Abstract 37P
Background
Dysregulated Wnt signalling initiates and drives colorectal cancer (CRC) through proliferation and immune evasion. Microsatellite stable (MSS) CRC patients have poor outcomes on 3rd line standard of care (SoC), are immune cold and refractory to immune checkpoint inhibition (ICI). Wnt ligand dependent MSS CRCs are identified by loss of function RNF43 mutations or RSPO2/3 fusions; this subgroup has high co-occuring MAPK pathway mutations (81%) and poor prognosis. Inhibiting PORCN, which activates Wnt ligands, is the only successful clinical approach to date to block Wnt signalling.
Methods
Eligible pts were ≥18 yrs with histologically confirmed RNF43/RSPO aberrated (FFPE tumour via verified tests) MSS metastatic CRC that had progressed on ≥1 prior SoC. Pts received RXC004 monotherapy (2mg QD; Arm A) or in combination with nivolumab (1.5mg QD; Arm B). Pts received denosumab to prevent bone mineral density (BMD) loss, a known Wnt inhibitor effect. The primary endpoint was disease control rate (DCR, Arm A) or objective response rate (ORR, Arm B). Secondary objectives included safety and PK. PD assessed changes in Wnt pathway, immune cells and FDG-PET in tumour; and circulating tumour DNA (ctDNA).
Results
25 pts were enrolled (Arm A=17, Arm B=8) with 20 efficacy evaluable. In Arm A, 5/13 (38%) had best objective response (BOR) of stable disease (SD), with 15% (2/13) achieving DCR ≥16wks. In Arm B, 2/7 (29%) had BOR of partial response (PR; 1 confirmed, 1 unconfirmed) and 2/7 (29%) had SD, resulting in a RECIST-confirmed ORR of 14% (1/7) and DCR ≥16wks of 57% (4/7). Common AEs overall were dysgeusia, nausea, decreased appetite, diarrhoea, vomiting, alopecia, TBL increased and fatigue. No bone fragility events or BMD loss occurred. Wnt pathway, SUVmax and ctDNA reductions, and immune evasion reversal were seen.
Conclusions
RXC004 was tolerable; denosumab prevented BMD loss. In this poor prognosis subgroup, RXC004 monotherapy was comparable to late-line SoC in mCRC, whilst the nivolumab combination suggests improvement versus SoC and warrants further clinical investigation.
Clinical trial identification
EudraCT 2020-003132-24.
Legal entity responsible for the study
Redx Pharma.
Funding
Redx Pharma.
Disclosure
N. Cook: Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: Taiho, Roche, AstraZeneca, RedX, Orion, Avacta, Bayer, Eisai, UCB, Starpharma, Boehringer Ingelheim, Stemline; Non-Financial Interests, Advisory Role: Roche. S. Kopetz: Financial Interests, Personal, Advisory Board: Roche, EMD Serono, Merck, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca, Bayer, Pierre Fabre, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Jacobio, Pfizer, Repare Therapeutics, GSK, Jazz, Xilis, AbbVie, Gilead, Mirati, Flame, Servier, Carina, Bicara, Endeavor BioMedicines, Numab Pharma, Janssen; Financial Interests, Personal, Other, Research: Inivata, Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis; Financial Interests, Personal, Other, Consultant: Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Bristol Myers Squibb-Medarex, Amgen, Tempus, Foundation Medicine, Harbinger Oncology, Takeda, CureTeq, Zentalis, Black Stone Therapeutics, NeoGenomics Laboratories, Accademia Nazionale Di Medicina; Financial Interests, Personal, Stocks/Shares: Lutris, Iylon, Navire, Xilis; Financial Interests, Personal, Ownership Interest: Frontier Medicines. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Astellas, Bayer, BMS, Boehringer Ingelheim, Esteve, Hutchmed, Ipsen, Midatech Pharma, MSD, Novartis, PharmaMar, Servier, Takeda; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Chair elect: European Neuroendocrine Tumor Society (ENETS); Non-Financial Interests, Leadership Role, Past president, Member of the Executive Committee: Grupo Español de Tumores Neuroendocrinos (GETNE); Other, Honoraria received by spouse for advisory board or invited speaker roles: Abbie, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. J. Maurel: Financial Interests, Personal, Advisory Board: Advance Medical, Cancer Expert Now, MSD; Financial Interests, Personal, Other, Financial travel and congress: Amgen; Financial Interests, Institutional, Invited Speaker: Amgen, Merck, Guardant, Terumo; Financial Interests, Institutional, Funding: Incyte; Non-Financial Interests, Leadership Role: GEMCAD (Grupo Español Multidisciplinar en Cancer Digestivo). I. Chau: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Eli Lilly, MSD, Roche, Merck Serono, AstraZeneca, OncXerna, Astella, Incyte, GSK, Sotio, Daiichi Sankyo, Eisai, Taiho, Seagen, Turning Point Therapeutics, Novartis, Takeda, Elevation Oncology; Financial Interests, Personal, Invited Speaker: Eisai, Eli Lilly, Servier, Roche; Financial Interests, Institutional, Invited Speaker: Cilag-Janssen, Eli Lilly. L. Goodwin, C. Phillips, J. Robertson, H. Timmis, E. Asken: Financial Interests, Institutional, Sponsor/Funding: Redx Pharma. D. Wilson, S.A. Woodcock: Financial Interests, Institutional, Sponsor/Funding: RedX Pharma. All other authors have declared no conflicts of interest.