Abstract CT034: Phase I study of WNT974 + spartalizumab in patients (pts) with advanced solid tumors

Abstract

Background: WNT974, a Porcupine inhibitor, has shown evidence of Wnt pathway inhibition in clinical trials. Dysregulated Wnt signaling has been linked to immunotherapy resistance, suggesting WNT974 may act synergistically with checkpoint inhibitors. Spartalizumab is an αPD-1 mAb with demonstrated clinical activity in solid tumors. Methods: In this Phase I, open-label trial (NCT01351103) adult pts received WNT974 ± spartalizumab; here we report on the dose escalation of the combination. Eligible pts had melanoma (including uveal), lung SCC, HNSCC, esophageal SCC, cervical SCC, or TNBC. Pts with melanoma, lung SCC, or HNSCC must have had a best response of progressive disease (primary refractory) to prior αPD-1 therapy; other pts were naïve or primary refractory to prior αPD-1. WNT974 was dosed orally QD in 28-day cycles (2.5-10 mg, Days 1-8 or 1-15 of Cycles 1 or 1-4); spartalizumab was dosed IV at 400 mg Q4W. Objectives were to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE), safety, pharmacokinetics (PK), pharmacodynamics, and activity of WNT974 + spartalizumab. Pre- and on-treatment pt samples were collected: skin samples for RT-PCR analysis of AXIN2, a marker of Wnt pathway activity; tumor samples for RNAseq of AXIN2 and immune cell markers. Results: As of Sept 2, 2019, 27 pts were enrolled: 24 discontinued (18 due to disease progression; 67%), 3 were ongoing. Most common tumor types were non-uveal melanoma (n=8), TNBC (n=7), and uveal melanoma (n=5); 63% had received prior αPD-1. PK parameters for WNT974 + spartalizumab were consistent with prior single agent data. Dose-limiting toxicities were reported in 2 pts: Grade (G) 2 spinal compression fracture that occurred in the setting of trauma and G3 arthralgia. 78% of pts experienced a treatment-related AE, the most common being hypothyroidism (19%); 4 pts (15%) had 7 suspected-related G3/4 AEs (arthralgia, atrial fibrillation, diabetes mellitus, diabetic ketoacidosis, hyperglycemia, hyponatremia, and maculopapular rash). One pt (4%) with TNBC had a partial response, 11 pts (41%) had stable disease (SD), 13 pts (48%) had progressive disease; response was unknown in 2 pts. SD was reported in 9/17 pts (53%) who were primary refractory to prior αPD-1; 4 remained on study >24 wks. All pts with uveal melanoma (n=5) had SD. Evidence of Porcupine inhibition, assessed by skin AXIN2 suppression, was detected at all dose levels studied. Pts with the largest reductions in tumor size had on-treatment increases in immune marker mRNA in tumor samples, including a pt with αPD-1 primary refractory melanoma with high baseline AXIN2 expression and 42% reduction in the sum of target lesion diameters; this pt remained on study at 48 wks at the cutoff date. Conclusions: WNT974 + spartalizumab was well tolerated; MTD/RDE have not been determined. Preliminary data suggest blocking Wnt signaling may enable response to checkpoint inhibition in some pts. Citation Format: Filip Janku, Filip de Vos, Maria de Miguel, Patrick Forde, Antoni Ribas, Misako Nagasaka, Guillem Argiles, Ana Maria Arance, Aitano Calvo, Marios Giannakis, Maritza Melendez, Jiachang Gong, Sebastian Szpakowski, Rebecca Kan, Susan E. Moody, Maja De Jonge. Phase I study of WNT974 + spartalizumab in patients (pts) with advanced solid tumors [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 CT034.

WLS-Wnt signaling promotes neuroendocrine prostate cancer

“…This multi-site trial is still in the recruiting phase for most of the sites participating in the trial but is currently active and set to be completed in 2022. The results of the interim analysis recently demonstrated that a combined use of LGK974 (named as WNT974 in this trial) G spartalizumab alongside effective skin AXIN2 suppression was well tolerated in patients with several types of advanced solid tumors (Janku et al, 2020). Nevertheless, more attention to the end results of this trial would be needed for an overall assessment of the safety and potential of LGK974 for further clinical development.…”

Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy

“…Bone-related AEs, including bone fracture, emerged in the initial part of both phase I studies and were not observed subsequently after monitoring protocols, intermittent dosing, and prophylactic bone protective agents were initiated ( Davis et al, 2020 ; Moore et al, 2019 ). This safety profile has been manageable and lacks immune-related AEs, an encouraging attribute for combining these agents with ICI therapy ( Janku et al, 2020 ).…”

Genomic Profiling Reveals the Molecular Landscape of Gastrointestinal Tract Cancers in Chinese Patients

“…Recent studies found that depletion of RNF43 enhanced tumor growth in GI cancers and conferred resistance to DNA-damageinducing chemotherapies and γ-radiation in gastric cancer cells (Neumeyer et al, 2019(Neumeyer et al, , 2020. Additionally, preclinical cancer models have shown the responsiveness of RNF43 mutations to Wnt inhibitors, several of which are in clinical trials (Janku et al, 2015(Janku et al, , 2020Yu et al, 2020). Therefore, screening for RNF43 mutational status could direct therapy selections for GI cancer treatments.…”