Maria M. Rubinstein

A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor–Positive Advanced or Recurrent Endometrial Cancer

Abstract Purpose: Inhibition of the cyclin D–cyclin-dependent kinase (CDK)4/6–INK4–retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer are suboptimal, perhaps due to genomic alterations that promote estrogen receptor–independent cyclin D1–CDK4/6 activation. We hypothesized that the addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant would be an effective therapeutic strategy in patients with advanced or recurrent endometrial cancer. Patients and Methods: In this phase II study, patients with advanced or recurrent endometrial cancer received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included estrogen receptor or progesterone receptor expression ≥1% by IHC, measurable disease, ≤2 prior lines of chemotherapy, and ≤1 prior lines of hormonal therapy. The primary endpoint was the objective response rate by RECIST v1.1. Results: Twenty-seven patients initiated therapy, and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number–low/no specific molecular profile tumors, 1 response (9%) was in a microsatellite instability–high tumor, and no responses were observed in copy number–high/TP53abnormal tumors. The objective response rate was 44% (90% confidence interval, 27.0%–62.1%). The median duration of response was 15.6 months. The median progression-free survival was 9.0 months (90% confidence interval, 1.8–20.4). The most common grade ≥3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified. Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent endometrial cancer; a randomized trial is planned. See related commentary by Garg and Oza, p. 2073

Microsatellite Instability–High Endometrial Cancers with MLH1 Promoter Hypermethylation Have Distinct Molecular and Clinical Profiles

Abstract Purpose: Microsatellite instability–high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). Experimental Design: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan–Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. Results: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). Conclusions: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.

ADAGIO: A Phase IIb, Open-Label, Single-Arm, Multicenter Study Assessing the Efficacy and Safety of Adavosertib (AZD1775) as Treatment for Recurrent or Persistent Uterine Serous Carcinoma

PURPOSE This phase IIb, single-arm, multicenter, global study (ADAGIO; ClinicalTrials.gov identifier: NCT04590248 ) assessed the efficacy and safety of adavosertib in patients with recurrent/persistent uterine serous carcinoma (USC) who had previously received platinum-based chemotherapy. METHODS Eligible patients were age 18 years and older and had histologically confirmed recurrent/persistent USC, previously treated with at least one platinum-based chemotherapy regimen, and with evidence of measurable disease. Adavosertib was administered orally at 300 mg once daily on days 1-5 and 8-12 of a 21-day cycle until discontinuation criteria were met. The primary end point was objective response rate (ORR) by blinded independent central review (BICR). Secondary end points included duration of response (DoR), progression-free survival (PFS), safety, and tolerability. Biomarkers previously associated with adavosertib response in other settings were assessed in archival tissue samples. RESULTS In 104 evaluable patients, one complete response and 26 partial responses were observed, for an ORR by BICR of 26.0% (95% CI, 17.9 to 35.5). Median DoR was 4.7 months (95% CI, 3.8 to 8.3); median PFS was 2.8 months (95% CI, 2.6 to 3.9). Biomarker analysis identified no single predictive alteration for adavosertib response, although a trend was observed for CCNE1 amplification or high cyclin E1 protein expression. Most patients (97.2%) experienced treatment-related adverse events (TRAEs), most frequently diarrhea (59.6%), nausea (59.6%), and anemia (58.7%). Grade ≥3 TRAEs occurred in 60.6% of patients, with neutropenia (21.1%) and fatigue (13.8%) most common. 17.4% of patients discontinued adavosertib due to AEs (treatment-related in 14.7%). CONCLUSION Adavosertib showed some antitumor activity in patients with recurrent/persistent USC. However, at 300 mg once daily dosing, it was not well tolerated in this population. Exploratory biomarker studies suggest CCNE1 /cyclin E1 expression may enrich for response to Wee1 inhibition in USC.