Rebecca A. Previs

Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification

PURPOSE Preclinical cancer models harboring CCNE1 amplification were more sensitive to adavosertib treatment, a WEE1 kinase inhibitor, than models without amplification. Thus, we conducted this phase II study to assess the antitumor activity of adavosertib in patients with CCNE1-amplified, advanced refractory solid tumors. PATIENTS AND METHODS Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring CCNE1 amplification, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function were studied. Patients received 300 mg of adavosertib once daily on days 1 through 5 and 8 through 12 of a 21-day cycle. The trial followed Bayesian optimal phase II design. The primary end point was objective response rate (ORR). RESULTS Thirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue. CONCLUSION Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring CCNE1 amplification, especially in epithelial ovarian cancer. Further study of adavosertib, alone or in combination with other therapeutic agents, in CCNE1-amplified epithelial ovarian cancer is warranted.

Associations of Healthcare Affordability, Availability, and Accessibility with Quality Treatment Metrics in Patients with Ovarian Cancer

Abstract Background: Differential access to quality care is associated with racial disparities in ovarian cancer survival. Few studies have examined the association of multiple healthcare access (HCA) dimensions with racial disparities in quality treatment metrics, that is, primary debulking surgery performed by a gynecologic oncologist and initiation of guideline-recommended systemic therapy. Methods: We analyzed data for patients with ovarian cancer diagnosed from 2008 to 2015 in the Surveillance, Epidemiology, and End Results–Medicare database. We defined HCA dimensions as affordability, availability, and accessibility. Modified Poisson regressions with sandwich error estimation were used to estimate the relative risk (RR) for quality treatment. Results: The study cohort was 7% NH-Black, 6% Hispanic, and 87% NH-White. Overall, 29% of patients received surgery and 68% initiated systemic therapy. After adjusting for clinical variables, NH-Black patients were less likely to receive surgery [RR, 0.83; 95% confidence interval (CI), 0.70–0.98]; the observed association was attenuated after adjusting for healthcare affordability, accessibility, and availability (RR, 0.91; 95% CI, 0.77–1.08). Dual enrollment in Medicaid and Medicare compared with Medicare only was associated with lower likelihood of receiving surgery (RR, 0.86; 95% CI, 0.76–0.97) and systemic therapy (RR, 0.94; 95% CI, 0.92–0.97). Receiving treatment at a facility in the highest quartile of ovarian cancer surgical volume was associated with higher likelihood of surgery (RR, 1.12; 95% CI, 1.04–1.21). Conclusions: Racial differences were observed in ovarian cancer treatment quality and were partly explained by multiple HCA dimensions. Impact: Strategies to mitigate racial disparities in ovarian cancer treatment quality must focus on multiple HCA dimensions. Additional dimensions, acceptability and accommodation, may also be key to addressing disparities.

Oncolytic adenovirus MEM-288 encoding membrane-stable CD40L and IFNβ induces an anti-tumor immune response in high grade serous ovarian cancer

Single agent immune checkpoint inhibitors have been ineffective for patients with advanced stage and recurrent high grade serous ovarian cancer (HGSOC). Using pre-clinical models of HGSOC, we evaluated the anti-tumor and immune stimulatory effects of an oncolytic adenovirus, MEM-288. This conditionally replicative virus encodes a modified membrane stable CD40L and IFNβ. We demonstrated this virus successfully infects HGSOC cell lines and primary human ascites samples in vitro. We evaluated the anti-tumor and immunostimulatory activity in vivo in immune competent mouse models. Intraperitoneal delivery of MEM-288 decreased ascites and solid tumor burden compared to controls, and treatment generated a systemic anti-tumor immune response. The tumor microenvironment had a higher proportion of anti-tumor macrophages and decreased markers of angiogenesis. MEM-288 is a promising immunotherapy agent in HGSOC, with further pre-clinical studies required to understand the mechanism of action in the peritoneal microenvironment and clinical activity in combination with other therapies.

Health Care Access Dimensions and Racial Disparities in End-of-Life Care Quality among Patients with Ovarian Cancer

Abstract This study investigated the association between health care access (HCA) dimensions and racial disparities in end-of-life (EOL) care quality among non-Hispanic Black (NHB), non-Hispanic White (NHW), and Hispanic patients with ovarian cancer. This retrospective cohort study used the Surveillance, Epidemiology, and End Results–linked Medicare data for women diagnosed with ovarian cancer from 2008 to 2015, ages 65 years and older. Health care affordability, accessibility, and availability measures were assessed at the census tract or regional levels, and associations between these measures and quality of EOL care were examined using multivariable-adjusted regression models, as appropriate. The final sample included 4,646 women [mean age (SD), 77.5 (7.0) years]; 87.4% NHW, 6.9% NHB, and 5.7% Hispanic. In the multivariable-adjusted models, affordability was associated with a decreased risk of intensive care unit stay [adjusted relative risk (aRR) 0.90, 95% confidence interval (CI): 0.83–0.98] and in-hospital death (aRR 0.91, 95% CI: 0.84–0.98). After adjustment for HCA dimensions, NHB patients had lower-quality EOL care compared with NHW patients, defined as: increased risk of hospitalization in the last 30 days of life (aRR 1.16, 95% CI: 1.03–1.30), no hospice care (aRR 1.23, 95% CI: 1.04–1.44), in-hospital death (aRR 1.27, 95% CI: 1.03–1.57), and higher counts of poor-quality EOL care outcomes (count ratio:1.19, 95% CI: 1.04–1.36). HCA dimensions were strong predictors of EOL care quality; however, racial disparities persisted, suggesting that additional drivers of these disparities remain to be identified. Significance: Among patients with ovarian cancer, Black patients had lower-quality EOL care, even after adjusting for three structural barriers to HCA, namely affordability, availability, and accessibility. This suggests an important need to investigate the roles of yet unexplored barriers to HCA such as accommodation and acceptability, as drivers of poor-quality EOL care among Black patients with ovarian cancer.