Pembrolizumab plus chemotherapy in frontline treatment of advanced epithelial ovarian cancer: clinical and translational results from a phase II trial

We evaluated the efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC). Additionally, chemotherapy-induced changes in the tumor microenvironment and biomarkers of response were evaluated. In this single-arm phase II trial, eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction; then, adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab was given for 3 cycles and maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA-sequencing, reverse phase protein array analyses were performed on pre- and post-chemotherapy samples. Thirty-one eligible patients were enrolled. Median PFS was 14.88 months overall (95% CI 12.40 – 23.00). Among those with PD-L1 Combined Positive Score (CPS), the median PFS and OS were not reached compared to those with CPS<10 (10.50 and 30.90 months, respectively). All patients who initiated chemotherapy with pembrolizumab therapy completed their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling. In conclusion, pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS≥10 may benefit more from this regimen and future studies should investigate this potential biomarker. Funding for this investigator-initiated trial was provided by Merck. Clinicaltrials.gov: NCT02520154. Tumor specimens were collected at two time points: 1) prior to start of neoadjuvant chemotherapy and 2) at time of interval cytoreduction. Pre-neoadjuvant chemotherapy samples were obtained either at the time of diagnostic laparoscopy or via diagnostic biopsies performed by interventional radiology. RNA-seq was performed in the MD Anderson Cancer Genomics Core Laboratory.