The combination of abemaciclib and letrozole produced encouraging responses with an acceptable toxicity profile in patients with estrogen receptor–positive, recurrent or metastatic endometrial cancer with endometrioid histology, according to data from a phase 2 trial.
The combination of abemaciclib (Verzenio) and letrozole produced encouraging responses with an acceptable toxicity profile in patients with estrogen receptor (ER)–positive, recurrent or metastatic endometrial cancer with endometrioid histology, according to data from a phase 2 trial (NCT03675893) presented during the 2022 SGO Annual Meeting on Women’s Cancer.1
At a median follow-up of 12.5 months, the doublet elicited an objective response rate (ORR) of 30.0% (95% CI, 14.7%-49.4%), which included a partial response rate of 30%; 1 of these responses was unconfirmed, and all these responses occurred in those with endometrioid tumors. Moreover, the stable disease rate with the combination was 43.3%, and 23.3% of patients experienced disease progression.
Notably, 75% of patients had their tumors shrink or become stable, and approximately 30% of patients had experienced tumor shrinkage of more than 30%.2 Moreover, the median progression-free survival (PFS) with the doublet 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%).
“Letrozole/abemaciclib exhibited promising activity in patients with recurrent, ER-positive endometrioid endometrial carcinoma and met the predetermined criteria to be worthy of further evaluation in this patient population,” Panagiotis (Panos) A. Konstantinopoulos, MD, PhD, lead study author, as well as director of Translational Research in Gynecologic Oncology and physician at Dana-Farber Cancer Institute, stated in a presentation on the data.
It is known that approximately 70% of endometrioid endometrial cancers have ER positivity, and that concurrent activation of PI3K and RTK/RAS/b-catenin pathways encourage endocrine therapy resistance, according to Konstantinopoulos, who is also an associate professor of medicine at Harvard Medical School. Moreover, these pathways have been found to converge in the upregulation of CCND1, which activates CDK4/6 and results in cell cycle progression.
The CDK4/6 inhibitor abemaciclib can target the point where those pathways converge and is hypothesized to possess the potential to overcome that resistance to endocrine treatment. To explore this further, investigators launched a phase 2 trial designed to examine the combination of abemaciclib and letrozole in 30 patients with recurrent, ER-positive endometrial cancer.
To be eligible for enrollment, patients needed to have measurable disease per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1. Although there was no limit to the number of prior therapies that could have been received, and any previous treatment with hormonal therapy was permitted, patients were not allowed to have received a prior CDK4/6 inhibitor.
Study participants were given letrozole at a daily dose of 2.5 mg in combination with abemaciclib at a twice-daily dose of 150 mg. Treatment was administered until unacceptable toxicity or disease progression.
The co-primary end points of the research were PFS of 6 months or longer following therapy initiation and ORR. Key secondary end points included PFS and overall survival (OS), as well as toxicity. Biomarkers of response and resistance served as important exploratory end points.
Among the 30 patients included, the median age was 66.2 years (range, 53.8-79.6), and 93.3% of patients had endometrioid histology; 1 patient each had serous and carcinosarcoma histologies. Moreover, 36.7% of patients had grade I disease, 23.3% had grade II disease, and 40% had grade III or undifferentiated disease, which included the 1 patient with serous disease and the 1 patient with carcinosarcoma. Half of patients previously received hormonal therapy, and the median number of prior lines of systemic therapy that had been received was 3 (range, 1-8).
At the time of data cutoff, which was December 3, 2021, a total of 9 patients were still receiving protocol therapy.
Additional data showed that responses with the doublet were observed irrespective of progesterone receptor (PR) status, grade of disease, and prior receipt of hormonal treatment.
In those with PR negativity (n = 6), the ORR achieved with the combination was 33%; this rate was 29% in those with PR positivity (n = 21). Moreover, the doublet resulted in ORRs of 46% in those with grade I disease (n = 11) and 29% in those with grade II disease (n = 7). The ORR was 17% in those with all grade III/undifferentiated disease including those with serious and carcinosarcoma histologies (n = 12), and 20% in those with grade III/undifferentiated endometrioid disease (n = 10). Additionally, the ORR was 27% in those who received prior hormonal therapy (n = 15) vs 33% in those who did not (n = 15).
Investigators also conducted an exploratory analysis of response across well-established molecular subtypes of endometrial carcinoma. Among the 22 patients included in the analysis, no POLE-mutated tumors were identified.
Three patients had mismatch repair deficient disease, and 2 of these patients achieved an objective response to treatment with the doublet; the third patient was free of disease progression for more than 6 months.
TP53 mutations were identified in a total of 11 patients; 3 of these patients had grade I or II disease, and 8 patients had grade 3 or undifferentiated disease. Nine percent of those in this subset experienced an objective response to the doublet vs 55% of those who were found to have TP53 wild-type disease (Fischer exact test; P = .064).
Notably, none of the 3 patients with TP53-mutated, grade I or II tumors experienced a response to treatment with the combination. The only patient with TP53-mutated disease who responded to treatment had a grade III tumor that harbored a CDKN2A mutation, which was linked with response to CDK4/6 inhibition, according to Konstantinopoulos.
Regarding toxicity, the most common grade 3 adverse effects reported with abemaciclib plus letrozole included neutropenia (13.3%), anemia (13.3%), diarrhea (6.7%), thrombocytopenia (6.7%), alanine aminotransferase increased (6.7%), fatigue (3.3%), nausea (3.3%), aspartate aminotransferase increased (3.3%), white blood cell decreased (3.3%), and urinary tract infection (3.3%).
Only 3 patients experienced grade 4 toxicities; 2 patients had grade 4 neutropenia and 1 patient had grade 4 anemia.
“Letrozole/abemaciclib demonstrated an acceptable safety profile with no unexpected toxicities,” Konstantinopoulos concluded. “Exploratory analysis suggested that TP53 mutation may be associated with inferior response to letrozole/abemaciclib, possibly reflecting enrichment with grade III tumors that are not hormonally driven or presence of alternative non–CDK4/6-dependent bypass mechanisms in TP53-mutated tumors.”