Alexi A Wright

Usability, Acceptability, and Barriers to Implementation of a Collaborative Agenda-Setting Intervention (CASI) to Promote Person-Centered Ovarian Cancer Care: Development Study

Abstract Background People with advanced ovarian cancer and their caregivers report unmet supportive care needs. We developed a Collaborative Agenda-Setting Intervention (CASI) to elicit patients’ and caregivers’ needs through the patient portal before a clinic visit and to communicate these needs to clinicians using the electronic health record. Objective We aimed to assess the usability and acceptability of the CASI and identify barriers to and facilitators of its implementation. Methods We recruited English- and Spanish-speaking patients, caregivers, and clinicians from the gynecologic oncology program at a comprehensive cancer center. Participants used the CASI prototype and then completed individual cognitive interviews and surveys. We assessed usability with the System Usability Scale (scores range 0‐100, scores ≥70 indicate acceptable usability) and acceptability with the Acceptability of Intervention Measure and Intervention Appropriateness Measure (scores for both measures range from 1 to 5, higher scores indicate greater acceptability). Interviews were audio recorded, transcribed, and analyzed using directed content analysis. Domains and constructs from the Consolidated Framework for Implementation Research comprised the initial codebook. We analyzed survey data using descriptive statistics and compared usability and acceptability scores across patients, caregivers, and clinicians using analyses of variance. Results We enrolled 15 participants (5 patients, 5 caregivers, and 5 clinicians). The mean System Usability Scale score was 72 (SD 16). The mean Acceptability of Intervention Measure and Intervention Appropriateness Measure scores were 3.9 (SD 1.0) and 4.1 (SD 0.8), respectively. Participants viewed the CASI content and format positively overall. Several participants appreciated the CASI’s integration into the clinical workflow and its potential to increase attention to psychosocial concerns. Suggestions to refine the CASI included removing redundant items, simplifying item language, and adding options to request a conversation or opt out of supportive care referrals. Key barriers to implementing the CASI include its complexity and limited resources available to address patients’ and caregivers’ needs. Conclusions The CASI is usable and acceptable to patients with advanced ovarian cancer, caregivers, and clinicians. We identified several barriers to and facilitators of implementing the CASI. In future research, we will apply these insights to a pilot randomized controlled trial to assess the feasibility of comparing the CASI to usual care in a parallel group-randomized efficacy trial.

A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor–Positive Recurrent Endometrial Cancer

PURPOSE Estrogen receptor (ER)–positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/β-catenin (CTNNB1) pathway alterations in approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting. METHODS We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormonal therapy was allowed. Primary end points were objective response rate by RECIST 1.1 and progression-free survival (PFS) rate at 6 months. RESULTS At the data cutoff date (December 03, 2021), 30 patients (28 with endometrioid EC) initiated protocol therapy; 15 (50%) patients had prior hormonal therapy. There were nine total responses (eight confirmed), for an objective response rate of 30% (95% CI, 14.7 to 49.4), all in endometrioid adenocarcinomas. Median PFS was 9.1 months, PFS at 6 months was 55.6% (95% CI, 35.1 to 72), and median duration of response was 7.4 months. Most common ≥ grade 3 treatment-related adverse events were neutropenia (20%) and anemia (17%). Responses were observed regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status. Exploratory tumor profiling revealed several mechanistically relevant candidate predictors of response ( CTNNB1, KRAS, and CDKN2A mutations) or absence of response ( TP53 mutations), which require independent validation. CONCLUSION Letrozole/abemaciclib demonstrated encouraging and durable evidence of activity in recurrent ER positive endometrioid EC.

Serial Circulating Tumor DNA Sequencing to Monitor Response and Define Acquired Resistance to Letrozole/Abemaciclib in Endometrial Cancer

PURPOSE In a phase II study, letrozole/abemaciclib demonstrated an objective response rate of 30% and a median progression-free survival (PFS) of 9.1 months in recurrent estrogen receptor–positive endometrial cancer (EC). While tissue-based tumor profiling revealed several mechanistically relevant candidate baseline genomic predictors of response, circulating tumor DNA (ctDNA) is a less invasive alternative to monitor therapeutic efficacy and define acquired resistance. METHODS Serial plasma specimens were obtained at baseline, C2D1, C3D1, C8D1, the time of objective response, and the time of progression. Samples were analyzed using the Guardant Reveal assay to assess methylation-based tumor fraction (TF), with the Guardant360 assay providing genotyping of >700 genes in samples with detectable ctDNA. Treatment response was assessed using a measure of the relative change in TF pre- versus on-treatment. RESULTS A total of 99 of 102 (97%) samples from 28 patients were successfully analyzed. Patients with above median baseline TF exhibited worse median PFS (2.0 months v 16.5 months, P < .005, hazard ratio [HR], 24.1) and worse overall survival (OS) (10.7 months v not yet reached, P < .005, HR, 14.8). Patients with molecular response (MR) after the first or second cycle of letrozole/abemaciclib therapy had significantly better median PFS and OS regardless of the cutoff used for definition of MR. ctDNA analysis of postprogression specimens identified several acquired genomic alterations associated with resistance to letrozole/abemaciclib therapy in more than half of the patients, including PI3K pathway, receptor tyrosine kinase ( FGFR1 , 2 and ERBB2 alterations), cell cycle pathway ( RB1 and CCNE1 alterations), and ESR1 and MAPK pathway alterations. Two of the three patients with mismatch repair–deficient ECs acquired ESR1 mutations at the time of progression. CONCLUSION Baseline and on-treatment ctDNA dynamics may provide an early indication of benefit from letrozole/abemaciclib in EC. ctDNA at the time of progression may identify resistance alterations that may inform subsequent therapy.

RESOLVE: Abemaciclib + Letrozole +/- Metformin, Zotatifin, or Gedatolisib in Endometrial or Low-Grade Serous Ovarian Cancer

This research study is studying a combination of targeted therapies as a possible treatment for estrogen-receptor positive (ER+) endometrial cancer and low-grade serous ovarian cancer. The drugs involved in this study are: * Abemaciclib (also known as Verzenio™) * Letrozole (also known as Femara®) * Metformin (also known as Glucophage®) * Zotatifin (also known as eFT226) * Gedatolisib (also known as PF-05212384)