TY - JOUR
T1 - Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours
AU - Rodon, Jordi
AU - Argilés, Guillem
AU - Connolly, Roisin M.
AU - Vaishampayan, Ulka
AU - de Jonge, Maja
AU - Garralda, Elena
AU - Giannakis, Marios
AU - Smith, David C.
AU - Dobson, Jason R.
AU - McLaughlin, Margaret E.
AU - Seroutou, Abdelkader
AU - Ji, Yan
AU - Morawiak, Jennifer
AU - Moody, Susan E.
AU - Janku, Filip
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Cancer Research UK.
PY - 2021/7/6
Y1 - 2021/7/6
N2 - Background: This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours. Methods: Patients (n = 94) received oral WNT974 at doses of 5–30 mg once-daily, plus additional dosing schedules. Results: The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8). Conclusions: Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity. Clinical trial registration: NCT01351103.
AB - Background: This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours. Methods: Patients (n = 94) received oral WNT974 at doses of 5–30 mg once-daily, plus additional dosing schedules. Results: The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8). Conclusions: Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity. Clinical trial registration: NCT01351103.
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U2 - 10.1038/s41416-021-01389-8
DO - 10.1038/s41416-021-01389-8
M3 - Article
C2 - 33941878
AN - SCOPUS:85105212701
SN - 0007-0920
VL - 125
SP - 28
EP - 37
JO - British journal of cancer
JF - British journal of cancer
IS - 1
ER -