Emily K. Hill

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium

Purpose: The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer. Patients and Methods: This single-arm, open-label, multicenter phase II study enrolled patients with RECIST measurable advanced endometrial cancer. Patients could have received ≤ 1 prior platinum-based regimen and ≤ one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared with historical control rate of 50%. Results: A total of 46 patients were enrolled and 43 were evaluable for ORR. Median age was 66 (range: 43–86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic endometrial cancer. Patients received carboplatin AUC6, paclitaxel 175 mg/m2, and pembrolizumab 200 mg i.v. every 3 weeks for up to six cycles. ORR was 74.4% (32/43), higher than historic controls (P = 0.001). Median progression-free survival (PFS) was 10.6 months (95% confidence interval, 8.3–13.9 months). The most common grade 1–2 treatment-related adverse event (TRAE) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%), and neuropathy (13%), while the most common grade 3–4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T-cell populations at baseline in responders. The CD8+ T-cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared with nonresponders. Conclusions: Addition of pembrolizumab to carboplatin and paclitaxel for advanced endometrial cancer was tolerated and improved ORR compared with historical outcomes. Significance: The results of the study support that the combination of pembrolizumab with carboplatin and paclitaxel is well tolerated and active in patients with advanced endometrial cancer. The duration of response and the PFS were significantly longer in patients with mismatch repair deficient/microsatellite instability-high compared with mismatch repair proficient/microsatellite stable tumors. Responders to treatment tend to have enriched CD8+ T-cell and CD4+ T-cell populations among peripheral blood mononuclear cells at baseline.

A Surgical Window Trial Evaluating Medroxyprogesterone Acetate with or without Entinostat in Patients with Endometrial Cancer and Validation of Biomarkers of Cellular Response

Abstract Purpose: This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone versus MPA plus the histone deacetylase (HDAC) inhibitor entinostat on regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma. Patients and Methods: This multisite, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth on days 1, 8, and 15 was randomly assigned with equal probability. Surgery followed on days 21–24. Pretreatment and posttreatment tissue was assessed for PR H-scores, Ki-67 levels, and histologic response. Results: Fifty patients were accrued in 4 months; 22 and 20 participants had PR evaluable pretreatment and posttreatment slides in the MPA and MPA/entinostat arms, respectively. Median posttreatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs. 27, MPA/entinostat 260 vs. 23, respectively, P = 0.87). Decreased Ki-67 was shown in 90% treated with MPA/entinostat compared with 68% treated with MPA alone (P = 0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) versus not decreased (45). The decrease in PR pretreatment versus posttreatment was associated with loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (P < 0.008). Conclusions: This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki-67 as secondary endpoint. Despite no immediate effect of entinostat on PR in this short-term study, lessons learned can inform future window and treatment trials.