapy because of toxicity. There were no new safety signals or unexpected toxicities, and adverse events were comparable with those observed in previous studies.”

Reference

Konstantinopoulos PA, Lee EK, Xiong N, et al. A phase II, two-stage study of letrozole and abemaciclib in estrogen receptor-positive recurrent endometrial cancer. J Clin Oncol. Published online September 29, 2022. doi:10.1200/JCO.22.00628


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