Abstract B119: Relationship of NaPi2b expression and efficacy of XMT-1536, a NaPi2b targeting antibody-drug conjugate (ADC), in an unselected panel of human primary ovarian mouse xenograft models
Authors: Mosher Rebecca , Poling Laura , Qin LiuLiang , Bodyak Natalya , Bergstrom Donald 
Published: August 2018

Abstract
NaPi2b (SLC34A2) is expressed in many human ovarian and lung cancers. Previous human clinical trials with a NaPi2b targeting MMAE ADC have shown objective tumor responses, but have not shown a strong relationship between NaPi2b expression and the probability of response. XMT-1536 is a NaPi2b targeting ADC comprising a novel humanized antibody conjugated with 10-15 auristatin F-HPA (AF-HPA) payload molecules via the Dolaflexin platform. AF-HPA is capable of controlled bystander-effect killing, resulting in efficacy in tumors with heterogeneous antigen expression, and is metabolized intratumorally to an active nonpermeable metabolite to enable greater systemic tolerability. Previously presented preclinical studies using XMT-1536 have demonstrated efficacy in vivo in the NaPi2b-expressing OVCAR3 ovarian cancer line model. Here, we describe the evaluation of XMT-1536 in a panel of patient-derived xenograft models of human ovarian cancer, unselected for NaPi2b expression. The efficacy data from this study were compared to characteristics of each model, including NaPi2b expression, to predict a model for stratification of patients in XMT-1536 clinical trials.
Primary ovarian cancer models were derived from serous ovarian or fallopian tube cancers and implanted in immunocompromised mice. Once tumors reached a stratified mean volume of 125-250 mm3, mice were treated with 3 mg/kg XMT-1536 weekly for three weeks in groups of n=3. Untreated animals in groups of n=2-4 were included as a control. The planned study endpoint was a tumor volume of 1 cm3 or 45 days. In a case of complete response, mice were followed for a longer time course to evaluate for tumor regrowth. An immunohistochemistry (IHC) assay to detect NaPi2b was established. Tumor blocks from untreated study animals were evaluated to determine an efficacy/staining pattern relationship. The established protocol was also applied to a series of human primary ovarian tumors. As of July 2017, treatment response data are available for 19 primary ovarian cancer mouse xenograft models, and NaPi2b IHC results are available for 15 models. XMT-1536 induced at least 50% reduction in tumor volume relative to baseline in 10/19 (53%) of all tested models, with tumor volume reduction greater than 50% in 8/15 (53%) of models with available IHC data. There was an association between NaPi2b IHC H-score and tumor volume change after XMT-1536 treatment (Spearman rank coefficient 0.72). Among tumors with H-score ≥70, 8/10 (80%) models achieved 50% or greater reduction in tumor volume after XMT-1536 treatment vs 0/5 (0%) models with H-score &lt;70. Applying the same IHC assay to primary human ovarian tumors, 12/20 (60%) tested tumors had an H-score ≥70. This study demonstrates broad activity of XMT-1536 in a panel of primary ovarian cancer mouse xenograft models without molecular selection for NaPi2b expression. NaPi2b expression measured by IHC assay is associated with the probability of tumor model response to XMT-1536 treatment and may be useful for patient stratification/selection in the clinic. XMT-1536 is scheduled to enter phase 1 evaluation in patients with ovarian cancer and other NaPi2b-expressing tumors in early 2018. The trial will include mandatory tissue collection to evaluate the relationship of NaPi2b expression with activity of XMT-1536.
Citation Format: Rebecca Mosher, Laura Poling, LiuLiang Qin, Natalya Bodyak, Donald Bergstrom. Relationship of NaPi2b expression and efficacy of XMT-1536, a NaPi2b targeting antibody-drug conjugate (ADC), in an unselected panel of human primary ovarian mouse xenograft models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B119.