Abstract CT175: Biomarker analyses from a phase I study of WNT974, a first-in-class Porcupine inhibitor, in patients (pts) with advanced solid tumors
Authors: Rodon Jordi , Argilés Guillem , Connolly Roisin M. , Vaishampayan Ulka , Jonge Maja de , Garralda Elena , Giannakis Marios , Smith David C. , Dobson Jason R. , McLaughlin Margaret , Seroutou Abdelkader , Ji Yan , Dolan Sinead , Morawiak Jennifer , Moody Susan , Janku Filip 
Published: August 2018

Background: Dysregulated Wnt/β-catenin signaling has been linked to several cancers, including pancreatic cancer (PC) and colorectal cancer (CRC). WNT974 (formerly LGK974) - a first-in-class, selective, oral inhibitor of Porcupine (an O-acyltransferase required for Wnt activation and secretion) - has shown preclinical activity in tumor models with mutations upstream in the Wnt pathway. Furthermore, dysregulated Wnt signaling has been linked to T-cell exclusion in tumor tissue and resistance to immunotherapy, suggesting WNT974 may act synergistically with checkpoint inhibitors.

Methods: This ongoing Phase I, open-label, dose-escalation and -expansion study (NCT01351103) is designed to determine the maximum tolerated dose and/or recommended dose for expansion, characterize the safety and tolerability, and assess preliminary antitumor activity, pharmacokinetic (PK), and pharmacodynamic properties of WNT974, alone or combined with PDR001 (spartalizumab, an anti-PD-1 antibody) in advanced/metastatic solid tumors. Here, we focus on preliminary biomarker analyses from the single-agent part of the study. The study initially enrolled pts with lobular breast cancer and melanoma and was later amended to enroll pts with triple negative breast cancer (TNBC), PC, and CRC, and those with tumors with genetic alterations upstream in the Wnt pathway. Pre and on-treatment skin and tumor tissue specimens were collected for RT-PCR analysis of AXIN2, a marker of Wnt pathway activity. NanoString gene expression was measured in a subset of pts using remnant RNA from the tumor samples, and chemokine and dendritic cell signatures were analyzed pre and on-treatment.

Results: At the data cut-off date, March 2, 2017, 94 pts were enrolled. Median age was 58.5 years (range, 28-77), 43% were male, and the most common cancer types were PC (30%), melanoma (26%), and breast cancer (21%). Patients received single-agent WNT974 orally at doses of 5, 7.5, 10, 15, 20, 22.5, or 30 mg daily, 30 or 45 mg intermittently (4 days on, 3 days off), or 5 mg twice daily. Median duration of exposure was 4.9 weeks (range, 0.1-27.7). Safety, tolerability, and PK have previously been reported. AXIN2 expression in paired samples from skin and tumor showed evidence of Wnt pathway inhibition in all indications; this was not dose-dependent in the dose range studied. Immune signature analyses of a paired tumor sample subset (n=8) revealed an inverse association between change in AXIN2 expression and change in chemokine and activated dendritic cell signatures.

Conclusions: Biomarker analyses show that WNT974 can potently inhibit Wnt pathway activity in skin and tumors. Immune signature data suggest that WNT974 treatment may promote T-cell recruitment into tumors, and support investigation of the combination of WNT974 with immunotherapy. The combination part of this study evaluating WNT974 combined with PDR001 (spartalizumab) is ongoing.

Citation Format: Jordi Rodon, Guillem Argilés, Roisin M. Connolly, Ulka Vaishampayan, Maja de Jonge, Elena Garralda, Marios Giannakis, David C. Smith, Jason R. Dobson, Margaret McLaughlin, Abdelkader Seroutou, Yan Ji, Sinead Dolan, Jennifer Morawiak, Susan Moody, Filip Janku. Biomarker analyses from a phase I study of WNT974, a first-in-class Porcupine inhibitor, in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT175.