Checkpoint blockade combined with neoadjuvant chemotherapy (NACT) in advanced-stage epithelial ovarian cancer (EOC): preliminary results from a phase II clinical trial

Abstract

<h3>Objectives:</h3> Standard of care treatment for advanced stage EOC is a combination of chemotherapy and surgery. Despite this approach, the majority of women remain incurable, underscoring the need for novel therapeutics. This study assessed the pathologic objective response rate (pORR), historically reported as 6-10% and tumor transcriptomic changes in women with advanced stage EOC treated with neoadjuvant pembrolizumab, paclitaxel, and carboplatin. <h3>Methods:</h3> This was an open-label, single-arm, phase II trial for women with newly diagnosed biopsy proven EOC dispositioned to receive carboplatin, paclitaxel and pembrolizumab 200mg/m² every 21 days. Patients received 3-4 cycles prior to interval debulking surgery followed by another 3-4 cycles of adjuvant therapy. A planned interim analysis to assess futility (based on reported historic response with NACT, required 1 pORR) was completed after enrollment of 20 of planned 40 evaluable patients. Transcriptomic analyses of bulk RNA to identify functional genes and significant pathways from matched specimens from treatment naïve tumor, and tumor after 3-4 cycles of NACT plus immune checkpoint inhibitor, (ICI) were completed. Strand-specific RNA libraries were sequenced using single-end reads (50 bp, average 40 million reads per sample) on the DNBS<i>eq platform.</i> Differentially expressed genes (DEG) with a false discovery rate q < 0.05 and a fold change of > 1.5 were used. <h3>Results:</h3> Interim data for the first 20 patients evaluable for pORR are reported. Most women were White (95%) and had high grade serous histology (100%). In 11 cases (55%), R0 (complete) cytoreduction was achieved. There have been no surgical complications related to combination treatment. Treatment was generally well tolerated, with mostly grade 1/2 toxicity: 30% pruritic rash, 10% thyroid abnormalities. One patient had grade 3 nephritis that recovered with treatment. A total of 6 patients achieved a pathologic complete response (pCR, 30%) and another 4 (25%) pathologic partial response (pPR) for a 55% pORR. There were 4 pts with deleterious genetic mutation in the homologous recombination pathway (20%) and 2 patients with Fanconi anemia somatic mutations (10%). There were 863 DEGs between the chemonaïve and ICI+NACT matched tumors. ICI+NACT induced activation of PI3K-Akt pathway, myeloid differentiation, AGE-RAGE signaling, and focal adhesion kinase pathways which included upregulation of FXR, NLRP11 and FOXL2 expression, known regulators of inflammation and immune responses. <h3>Conclusions:</h3> Interim analysis demonstrates an increase in pORR compared to previously reported in literature (6-10%) and is generally well tolerated. Transcriptomic analyses revealed specific ICI induced gene signatures when combined with NACT. Further characterization of complete and partial responders are needed to improve patient selection for ICI therapies.