KGOG 3046/TRU-D: a phase II study of durvalumab and tremelimumab with front-line neoadjuvant chemotherapy in patients with advanced-stage epithelial ovarian cancer

Abstract

<h3>Objectives:</h3> We hypothesized that adding durvalumab and tremelimumab to chemotherapy in advanced-stage epithelial ovarian cancer (aEOC) would increase progression-free survival (PFS) with minimal effects on safety. KGOG 3046 (NCT03899610) is a single-arm phase 2 study evaluating the combination of dual immune checkpoint inhibition and neoadjuvant chemotherapy (NAC) for the upfront treatment of aEOC. <h3>Methods:</h3> Patients with FIGO stage IIIC-IV EOC were offered three cycles of durvalumab (1500 mg), tremelimumab (75 mg) with chemotherapy for NAC followed by interval debulking surgery (IDS). After surgery, three cycles of durvalumab (1120 mg) and adjuvant chemotherapy followed by durvalumab maintenance (1120 mg [total 12 cycles]) were administered. During treatment, serial biopsies were performed at pre-treatment, IDS, and progression to identify immune biomarkers and changes in the tumor microenvironment. The primary endpoint was a 12 months PFS rate. Interim analysis was performed to evaluate outcomes after NAC (RECIST after NAC, R0 rate at IDS, the rate of CRS 3 at IDS, safety, a range of translational parameters) after all patients underwent IDS. <h3>Results:</h3> A total of 23 patients were enrolled with a median age of 60 years (range:44-77 years). The majority were presented with high-grade serous carcinoma (87.0%) and stage IV disease (60.9%). After NAC, 3 patients experienced a complete response (13.0%) and 20 patients had a partial response (87.0%). At IDS, R0 resection was achieved in 17 patients (73.9%); 9 patients (39.1%) had a CRS of 3; pathologic complete remission was achieved in 4 patients (17.4%). A total of 2 patients (8.7%) delayed IDS due to grade 4 skin rash and pneumonitis, respectively. Skin rashes were the most common adverse events (56.5%) and grade ≥3 events occurred in 3 patients (13.0%), which completely resolved after steroid use. Treatment was associated with tumor microenvironment conversion to an "inflamed" phenotype, with a significant increase in cytolytic index (P=0.015), stromal score (P<0.001) and immune score (P=0.004) on whole-transcriptome sequencing. <h3>Conclusions:</h3> These interim data highlight the clinical activity and a manageable toxicity profile for the addition of durvalumab and tremelimumab to NAC in aEOC. Additional correlative data will be presented at the meeting. This study is actively enrolling patients in an expansion cohort.