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/m(2), 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.