Abstract 391P
Background
Dysregulated Wnt signalling drives many GI cancers through effects on proliferation and immune evasion. Wnt-dependent pancreatic ductal adenocarcinomas (PDAC) are identified by loss of function (LoF) RNF43 mutations, whilst ∼70% of biliary tract cancers (BTC) have high Wnt ligand expression. PDAC and BTC have poor prognoses and outcomes with standard treatments. Inhibiting Protein-serine O-palmitoyltransferase (PORCN), which activates Wnt ligands, is the only successful clinical approach to date to block the Wnt pathway.
Methods
Eligible patients were ≥18 yrs with histologically-confirmed advanced PDAC (Module 1 [M1]) or BTC (M2, M3) that had progressed after first-line treatment. M1 pts had RNF43_LoF detectable in archival FFPE tumour. M2 and M3 pts were molecularly-unselected. Pts received RXC004 monotherapy (2mg QD; M1 and M2) or in combination (1.5mg QD) with pembrolizumab (M3). Pts received denosumab to prevent bone mineral density (BMD) loss, a known effect of Wnt inhibition. The primary endpoint was progression free survival at 6 months (PFS6) for M1 and M2, and objective response rate (ORR) for M3. Secondary endpoints included safety, PK and disease control rate (DCR) at ≥6 wks.
Results
45 pts were enrolled (M1=6, M2=20, M3=19) with 37 efficacy evaluable. In M1, 1/5 (20%) achieved confirmed PR (cPR); DCR was 20%; no pts achieved PFS6. In M2, 1/18 (6%) achieved cPR, 4/18 (22%) had stable disease (SD), with an overall DCR of 28%; 1/18 (6%) reached PFS6. In M3, ORR was 0% with an overall DCR of 43% (6/14). The most common AEs overall were dysgeusia, nausea, vomiting, fatigue, constipation, diarrhoea; in M3, auto-immune events including colitis were observed. No bone fragility events or BMD loss occurred.
Conclusions
RXC004 was tolerable; denosumab prevented BMD loss. No conclusions on efficacy can be drawn in PDAC due to insufficient recruitment. Whilst some durable clinical benefit was seen, efficacy results in unselected advanced BTC pts are not sufficient to support further development. Identification of BTC pt subgroups that would benefit most from treatment with Wnt pathway inhibitors is warranted.
Clinical trial identification
EudraCT Number: 2020-005804-20.
Legal entity responsible for the study
Redx Pharma.
Funding
Redx Pharma.
Disclosure
J.A. Bridgewater: Financial Interests, Personal, Advisory Board: Taiho, BMS, Incyte, Basilea, Servier; Financial Interests, Personal, Other, Advisor: AstraZeneca; Financial Interests, Institutional, Funding: Incyte. R. Hubner: Financial Interests, Personal, Expert Testimony: Novartis, AstraZeneca; Financial Interests, Personal, Other, Clinical trial steering committee membership: Ipsen, BeiGene; Other, Conference attendance funding: Roche. N. Starling: Financial Interests, Personal, Advisory Board: GSK, Novartis, MSD Oncology, Servier, AstraZeneca, Pfizer, Gilead Sciences, Seagen, Janssen, Takeda, Moderna, BMS; Financial Interests, Personal, Invited Speaker: Eli Lilly, Pierre Fabre, Amgen, Merck Serono, Novartis, MSD Oncology, GSK, Servier, Seagen, BMS, AstraZeneca, Astellas; Financial Interests, Institutional, Research Grant, Sept 2017 (24m) Paid to institution research: Merck; Financial Interests, Institutional, Research Grant, Nov 2017 (48m) -Paid to institution research fund: AstraZeneca; Financial Interests, Institutional, Research Grant, Jan 2018 - Paid to institution research fund: Pfizer; Financial Interests, Institutional, Research Grant, July 2018 (36m) Paid to institution research fund: BMS; Financial Interests, Institutional, Research Grant, June 2022 - Paid to institution research fund: Guardant; Financial Interests, Institutional, Research Grant, August 2023 - Paid to institution research fund: Gilead; Non-Financial Interests, Advisory Role, Ad Board uncompensated: Guardant. M. Chisamore: Financial Interests, Institutional, Other: Merck & Co. Inc. L. Goodwin, D. Wilson, C. Phillips, J. Robertson, H. Timmis, Z. Setchellova, S.A. Woodcock: Financial Interests, Institutional, Sponsor/Funding: Redx Pharma. All other authors have declared no conflicts of interest.