Letrozole/Abemaciclib Demonstrate Promising, Long-Lasting Activity in Recurrent ER+ Endocrine Cancer

Letrozole (Femara) with abemaciclib (Verzenios) produced encouraging activity in patients with recurrent estrogen receptor (ER)–positive recurrent endometrial cancer and met the prespecified criteria warranting further evaluation, according to results from a phase 2 study (NCT03675893).

Of 30 patients who initiated protocol therapy, 8 had confirmed partial responses (PRs) and 1 had an unconfirmed PR, resulting in an objective response rate (ORR) of 30.0% (95% CI, 14.7%-49.4%). The median progression-free survival (PFS) was 9.1 months (95% CI, 3.5-16.5), and the 6-month PFS rate was 55.6% (95% CI, 35.1%-72.0%). Additionally, median overall survival (OS) was 21.6 months (95% CI, 10.6-nonevaluable [NE]). The median duration of response (DOR) among responders was 7.4 months (95% CI, 3-NE).

This single-arm, phase 2 study included a total of 30 patients who received the recommended phase 2 dose of abemaciclib of oral 150 mg twice daily and 2.5 mg of oral letrozole once daily.

Patients with pathologically confirmed endometrial cancer of any histology that was recurrent or metastatic and/or resistant to standard therapies were eligible to participate in the first portion of the study. For the second portion of the study, patients were required to have either histologically confirmed endometrioid endometrial cancer or endometrial carcinosarcoma with an endometrioid epithelial component. Additional inclusion criteria for all patients included having ER-positive disease, measurable disease by RECIST 1.1 criteria, no limit of prior therapies, an ECOG performance status of 0 or 1, availability of a formalin-fixed paraffin-embedded (FFPE) block or unstained slides, and normal organ/marrow function.

The primary end point of the study was the clinical activity of the study regimen as determined by the frequency of patients who had an objective response as best response per RECIST 1.1 criteria or a PFS lasting at least 6 months after beginning therapy. Secondary end points included duration of PFS, OS, DOR, and toxicities.

At baseline, the median patient age was 66.2 years (range, 53.8-79.6). Most patients were non-Hispanic (90%) and White (90%). A total of 93.3% patients had endometrioid histology. Additionally, 1 patient had serous histology, and 1 other patient had carcinosarcoma histology. Half of the patients (50%) had received prior hormone therapy. Patients received a median of 3 (range, 1-8) prior lines of therapy.

Archival FFPE specimens were available among 90% of patients for progesterone receptor (PR) immunohistochemistry and 73% of patients for next-generation sequencing. Investigators reported no statistically significant connection between PR status and clinical outcome; objective responses were seen in 29% (n = 6/21) of PR-positive patients and 33% (n = 2/6) of PR-negative patients. Two of 3 (67%) patients with mismatch repair–deficient tumors exhibited clinical benefit and 2 achieved an objective response. Presence of TP53 mutation was associated with a reduction in clinical benefit from the study regimen. In particular, 18% of TP53-mutated tumors exhibited clinical benefit vs 82% of TP53 wild-type tumors (P = .09). Six patients with no specific molecular profile tumors had clinical benefits including 4 objective responses. Moreover, 3 patients with CTNNB1 mutations all objectively responded and 2 other patients with KRAS mutations derived clinical benefit.

The most common grade 3 or higher treatment-related adverse effects (TEAEs) included neutropenia (20%) and anemia (17%). No grade 5 TEAEs were observed. A total of 16 (53%) patients had at least 1 dose reduction of abemaciclib due to diarrhea in 7 patients and fatigue in 6. Two patients discontinued treatment due to toxicity. Study investigators reported that the regimen yielded no new safety signals or unexpected toxicities.

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