Abstract
Abstract Purpose: DNIB0600A and DMUC5754A are two ADCs that conjugate the anti-mitotic agent MMAE with anti-NaPi2b and anti-MUC16 monoclonal antibodies, respectively. Both ADCs have shown promising anti-tumor activity in patients with platinum resistant ovarian cancer. Here we report biomarker analysis in patient samples collected from these phase 1 studies. The main goal of this study is to evaluate tissue-based biomarkers that can predict response or resistance to these ADCs. We also explored the utility of serum protein biomarkers and circulating tumor cells (CTCs) as potential surrogates for monitoring treatment response to ADCs and disease progression. Methods: Biomarker analysis was done on 55 ovarian cancer patients treated with clinically relevant doses (1.8-3.2mg/kg) from DNIB0600A and DMUC5754A Phase 1 studies. Protein and mRNA expression levels of NaPi2b and MUC16 targets were assessed in archival tumor specimen by immunohistochemistry (IHC) and qRT-PCR respectively. Serum collected at baseline and post-treatment were analyzed by CA125 and HE4 ELISA assays as well as by the OLINK 96-plex PEA protein biomarker panel. CTCs at baseline and post-treatment were analyzed using the Veridex CellSearch System. Results: Target expression in tumor tissues for both NaPi2b and MUC16 measured by IHC and qRT-PCR are concordant. High NaPi2b or MUC16 expression (IHC 2+/3+) was identified in all responders by RECIST criteria (11 from DNIB0600A and 5 from DMUC5754A) for respective target, while no patient from either study with IHC 0 showed RECIST response. In patients treated with DNIB0600A, longitudinal changes in serum CA125 level correlated with RECIST response. Additionally, CTC was detected in 60% of patients at baseline in the DNIB0600A trial, and decreased CTC counts was observed after 1-2 cycles of treatment for two-third of patients. In patients treated with DMUC5754A, circulating CA125 (i.e. extra-cellular domain of MUC16 shed in circulation) is cleared after initial dosing; therefore other ovarian cancer biomarkers including HE4 were assessed. Baseline serum HE4 level correlates well with the tumor burden at pre-treatment in DMUC5754A trial, and showed excellent correlation with RECIST response post-treatment. Conclusions: Target expression in archival tumor tissues is predictive to clinical response to ADCs. CTC enumeration as well as serum HE4 could be used as potential surrogate biomarkers for monitoring treatment response in ovarian cancer. Further validation of these findings is required. Citation Format: Yulei Wang, Ron Firestein, Lisa Ryner, Walter Darbonne, Yinghui Guan, Shan Lu, YJ Choi, Yuanyuan Xiao, Paul Polakis, Becky Suttmann, Rupal Desai, Ling Fu, Ola Saad, Kirsten Achilles Poon, Mitch Denker, Vincent Leveque, Teiko Sumiyoshi, Mark Lackner, David Shames, Eric Humke, Daniel Mayslar. Biomarker evaluation of phase 1 clinical trials of antibody-drug conjugates (ADCs) in platinum resistant ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1441.
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