Abstract CT188: Pharmacodynamic changes by durvalumab in combination with chemotherapy in women with untreated, advanced stage ovarian cancer
Authors: Westin Shannon N. , Lee Sanghoon , Zhao Li , Yuan Ying , Wu Jimin , Hajek Richard , Sharafi Sara , Meyer Larissa A. , Fleming Nicole D. , Jazaeri Amir , Coleman Robert L. , Lu Karen H. , Mills Gordon B. , Zhang Jianhua , Futreal Andrew , Sood Anil K. 
Published: September 2020

Abstract
Objectives: To evaluate safety and efficacy of durvalumab (D) in combination with paclitaxel (P) and carboplatin (C) in newly diagnosed, advanced-stage, high grade, non-mucinous ovarian cancer (OC). To investigate informative pharmacodynamic changes including proteome changes and immune-related pathways by treatment with immuno-oncology therapy in combination with chemotherapy. Methods: In this single arm phase II study, patients (pts) with untreated, advanced stage (III/IV) OC dispositioned to neoadjuvant chemotherapy (NACT) received D (750mg) with weekly P (80mg/m2) and C (AUC6) after baseline tissue biopsy. Matched biopsies were obtained at tumor reductive surgery (TRS) after 3 cycles. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. Reverse-phase protein arrays (RPPA) were performed on pre- and post-treatment tissues. Protein expression alteration and an enriched Reactome pathway analysis using differentially expressed proteins between pre- and post-treatments were assessed. Results: 19 pts were enrolled and 18 treated. Median age was 63 and 50% had stage III disease. No dose-limiting toxicities were observed. 94% of pts had an adverse event (AE). Most common AEs were anemia (94%), neutropenia (83%), fatigue (72%), hyperglycemia (73%), and thrombocytopenia (66%). Immune-related AEs observed included hyperthyroidism (22%), hypothyroidism (22%), diarrhea (6%), hypophysitis (6%). Eighty-three percent had optimal interval TRS, 70% had a pre-operative response by RECIST (PR=11, CR=1). At 13 months (mo) median follow up, 9 pts (50%) had disease progression and median PFS was 14.5 mo (95% CI: 9.2 - NA). Median OS was not reached; OS rate at 18 mo was 69% (95% CI 0.21 - 0.91). Fifty-five tumor specimens were available from 9 pts (31 pre- and 24 post-treatment). Thirteen significantly differentially expressed proteins among 211 proteins (adj. p&lt;0.1, log2FC≥1) were identified. One upregulated protein, XBP1 (log2FC=1.37) and 12 downregulated proteins were observed, including EMA, PAR, IGFBP2, and EVI1, at post- compared to pre-treatment. PD-L1 expression was significantly elevated post-treatment (adj. p=0.0065). Pathway analysis revealed pyruvate metabolism and citric acid (TCA) and PI3K/AKT were upregulated in post- compared to pre-treatment (p&lt;0.05, FDR&lt;1). Cell cycle, mismatch repair, DNA double-strand break ends processing, and homology-directed repair (HDR) through Homologous Recombination were downregulated in post- compared to pre-treatment samples (p&lt;0.05, FDR&lt;0.5). Conclusion: Durvalumab can be safely combined with chemotherapy in upfront OC with reasonable efficacy. Observed protein changes after treatment provide important implications for strategies combining immune agents and chemotherapy and inform biomarker development to individualize therapy based on induction exposure.
Citation Format: Shannon N. Westin, Sanghoon Lee, Li Zhao, Ying Yuan, Jimin Wu, Richard Hajek, Sara Sharafi, Larissa A. Meyer, Nicole D. Fleming, Amir Jazaeri, Robert L. Coleman, Karen H. Lu, Gordon B. Mills, Jianhua Zhang, Andrew Futreal, Anil K. Sood. Pharmacodynamic changes by durvalumab in combination with chemotherapy in women with untreated, advanced stage ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT188.